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Counterfactual inference for continuous rather than binary treatment variables is more common in real-world causal inference tasks. While there are already some sample reweighting methods based on Marginal Structural Model for eliminating the confounding bias, they generally focus on removing the treatment's linear dependence on confounders and rely on the accuracy of the assumed parametric models, which are usually unverifiable. In this paper, we propose a de-confounding representation learning (DRL) framework for counterfactual outcome estimation of continuous treatment by generating the representations of covariates decorrelated with the treatment variables. The DRL is a non-parametric model that eliminates both linear and nonlinear dependence between treatment and covariates. Specifically, we train the correlations between the de-confounding representations and the treatment variables against the correlations between the covariate representations and the treatment variables to eliminate confounding bias. Further, a counterfactual inference network is embedded into the framework to make the learned representations serve both de-confounding and trusted inference. Extensive experiments on synthetic and semi-synthetic datasets show that the DRL model performs superiorly in learning de-confounding representations and outperforms state-of-the-art counterfactual inference models for continuous treatment variables. In addition, we apply the DRL model to a real-world medical dataset MIMIC III and demonstrate a detailed causal relationship between red cell width distribution and mortality. [ABSTRACT FROM AUTHOR]

Endogenous neurotoxin 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroiso-quinoline (Salsolinol, SAL) is a dopamine metabolite that is toxic to dopaminergic neurons in vitro and in vivo, and is involved in the pathogenesis of Parkinson's disease (PD). However, the molecular mechanism by which SAL induces neurotoxicity in PD remains challenging for future investigations. This study found that SAL induced neurotoxicity in SH-SY5Y cells and mice. RNA sequencing (RNAseq) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were used to detect differentially expressed genes in SAL-treated SH-SY5Y cells. We found that NLR family pyrin domain-containing 3 (NLRP3)-dependent pyroptosis was enriched by SAL, which was validated by in vitro and in vivo SAL models. Further, NLRP3 inflammasome-related genes (ASC, NLRP3, active caspase 1, IL-1β, and IL-18) were increased at the mRNA and protein level. Acteoside mitigates SAL-induced neurotoxicity by inhibiting NLRP3 inflammasome-related pyroptosis in in vitro and in vivo PD models. In summary, the present study suggests for the first time that NLRP3-dependent pyroptosis plays a role in the pathogenesis of SAL-induced PD, and acteoside mitigates SAL-induced pyroptosis-dependent neurotoxicity in in vitro and in vivo PD models. The present results demonstrated a new mechanism whereby SAL mediates neurotoxicity by activating NLRP3-dependent pyroptosis, further highlighting SAL-induced pyroptosis-dependent neurotoxicity as a potential therapeutic target in PD. [ABSTRACT FROM AUTHOR]

The deregulation of HGF/c-Met signaling is implicated in epithelial-mesenchymal transition (EMT) and progress of hepatocellular carcinoma (HCC). However, the epigenetic mechanisms that HGF/c-Met regulates EMT and metastasis of HCC cells are less explored. In this study, we demonstrated that HCC cells express a high level of SUMO/sentrin-specific protease 1 (Senp1) which is induced by HGF/c-Met signals. Lentivirus-mediated small hairpin RNA (shRNA) transduction results in Senp1 silence in HCC cells. Senp1 silence reduces the HGF-induced proliferation and migration of HCC cells. Senp1 inhibition also induces HCC cell apoptosis and growth arrest. Furthermore, Senp1 knockdown inhibits epithelial-to-mesenchymal transition, with increase of E-cadherin and ZO-1 expression, decrease of fibronectin and N-cadherin expression. The EMT-related transcription factor Zeb1 was SUMO-modified and decreased in Senp1-silenced HCC cells. These results delineate that senp1 might play an important role in the regulation of HGF-induced invasion and migration of HCC cells. [ABSTRACT FROM AUTHOR]