Acetylcholine (ACh), the first neurotransmitter to be identified1, exerts many of its physiological actions via activation of a family of G protein-coupled receptors (GPCRs) known as muscarinic ACh receptors (mAChRs). Although the five mAChR subtypes (M1-M5) share a high degree of sequence homology, they show pronounced differences in G protein coupling preference and the physiological responses they mediate.2–4 Unfortunately, despite decades of effort, no therapeutic agents endowed with clear mAChR subtype selectivity have been developed to exploit these differences.5–6 We describe here the structure of the Gq/11-coupled M3 mAChR bound to the bronchodilator drug tiotropium and identify the binding mode for this clinically important drug. This structure, together with that of the Gi/o-coupled M2 receptor, offers new possibilities for the design of mAChR subtype-selective ligands. Importantly, the M3 receptor structure allows the first structural comparison between two members of a mammalian GPCR subfamily displaying different G-protein coupling selectivities. Furthermore, molecular dynamics simulations suggest that tiotropium binds transiently to an allosteric site en route to the binding pocket of both receptors. These simulations offer a structural view of an allosteric binding mode for an orthosteric GPCR ligand and raise additional opportunities for the design of ligands with different affinities or binding kinetics for different mAChR subtypes. Our findings not only offer new insights into the structure and function of one of the most important GPCR families, but may also facilitate the design of improved therapeutics targeting these critical receptors.

This study aimed to establish and validate an ultrasound radiomics nomogram for the preoperative prediction of central lymph node (LN) metastasis in patients with papillary thyroid carcinoma (PTC). Patients and Methods: The prediction model was developed in 609 patients with clinicopathologically confirmed unifocal PTC who received ultrasonography between Jan 2018 and June 2018. Radiomic features were extracted after the ultrasonography of PTC. Lasso regression model was used for data dimensionality reduction, feature selection, and radiomics signature building. The predicting model was established based on the multivariable logistic regression analysis in which the radiomics signature, ultrasonography-reported LN status, and independent clinicopathologic risk factors were incorporated, and finally a radiomics nomogram was established. The performance of the nomogram was assessed with respect to the discrimination and consistence. An independent validation was performed in 326 consecutive patients from July 2018 to Sep 2018. Results: The radiomics signature consisted of 23 selected features and was significantly associated with LN status in both primary and validation cohorts. The independent predictors in the radiomics nomogram included the radiomics signature, age, TG level, TPOAB level, and ultrasonography-reported LN status. The model showed good discrimination and consistence in both cohorts: C-index of 0.816 (95% CI, 0.808-0.824) in the primary cohort and 0.858 (95% CI, 0.849-0.867) in the validation cohort. The area under receiver operating curve was 0.858. In the validation cohort, the accuracy, sensitivity, specificity and AUC of this model were 0.812, 0.816, 0.810, and 0.858 (95% CI, 0.785-0.930), respectively. Decision curve analysis indicated the radiomics nomogram was clinically useful. Conclusion: This study presents a convenient, clinically useful ultrasound radiomics nomogram that can be used for the pre-operative individualized prediction of central LN metastasis in patients with PTC.

Diabetic nephropathy (DN) is one of the most common complications in diabetes mellitus and the leading cause of end-stage renal disease. TGF-β is a pleiotropic cytokine and has been recognized as a key mediator of DN. However, anti-TGF-β treatment for DN remains controversial due to the diverse role of TGF-β1 in DN. Thus, understanding the regulatory role and mechanisms of TGF-β in the pathogenesis of DN is the initial step towards the development of anti-TGF-β treatment for DN. In this review, we first discuss the diverse roles and signaling mechanisms of TGF-β in DN by focusing on the latent versus active TGF-β1, the TGF-β receptors, and the downstream individual Smad signaling molecules including Smad2, Smad3, Smad4, and Smad7. Then, we dissect the regulatory mechanisms of TGF-β/Smad signaling in the development of DN by emphasizing Smad-dependent non-coding RNAs including microRNAs and long-non-coding RNAs. Finally, the potential therapeutic strategies for DN by targeting TGF-β signaling with various therapeutic approaches are discussed.

Background: Podocyte injury has a direct causal relationship with proteinuria and glomerulosclerosis and, on a chronic level, can lead to irreversible disease progression. Podocyte injury plays a critically decisive role in the development of proteinuric kidney disease. In recent years, the research on podocyte injury has developed rapidly all over the world. However, no report has summarized the field of podocyte injury as a whole to date. Using bibliometric analysis, this study aimed to evaluate the current state of worldwide podocyte injury research in the last 30 years and identify important achievements, primary research fields, and emerging trends.Methods: Publications related to podocyte injury were retrieved from Web of Science Core Collection. HistCite, VOSviewer, CiteSpace, and the Bibliometrix Package were used for bibliometric analysis and visualization, including the analysis of the overall distribution of annual outputs, leading countries, active institutions and authors, core journals, co-cited references, and keywords. Total global citation score and total local citation score were used to assess the quality and impact of publications.Results: A total of 2,669 publications related to podocyte injury were identified. Publications related to podocyte injury tended to increase continuously. A total of 10,328 authors from 2,171 institutions in 69 countries published studies related to podocyte injury. China (39.46%) was the most prolific country, and the number of citations of studies in the United States (cited 36,896 times) ranked first. Moin A Saleem, John Cijiang He, and Zhihong Liu were the top three contributing authors, and Journal of the American Society of Nephrology and Kidney International were the most popular journals in the field. “Diabetic nephropathy” is the primary focus area of podocyte injury research, and “autophagy,” “microRNA,” and “inflammation” were the top keywords of emerging research hotspots, and traditional Chinese medicine monomer may be a neglected research gap.Conclusion: Our research found that global publications on podocyte injury have increased dramatically. Diabetic nephropathy is the main research field of podocyte injury, whereas autophagy, microRNA, and inflammation are the top topics getting current attention from scholars and which may become the next focus in podocyte injury research.