DINER: Debiasing Aspect-based Sentiment Analysis with Multi-variable Causal Inference

Though notable progress has been made, neural-based aspect-based sentiment analysis (ABSA) models are prone to learn spurious correlations from annotation biases, resulting in poor robustness on adversarial data transformations. Among the debiasing solutions, causal inference-based methods have attracted much research attention, which can be mainly categorized into causal intervention methods and counterfactual reasoning methods. However, most of the present debiasing methods focus on single-variable causal inference, which is not suitable for ABSA with two input variables (the target aspect and the review). In this paper, we propose a novel framework based on multi-variable causal inference for debiasing ABSA. In this framework, different types of biases are tackled based on different causal intervention methods. For the review branch, the bias is modeled as indirect confounding from context, where backdoor adjustment intervention is employed for debiasing. For the aspect branch, the bias is described as a direct correlation with labels, where counterfactual reasoning is adopted for debiasing. Extensive experiments demonstrate the effectiveness of the proposed method compared to various baselines on the two widely used real-world aspect robustness test set datasets.Comment: Accepted by ACL2024(Findings

STAR: Constraint LoRA with Dynamic Active Learning for Data-Efficient Fine-Tuning of Large Language Models

Though Large Language Models (LLMs) have demonstrated the powerful capabilities of few-shot learning through prompting methods, supervised training is still necessary for complex reasoning tasks. Because of their extensive parameters and memory consumption, both Parameter-Efficient Fine-Tuning (PEFT) methods and Memory-Efficient Fine-Tuning methods have been proposed for LLMs. Nevertheless, the issue of large annotated data consumption, the aim of Data-Efficient Fine-Tuning, remains unexplored. One obvious way is to combine the PEFT method with active learning. However, the experimental results show that such a combination is not trivial and yields inferior results. Through probe experiments, such observation might be explained by two main reasons: uncertainty gap and poor model calibration. Therefore, in this paper, we propose a novel approach to effectively integrate uncertainty-based active learning and LoRA. Specifically, for the uncertainty gap, we introduce a dynamic uncertainty measurement that combines the uncertainty of the base model and the uncertainty of the full model during the iteration of active learning. For poor model calibration, we incorporate the regularization method during LoRA training to keep the model from being over-confident, and the Monte-Carlo dropout mechanism is employed to enhance the uncertainty estimation. Experimental results show that the proposed approach outperforms existing baseline models on three complex reasoning tasks.Comment: Accepted by ACL2024(Findings

Fine-grainedly Synthesize Streaming Data Based On Large Language Models With Graph Structure Understanding For Data Sparsity

Due to the sparsity of user data, sentiment analysis on user reviews in e-commerce platforms often suffers from poor performance, especially when faced with extremely sparse user data or long-tail labels. Recently, the emergence of LLMs has introduced new solutions to such problems by leveraging graph structures to generate supplementary user profiles. However, previous approaches have not fully utilized the graph understanding capabilities of LLMs and have struggled to adapt to complex streaming data environments. In this work, we propose a fine-grained streaming data synthesis framework that categorizes sparse users into three categories: Mid-tail, Long-tail, and Extreme. Specifically, we design LLMs to comprehensively understand three key graph elements in streaming data, including Local-global Graph Understanding, Second-Order Relationship Extraction, and Product Attribute Understanding, which enables the generation of high-quality synthetic data to effectively address sparsity across different categories. Experimental results on three real datasets demonstrate significant performance improvements, with synthesized data contributing to MSE reductions of 45.85%, 3.16%, and 62.21%, respectively

A real-world disproportionality analysis of FDA adverse event reporting system (FAERS) events for lecanemab

BackgroundLecanemab is a humanized murine IgG1 antibody. Recent Phase 3 clinical trials have demonstrated its ability to reduce brain amyloid-β (Aβ) load and slow cognitive decline in patients with early Alzheimer’s disease (AD). However, since its approval, reports on adverse effects (AEs) associated with lecanemab have been limited. To better understand the AEs related to lecanemab and provide guidance for future clinical use, we analyzed lecanemab-associated AEs using data from the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS).MethodsWe extracted all AEs reports from the FAERS database for the period from the first quarter of 2023 to the third quarter of 2024. Using the Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), and Multi-item Gamma Poisson Shrinker (MGPS) algorithms, we conducted a comprehensive analysis of lecanemab-related AEs, restricting the analysis to AEs with the role code of primary suspect (PS).ResultsA total of 811 AEs reports related to lecanemab used in AD patients and 506 AEs in Non-AD patients were included. The preferred terms (PTs) identified as positive across all four algorithms included headache, Amyloid Related Imaging Abnormalities-oedema/effusion (ARIA-E), chills, Amyloid Related Imaging Abnormalities-haemosiderosis/microhaemorrhage (ARIA-H), fatigue, infusion-related reaction, nausea, pyrexia, pain, influenza like illness, and so on. Among these, ARIA-E, ARIA-H, brain oedema and status epilepticus were associated with Important Medical Events (IMEs) for AD patients, and brain oedema, cerebral haemorrhage, cerebral microhaemorrhage, subdural haematoma, ischaemic stroke, cerebral infarction were associated with IMEs for Non-AD patients. At the system organ class (SOC) level, the highest signal detection for lecanemab was observed in nervous system disorders among AD and Non-AD patients [ROR for AD: 2.42 (2.2–2.65); ROR for Non-AD: 6.97 (6.12–7.95)]. The median time to the occurrence of these AEs was 44 days after administration in AD patients and 30 days for Non-AD patients.ConclusionThis study utilized the FAERS database to evaluate lecanemab-associated AEs in AD and non-AD patients, along with their temporal patterns post-marketing authorization, thereby establishing a foundation for subsequent clinical pharmacovigilance. A biweekly 10 mg/kg was identified as the optimal therapeutic dosage. ARIA emerged as frequent treatment-related AEs, with APOEɛ4 carriers demonstrating heightened susceptibility. This necessitates serial brain MRI surveillance for all patients during treatment, aimed not only at early ARIA detection but also vigilant monitoring of IMEs including cerebral haemorrhage, cerebral microhaemorrhages, subdural haematoma, cerebral edema, ischaemic stroke, and cerebral infarction. While AD patients predominantly exhibited non-specific clinical manifestations, non-AD cohorts showed elevated risks of stroke-related complications. Consequently, dynamic neurological deficit monitoring is indispensable for non-AD populations receiving lecanemab to mitigate adverse outcomes. Finally, comprehensive reassessment of anticoagulant or antiplatelet therapy indications is warranted in both AD and non-AD patients to reduce hemorrhagic risks

Genetic liability to inflammatory bowel disease is causally associated with increased risk of erectile dysfunction: Evidence from a bidirectional Mendelian randomization study

Background: Several observational cohort studies suggested a close correlation between inflammatory bowel disease and erectile dysfunction. Nevertheless, whether there was a causal effect between them remained debatable. In this study, we aimed to detect the underlying causal links between genetically predicted inflammatory bowel disease and the risk of erectile dysfunction.Methods: A bidirectional Mendelian randomization (MR) study was performed to assess the causal link between inflammatory bowel disease and erectile dysfunction. Inverse variance weighted (IVW), MR-Egger, weighted median, weighted mode, and simple mode were utilized to estimate the causality. The top single nucleotide polymorphisms (SNPs) associated with inflammatory bowel disease cases (n = 25,800) and erectile dysfunction cases (n = 1,154) were extracted from the summary genome-wide association study (GWAS) data obtained from a publicly attainable database. MR-PRESSO global outlier test and MR-Egger regression were utilized to explore the horizontal pleiotropy and outlier instrumental variables. Cochran’s Q statistic was utilized to detect the heterogeneity.Results: In the forward MR study, the IVW approach demonstrated that genetically determined inflammatory bowel disease exhibited a suggestively causal association with an increased risk of erectile dysfunction (OR: 1.11, 95% CI: 1.02–1.21, p = 0.019), and also the genetically determined Crohn’s disease was found to be causally associated with an increased risk of erectile dysfunction (OR: 1.09, 95% CI: 1.02–1.17, p = 0.014). However, the MR analysis results showed no significant evidence supporting a causal effect of ulcerative colitis with erectile dysfunction (OR: 1.02, 95% CI: 0.92–1.14, p = 0.679). Furthermore, the reverse MR analysis showed no causal effects of genetically determined erectile dysfunction on inflammatory bowel disease. Additionally, sensitivity analysis demonstrated no pleiotropy and heterogeneity.Conclusion: Our MR analysis substantiated causal links of inflammatory bowel disease and Crohn’s disease on erectile dysfunction, which may further elucidate how inflammatory bowel disease impacted the initiation and development of erectile dysfunction, and facilitated the prevention and clinical management of inflammatory bowel disease in individuals with erectile dysfunction

Designed Supramolecular Filamentous Peptides: Balance of Nanostructure, Cytotoxicity and Antimicrobial Activity

This work demonstrates a design strategy to optimize antimicrobial peptides with an ideal balance of minimal cytotoxicity, enhanced stability, potent cell penetration and effective antimicrobial activity, which hold great promise for the treatment of intracellular microbial infections and potentially systemic anti-infective therapy

When herpes simplex virus encephalitis meets antiviral innate immunity

Herpes simplex virus (HSV) is the most common pathogen of infectious encephalitis, accounting for nearly half of the confirmed cases of encephalitis. Its clinical symptoms are often atypical. HSV PCR in cerebrospinal fluid is helpful for diagnosis, and the prognosis is usually satisfactory after regular antiviral treatment. Interestingly, some patients with recurrent encephalitis have little antiviral effect. HSV PCR in cerebrospinal fluid is negative, but glucocorticoid has a significant effect after treatment. Specific antibodies, such as the NMDA receptor antibody, the GABA receptor antibody, and even some unknown antibodies, can be isolated from cerebrospinal fluid, proving that the immune system contributes to recurrent encephalitis, but the specific mechanism is still unclear. Based on recent studies, we attempt to summarize the relationship between herpes simplex encephalitis and innate immunity, providing more clues for researchers to explore this field further

Myogenic differentiation and reparative activity of stromal cells derived from pericardial adipose in comparison to subcutaneous origin

INTRODUCTION: Adipose tissue-derived stromal cells (ADSCs) are abundant and easy to obtain, but the diversity of differentiation potential from different locations may vary with the developmental origin of their mesenchymal compartment. We therefore aim to compare the myogenic differentiation and reparative activity of ADSCs derived from the pericardial tissue to ADSCs of subcutaneous origin. METHODS: Pericardial and inguinal adipose tissues from Wistar rats were surgically obtained, and the stromal fraction was isolated after enzymatic digestion. The phenotypic epitopes of the resultant two types of ADSCs were analyzed with flow cytometry, and the expression of transcriptional factors was analyzed with immunostaining. Furthermore, their potential toward adipogenic, osteogenic, and myogenic differentiation also was compared. Finally, the reparative activity and the resultant functional benefits were examined by allograft transplantation into an infarcted model in rats. RESULTS: ADSCs from two adipose sources showed identical morphology and growth curve at the initial stage, but inguinal ADSCs (ingADSCs) sustained significantly vigorous growth after 25 days of cultivation. Although both ADSCs shared similar immunophenotypes, the pericardial ADSCs (periADSC) intrinsically exhibited partial expression of transcription factors for cardiogenesis (such as GATA-4, Isl-1, Nkx 2.5, and MEF-2c) and more-efficient myogenic differentiation, but less competent for adipogenic and osteogenic differentiation. After in vivo transplantation, periADSCs exhibited significantly vigorous reparative activity evidenced by thickening of ventricular wall and pronounced vasculogenesis and myogenesis, although the majority of prelabeled cells disappeared 28 days after transplantation. The structural repair also translated into functional benefits of hearts after infarction. CONCLUSIONS: Although two sources of ADSCs are phenotypically identical, pericADSCs constituted intrinsic properties toward myogenesis and vasculogenesis, and thus provided more potent reparative effects after transplantation; therefore, they represent an attractive candidate cell donor for cardiac therapy

Structure-Activity Relationship Study Enables the Discovery of a Novel Berberine Analogue as RXRα Activator to Inhibit Colon Cancer

黄连素是从黄连、黄柏等传统中药中提取的单体化合物，常用于治疗痢疾及其它消化道感染。近年来，黄连素的抗心律失常、调控能量代谢、降血糖血脂和抗癌等多重功效使其成为一个“明星”中药单体化合物。尽管黄连素具有很好的安全性，但其抗癌作用在临床应用上仍具有许多局限性，包括抗癌活性低、溶解度和生物利用度低等。然而，由于黄连素的分子靶点不清楚，以往对黄连素的改造比较盲目和随机，并未取得较好的进展。胡天惠团队与张延东团队紧密合作、优势互补，针对黄连素与RXR的结合模式，运用结构生物学方法和全合成相结合，设计合成了多种黄连素衍生物，并开展了构效关系分析。发现黄连素衍生物B-12在结合并激活RXR、抗肠癌活性、溶解度和生物利用度方面均明显优于黄连素，且保留了黄连素的肿瘤选择性和低毒副作用，具有很好的临床转化前景。该研究也为结构生物学指导黄连素衍生物药物设计提供了理论基础。本论文的通讯作者为医学院占艳艳副教授、张延东教授和胡天惠教授。医学院博士生徐贝贝和化学化工学院博士生江训金为共同第一作者。We reported recently that berberine, a traditional oriental medicine to treat gastroenteritis, binds and activates Retinoid X receptor α (RXRα) to suppress the growth of colon cancer cells. Here, we extended our studies based on the binding mode of berberine with RXRα by design, synthesis and biological evaluation of a focused library of 15 novel berberine analogues. Among them, 3,9-dimethoxy-5,6-dihydroisoquinolino[3,2-a]isoquinolin-7-ium chloride (B-12) was identified as the optimal RXRα activator. More efficiently than berberine, B-12 bound and altered the conformation of RXRα/LBD, thereby suppressing Wnt/β-catenin pathway and colon cancer cell growth via RXRα mediation. In addition, B-12 not only preserved berberine’s tumor selectivity but also greatly improved its bioavailability. Remarkably, in mice, B-12 did not show obvious side effects including hypertriglyceridemia as other RXRα agonists, or induce hepatorenal toxicity. Together, our study describes an approach for the rational design of berberine-derived RXRα activators as novel effective antineoplastic agents for colon cancer.This work was supported by the National Natural Science Foundation of China (31770860, 21772164, 81572589, 81602560 and 21572187), and the Natural Science Foundation of Fujian Province (2018R1036-2, 2017J06020, 2019R1001-4, and 2019R1001-5). 项目得到了国家自然科学基金委促进海峡两岸科技合作联合基金重点项目、面上项目和福建省自然科学基金的支持

ULK1 phosphorylates Exo70 to suppress breast cancer metastasis

乳腺癌是威胁女性生命健康的“头号杀手”，而远处转移是乳腺癌患者死亡的主要原因。因此，了解乳腺癌如何发动侵袭和转移，对于有效治疗乳腺癌、延长病人生存期具有重要意义。本研究中，该团队发现ULK1通过结合并磷酸化胞泌蛋白复合体关键亚基Exo70来抑制乳腺癌转移。ULK1对Exo70上Ser47，Ser59和Ser89位点的磷酸化，严重地削弱了Exo70的自身寡聚化和与其它胞外分泌复合体亚基的结合，进而减少了细胞运动伪足形成以及基质金属蛋白酶的分泌，从而抑制乳腺癌细胞的迁移和侵袭。该论文首次揭示了胞外分泌复合体重要成员Exo70在乳腺癌中受到ULK1和ERK1/2的双重磷酸化调控，从而使得乳腺癌细胞可以根据外环境来决定潜伏还是发动侵袭转移，为乳腺癌的治疗提供了新的理论基础。 本论文的通讯作者为占艳艳副教授、郭巍教授和胡天惠教授。医学院博士生毛丽媛、占艳艳副教授、吴斌博士和医学院博士生于强为共同第一作者。【Abstract】Increased expression of protein kinase ULK1 was reported to negatively correlate with breast cancer metastasis. Here we report that ULK1 suppresses the migration and invasion of human breast cancer cells. The suppressive effect is mediated through direct phosphorylation of Exo70, a key component of the exocyst complex. ULK1 phosphorylation inhibits Exo70 homo-oligomerization as well as its assembly to the exocyst complex, which are needed for cell protrusion formation and matrix metalloproteinases secretion during cell invasion. Reversely, upon growth factor stimulation, Exo70 is phosphorylated by ERK1/2, which in turn suppresses its phosphorylation by ULK1. Together, our study identifies Exo70 as a substrate of ULK1 that inhibits cancer metastasis, and demonstrates that two counteractive regulatory mechanisms are well orchestrated during tumor cell invasion.This work was supported by the grants from the National Natural Science Foundation of China (81572589, U1405228, 81472568, and 31770860), the Natural Science Foundation of Fujian grant (2017J06020, 2018J01400, 2017R1036-4, 2017R1036-6, 2016R1034-1, and 2016R1034-4), and the Xiamen Science and Technology grant (3502Z20159013) to Y.-y.Z. and T.H., and National Institute of Health R01 GM111128 to W.G.该论文的研究成果是在国家自然科学基金和福建省基金的资助下，与美国宾夕法尼亚大学和清华大学共同协作完成的