Semiparametric proximal causal inference

Skepticism about the assumption of no unmeasured confounding, also known as exchangeability, is often warranted in making causal inferences from observational data; because exchangeability hinges on an investigator's ability to accurately measure covariates that capture all potential sources of confounding. In practice, the most one can hope for is that covariate measurements are at best proxies of the true underlying confounding mechanism operating in a given observational study. In this paper, we consider the framework of proximal causal inference introduced by Tchetgen Tchetgen et al. (2020), which while explicitly acknowledging covariate measurements as imperfect proxies of confounding mechanisms, offers an opportunity to learn about causal effects in settings where exchangeability on the basis of measured covariates fails. We make a number of contributions to proximal inference including (i) an alternative set of conditions for nonparametric proximal identification of the average treatment effect; (ii) general semiparametric theory for proximal estimation of the average treatment effect including efficiency bounds for key semiparametric models of interest; (iii) a characterization of proximal doubly robust and locally efficient estimators of the average treatment effect. Moreover, we provide analogous identification and efficiency results for the average treatment effect on the treated. Our approach is illustrated via simulation studies and a data application on evaluating the effectiveness of right heart catheterization in the intensive care unit of critically ill patients

Loss of Abhd5 Promotes Colorectal Tumor Development and Progression by Inducing Aerobic Glycolysis and Epithelial-Mesenchymal Transition

How cancer cells shift metabolism to aerobic glycolysis is largely unknown. Here, we show that deficiency of a/b-hydrolase domain-containing 5 (Abhd5), an intracellular lipolytic activator that is also known as comparative gene identification 58 (CGI-58), promotes this metabolic shift and enhances malignancies of colorectal carcinomas (CRCs). Silencing of Abhd5 in normal fibroblasts induces malignant transformation. Intestine-specific knockout of Abhd5 in ApcMin/+ mice robustly increases tumorigenesis and malignant transformation of adenomatous polyps. In colon cancer cells, Abhd5 deficiency induces epithelial-mesenchymal transition by suppressing the AMPKa-p53 pathway, which is attributable to increased aerobic glycolysis. In human CRCs, Abhd5 expression falls substantially and correlates negatively with malignant features. Our findings link Abhd5 to CRC pathogenesis and suggest that cancer cells develop aerobic glycolysis by suppressin

Macrophage CGI-58 Deficiency Activates ROS-Inflammasome Pathway to Promote Insulin Resistance in Mice

SummaryOvernutrition activates a proinflammatory program in macrophages to induce insulin resistance (IR), but its molecular mechanisms remain incompletely understood. Here, we show that saturated fatty acid and lipopolysaccharide, two factors implicated in high-fat diet (HFD)-induced IR, suppress macrophage CGI-58 expression. Macrophage-specific CGI-58 knockout (MaKO) in mice aggravates HFD-induced glucose intolerance and IR, which is associated with augmented systemic/tissue inflammation and proinflammatory activation of adipose tissue macrophages. CGI-58-deficient macrophages exhibit mitochondrial dysfunction due to defective peroxisome proliferator-activated receptor (PPAR)γ signaling. Consequently, they overproduce reactive oxygen species (ROS) to potentiate secretion of proinflammatory cytokines by activating NLRP3 inflammasome. Anti-ROS treatment or NLRP3 silencing prevents CGI-58-deficient macrophages from oversecreting proinflammatory cytokines and from inducing proinflammatory signaling and IR in the cocultured fat slices. Anti-ROS treatment also prevents exacerbation of inflammation and IR in HFD-fed MaKO mice. Our data thus establish CGI-58 as a suppressor of overnutrition-induced NLRP3 inflammasome activation in macrophages

3D sunken relief generation from a single image by feature line enhancement

Sunken relief is an art form whereby the depicted shapes are sunk into a given flat plane with a shallow overall depth. In this paper, we propose an efficient sunken relief generation algorithm based on a single image by the technique of feature line enhancement. Our method starts from a single image. First, we smoothen the image with morphological operations such as opening and closing operations and extract the feature lines by comparing the values of adjacent pixels. Then we apply unsharp masking to sharpen the feature lines. After that, we enhance and smoothen the local information to obtain an image with less burrs and jaggies. Differential operations are applied to produce the perceptive relief-like images. Finally, we construct the sunken relief surface by triangularization which transforms two-dimensional information into a three-dimensional model. The experimental results demonstrate that our method is simple and efficient

MGLL deficiency in tumor-associated macrophages promotes immunosuppression and colorectal peritoneal metastases in mice

Objective To investigate the effects and mechanisms of monoacylglycerol lipase (MGLL) in tumor-associated macrophages (TAMs) for the progression of colorectal cancer peritoneal metastases (CRC-PM). Methods After macrophage MGLL conditional knockout (cKO) mice was constructed, a CRC-PM model was established in these cKO mice. The effects and mechanism of MGLL deficiency on TAMs were studies with cell biological and RNA-Seq assays. Results Compared with the control mice, macrophage MGLL deficiency significantly shortened the survival time of CRC-PC mice (P < 0.05), increased the weight of peritoneal tumor masses (P < 0.05), diminished the percentage of T cells in the tumor microenvironment (P < 0.01), while elevated the percentage of M2 macrophages in cKO mice (P < 0.05). And the results of RNA-seq showed that TRLs, PD-1/PDL-1, and HIF-1 signal pathways were significantly changed in MGLL deficiency macrophages. Conclusion In the process of CRC-PC, MGLL deficiency leads to macrophage activation towards an M2-type phenotype and further destroys T cell-based anti-tumor immunity capacity, and ultimately promotes the progression of CRC-PC. The mechanisms may be due to the changes in TRLs, PD-1/PDL-1, and HIF-1 signal pathways

Ataxin-2: a powerful RNA-binding protein

Abstract Ataxin-2 (ATXN2) was originally discovered in the context of spinocerebellar ataxia type 2 (SCA2), but it has become a key player in various neurodegenerative diseases. This review delves into the multifaceted roles of ATXN2 in human diseases, revealing its diverse molecular and cellular pathways. The impact of ATXN2 on diseases extends beyond functional outcomes; it mainly interacts with various RNA-binding proteins (RBPs) to regulate different stages of post-transcriptional gene expression in diseases. With the progress of research, ATXN2 has also been found to play an important role in the development of various cancers, including breast cancer, gastric cancer, pancreatic cancer, colon cancer, and esophageal cancer. This comprehensive exploration underscores the crucial role of ATXN2 in the pathogenesis of diseases and warrants further investigation by the scientific community. By reviewing the latest discoveries on the regulatory functions of ATXN2 in diseases, this article helps us understand the complex molecular mechanisms of a series of human diseases related to this intriguing protein

Editorial : Macrophage immunity and metabolism in cancer: Novel diagnostic and therapeutic strategies

Non peer reviewe