Structural insights into the molecular effects of the anthelmintics monepantel and betaine on the Caenorhabditis elegans acetylcholine receptor ACR-23.

Anthelmintics are drugs used for controlling pathogenic helminths in animals and plants. The natural compound betaine and the recently developed synthetic compound monepantel are both anthelmintics that target the acetylcholine receptor ACR-23 and its homologs in nematodes. Here, we present cryo-electron microscopy structures of ACR-23 in apo, betaine-bound, and betaine- and monepantel-bound states. We show that ACR-23 forms a homo-pentameric channel, similar to some other pentameric ligand-gated ion channels (pLGICs). While betaine molecules are bound to the classical neurotransmitter sites in the inter-subunit interfaces in the extracellular domain, monepantel molecules are bound to allosteric sites formed in the inter-subunit interfaces in the transmembrane domain of the receptor. Although the pore remains closed in betaine-bound state, monepantel binding results in an open channel by wedging into the cleft between the transmembrane domains of two neighboring subunits, which causes dilation of the ion conduction pore. By combining structural analyses with site-directed mutagenesis, electrophysiology and in vivo locomotion assays, we provide insights into the mechanism of action of the anthelmintics monepantel and betaine.

Analyzing the dynamical sensitivity and soliton solutions of time-fractional Schrödinger model with Beta derivative.

In physical domains, Beta derivatives are necessary to comprehend wave propagation across various nonlinear models. In this research work, the modified Sardar sub-equation approach is employed to find the soliton solutions of (1+1)-dimensional time-fractional coupled nonlinear Schrödinger model with Beta fractional derivative. These models are fundamental in real-world applications such as control systems, processing of signals, and fiber optic networks. By using this strategy, we are able to obtain various unique optical solutions, including combo, dark, bright, periodic, singular, and rational wave solutions. In addition, We address the sensitivity analysis of the proposed model to investigate the truth that it is extremely sensitive. These studies are novel and have not been performed before in relation to the nonlinear dynamic features of these solutions. We show these behaviors in 2-D, contour 3-D structures across the associated physical characteristics. Our results demonstrate that the proposed approach offers useful results for producing solutions of nonlinear fractional models in application of mathematics and wave propagation in fiber optics.

Structure and mechanism of a neuropeptide-activated channel in the ENaC/DEG superfamily.

Phe-Met-Arg-Phe-amide (FMRFamide)-activated sodium channels (FaNaCs) are a family of channels activated by the neuropeptide FMRFamide, and, to date, the underlying ligand gating mechanism remains unknown. Here we present the high-resolution cryo-electron microscopy structures of Aplysia californica FaNaC in both apo and FMRFamide-bound states. AcFaNaC forms a chalice-shaped trimer and possesses several notable features, including two FaNaC-specific insertion regions, a distinct finger domain and non-domain-swapped transmembrane helix 2 in the transmembrane domain (TMD). One FMRFamide binds to each subunit in a cleft located in the top-most region of the extracellular domain, with participation of residues from the neighboring subunit. Bound FMRFamide adopts an extended conformation. FMRFamide binds tightly to A. californica FaNaC in an N terminus-in manner, which causes collapse of the binding cleft and induces large local conformational rearrangements. Such conformational changes are propagated downward toward the TMD via the palm domain, possibly resulting in outward movement of the TMD and dilation of the ion conduction pore.

Artificial Intelligence-Based Diagnostic Model for Detecting Keratoconus Using Videos of Corneal Force Deformation.

Purpose: To develop a novel method based on biomechanical parameters calculated from raw corneal dynamic deformation videos to quickly and accurately diagnose keratoconus using machine learning. Methods: The keratoconus group was included according to Rabinowitz's criteria, and the normal group included corneal refractive surgery candidates. Independent biomechanical parameters were calculated from dynamic corneal deformation videos. A novel neural network model was trained to diagnose keratoconus. Tenfold cross-validation was performed, and the sample set was divided into a training set for training, a validation set for parameter validation, and a testing set for performance evaluation. External validation was performed to evaluate the model's generalizability. Results: A novel intelligent diagnostic model for keratoconus based on a five-layer feedforward network was constructed by calculating four biomechanical characteristics, including time of the first applanation, deformation amplitude at the highest concavity, central corneal thickness, and radius at the highest concavity. The model was able to diagnose keratoconus with 99.6% accuracy, 99.3% sensitivity, 100% specificity, and 100% precision in the sample set (n = 276), and it achieved an accuracy of 98.7%, sensitivity of 97.4%, specificity of 100%, and precision of 100% in the external validation set (n = 78). Conclusions: In the absence of corneal topographic examination, rapid and accurate diagnosis of keratoconus is possible with the aid of machine learning. Our study provides a new potential approach and sheds light on the diagnosis of keratoconus from a purely corneal biomechanical perspective. Translational Relevance: Our findings could help improve the diagnosis of keratoconus based on corneal biomechanical properties.

Robust pyroptosis risk score guides the treatment options and predicts the prognosis of bladder carcinoma.

Background: Bladder carcinoma (BLCA) is a heterogeneous disease that makes it difficult to achieve proper individual treatment and predict prognosis. This study aimed to develop a risk score from a new perspective of pyroptosis and guide accurate treatment and prognosis prediction for BLCA. Methods: The TCGA-BLCA cohort data were downloaded from The Cancer Genome Atlas database. Two external validation cohorts were collected from the Gene Expression Omnibus. Another independent validation cohort (the Xiangya cohort) was recruited from our hospital. The least absolute shrinkage and selector operation (LASSO) algorithm and Cox regression models were used to establish the pyroptosis risk score. Thereafter, we correlated the pyroptosis risk score with prognosis, tumor microenvironment (TME) immune hallmarks, and multiple treatments, including anticancer immunotherapy, chemotherapy, radiotherapy, and targeted therapy. Results: The pyroptosis risk score was an independent prognostic predictor of BLCA. We found that the activities of multiple steps of the anticancer immune response cycle, such as the release of cancer cell antigens, CD8 T cell recruitment, and NK cell recruitment, were significantly higher in the high-risk score group than in the low-risk score group. In addition, the infiltration levels of the corresponding tumor-infiltrating immune cells (TIICs), such as CD8 T cells and NK cells, were positively correlated with the pyroptosis risk score. Thus, BLCA with a high-risk score may be associated with inflamed phenotypes. Simultaneously, the expression of multiple immune checkpoints (such as PD-L1, CTLA-4, and PD-1) and enrichment scores of gene signatures positively correlated with immunotherapy response were positively correlated with the pyroptosis risk score. Therefore, patients with a high pyroptosis risk score may be more sensitive to immunotherapy. In addition, patients with high pyroptosis risk scores may be more sensitive to chemotherapeutic drugs, such as cisplatin, docetaxel, and paclitaxel. In addition, the pyroptosis risk score accurately predicted the molecular subtypes of BLCA, which were cross-validated in several independent systems. Conclusions: This study developed and validated a robust pyroptosis risk score that can predict the clinical outcomes and TME immune phenotypes of BLCA. In summary, the pyroptosis risk score helps drive precision therapy in patients with BLCA.

Changes of Serum Adiponectin and Glycated Albumin Levels in Gestational Diabetes Mellitus Patients and Their Relationship with Insulin Resistance.

BACKGROUND: We aimed to investigate the changes of serum adiponectin and glycated albumin (GA) levels in gestational diabetes mellitus patients and their relationship with insulin resistance. METHODS: Overall, 137 pregnant women were enrolled from Jinan City People's Hospital, Laiwu District, China from Jan 2015 to Jun 2018. Among them, 71 pregnant women with gestational diabetes mellitus were examined as diabetes group, and 66 normal pregnant women as normal pregnant women group. In addition, 58 normal non-pregnant women of childbearing age who were examined in our hospital during the same period were selected as a control group. The serum adiponectin and GA levels of the three groups were compared, and the relationship between serum adiponectin, GA levels and insulin resistance was analyzed. RESULTS: The serum adiponectin level of pregnant women in gestational diabetes mellitus (GDM) group was significantly lower than that of normal pregnant women and control group (P=0.031, P=0.027). The serum GA level of pregnant women in GDM group was significantly higher than that of normal pregnant women and control group (P<0.001). Pearson correlation analysis showed that GA was positively correlated with Fasting plasma glucose (FPG), Fasting insulin (FINS) and Insulin resistance index(HOMA-IR) levels (P<0.001), while adiponectin was negatively correlated with FPG FINS and HOMA-IR levels (P<0.001). CONCLUSION: Abnormal levels of serum GA and adiponectin are closely related to insulin resistance in patients with gestational diabetes mellitus. Detection of serum GA and adiponectin levels can diagnose gestational diabetes mellitus quickly and effectively.

Auxin Signaling-Mediated Apoplastic pH Modification Functions in Petal Conical Cell Shaping.

The flowers of angiosperm species typically contain specialized conical cells. Although substantial progress has been achieved regarding the mechanisms underlying flower development, little is known about how petal cells achieve final conical shape. Here, we use 8-hydroxypyrene-1,3,6-trisulfonic acid trisodium salt (HPTS) as a fluorescent pH indicator for analyzing the apoplastic pH of conical cells in Arabidopsis and show that normal conical cell expansion requires auxin signaling and apoplastic pH changes. By combining imaging analysis and genetic and pharmacological experiments, we demonstrate that apoplastic acidification and alkalization correlate with an increase and decrease in tip sharpening of conical cells, respectively. Initial expansion of conical cells is accompanied by decreased apoplastic pH, which is associated with increased auxin signaling. Decreased auxin levels, transport, or signaling abolishes cell wall acidification and causes reduced tip sharpening and heights of conical cells. These findings provide an insight into apoplastic pH regulation of conical cell expansion.

Retraction Note: Oxidized Low-density Lipoprotein (ox-LDL) Cholesterol Induces the Expression of miRNA-223 and L-type Calcium Channel Protein in Atrial Fibrillation.

This Article has been retracted.

Oxidized Low-density Lipoprotein (ox-LDL) Cholesterol Induces the Expression of miRNA-223 and L-type Calcium Channel Protein in Atrial Fibrillation.

Atrial fibrillation (AF) is the most common sustained arrhythmia causing high morbidity and mortality. While changing of the cellular calcium homeostasis plays a critical role in AF, the L-type calcium channel α1c protein has suggested as an important regulator of reentrant spiral dynamics and is a major component of AF-related electrical remodeling. Our computational modeling predicted that miRNA-223 may regulate the CACNA1C gene which encodes the cardiac L-type calcium channel α1c subunit. We found that oxidized low-density lipoprotein (ox-LDL) cholesterol significantly up-regulates both the expression of miRNA-223 and L-type calcium channel protein. In contrast, knockdown of miRNA-223 reduced L-type calcium channel protein expression, while genetic knockdown of endogenous miRNA-223 dampened AF vulnerability. Transfection of miRNA-223 by adenovirus-mediated expression enhanced L-type calcium currents and promoted AF in mice while co-injection of a CACNA1C-specific miR-mimic counteracted the effect. Taken together, ox-LDL, as a known factor in AF-associated remodeling, positively regulates miRNA-223 transcription and L-type calcium channel protein expression. Our results implicate a new molecular mechanism for AF in which miRNA-223 can be used as an biomarker of AF rheumatic heart disease.