Discovery of novel SOS1 inhibitors using machine learning

Overactivation of the rat sarcoma virus (RAS) signaling is responsible for 30% of all human malignancies. Son of sevenless 1 (SOS1), a crucial node in the RAS signaling pathway, could modulate RAS activation, offering a promising therapeutic strategy for RAS-driven cancers. Applying machine learning (ML)-based virtual screening (VS) on small-molecule databases, we selected a random forest (RF) regressor for its robustness and performance. Screening was performed with the L-series and EGFR-related datasets, and was extended to the Chinese National Compound Library (CNCL) with more than 1.4 million compounds. In addition to a series of documented SOS1-related molecules, we uncovered nine compounds that have an unexplored chemical framework and displayed inhibitory activity, with the most potent achieving more than 50% inhibition rate in the KRAS G12C/SOS1 PPI assay and an IC50 value in the proximity of 20 μg mL−1. Compared with the manner that known inhibitory agents bind to the target, hit compounds represented by CL01545365 occupy a unique pocket in molecular docking. An in silico drug-likeness assessment suggested that the compound has moderately favorable drug-like properties and pharmacokinetic characteristics. Altogether, our findings strongly support that, characterized by the distinctive binding modes, the recognition of novel skeletons from the carboxylic acid series could be candidates for developing promising SOS1 inhibitors

α1A-Adrenergic Receptor Induces Activation of Extracellular Signal-Regulated Kinase 1/2 through Endocytic Pathway

G protein-coupled receptors (GPCRs) activate mitogen-activated protein kinases through a number of distinct pathways in cells. Increasing evidence has suggested that endosomal signaling has an important role in receptor signal transduction. Here we investigated the involvement of endocytosis in α1A-adrenergic receptor (α1A-AR)-induced activation of extracellular signal-regulated kinase 1/2 (ERK1/2). Agonist-mediated endocytic traffic of α1A-AR was assessed by real-time imaging of living, stably transfected human embryonic kidney 293A cells (HEK-293A). α1A-AR was internalized dynamically in cells with agonist stimulation, and actin filaments regulated the initial trafficking of α1A-AR. α1A-AR-induced activation of ERK1/2 but not p38 MAPK was sensitive to disruption of endocytosis, as demonstrated by 4°C chilling, dynamin mutation and treatment with cytochalasin D (actin depolymerizing agent). Activation of protein kinase C (PKC) and C-Raf by α1A-AR was not affected by 4°C chilling or cytochalasin D treatment. U73122 (a phospholipase C [PLC] inhibitor) and Ro 31–8220 (a PKC inhibitor) inhibited α1B-AR- but not α1A-AR-induced ERK1/2 activation. These data suggest that the endocytic pathway is involved in α1A-AR-induced ERK1/2 activation, which is independent of Gq/PLC/PKC signaling

Physical Extraction and Feature Fusion for Multi-Mode Signals in a Measurement System for Patients in Rehabilitation Exoskeleton

Measurement system of exoskeleton robots can reflect the state of the patient. In this study, we combined an inertial measurement unit and a visual measurement unit to obtain a repeatable fusion measurement system to compensate for the deficiencies of the single data acquisition mode used by exoskeletons. Inertial measurement unit is comprised four distributed angle sensors. Triaxial acceleration and angular velocity information were transmitted to an upper computer by Bluetooth. The data sent to the control center were processed by a Kalman filter to eliminate any noise. Visual measurement unit uses camera to acquire real time images and related data information. The two data acquisition methods were fused and have its weight. Comparisons of the fusion results with individual measurement results demonstrated that the data fusion method could effectively improve the accuracy of system. It provides a set of accurate real-time measurements for patients in rehabilitation exoskeleton and data support for effective control of exoskeleton robot

Creatine based polymer for codelivery of bioengineered MicroRNA and chemodrugs against breast cancer lung metastasis.

Metastasis is the major cause for breast cancer related mortality. The combination of miRNA-based therapy and chemotherapy represents a promising approach against breast cancer lung metastasis. The goal of this study is to develop an improved therapy that co-delivers a novel bioengineered miRNA prodrug (tRNA-mir-34a) and doxorubicin (DOX) via a multifunctional nanomicellar carrier that is based on a conjugate of amphiphilic copolymer POEG-VBC backbone with creatine, a naturally occurring cationic molecule. Co-delivery of DOX leads to more effective processing of tRNA-mir-34a into mature miR-34a and down-regulation of target genes. DOX + tRNA-mir-34a/POEG-PCre exhibits potent synergistic anti-tumor and anti-metastasis activity in vitro and in vivo. Interestingly, the enhanced immune response contributes to the overall antitumor efficacy. POEG-PCre may represent a safe and effective delivery system for an optimal chemo-gene combination therapy

Genome Sequence of the Edible Cultivated Mushroom <i>Lentinula edodes</i> (Shiitake) Reveals Insights into Lignocellulose Degradation

<div><p><i>Lentinula edodes</i>, one of the most popular, edible mushroom species with a high content of proteins and polysaccharides as well as unique aroma, is widely cultivated in many Asian countries, especially in China, Japan and Korea. As a white rot fungus with lignocellulose degradation ability, <i>L</i>. <i>edodes</i> has the potential for application in the utilization of agriculture straw resources. Here, we report its 41.8-Mb genome, encoding 14,889 predicted genes. Through a phylogenetic analysis with model species of fungi, the evolutionary divergence time of <i>L</i>. <i>edodes</i> and <i>Gymnopus luxurians</i> was estimated to be 39 MYA. The carbohydrate-active enzyme genes in <i>L</i>. <i>edodes</i> were compared with those of the other 25 fungal species, and 101 lignocellulolytic enzymes were identified in <i>L</i>. <i>edodes</i>, similar to other white rot fungi. Transcriptome analysis showed that the expression of genes encoding two cellulases and 16 transcription factor was up-regulated when mycelia were cultivated for 120 minutes in cellulose medium versus glucose medium. Our results will foster a better understanding of the molecular mechanism of lignocellulose degradation and provide the basis for partial replacement of wood sawdust with agricultural wastes in <i>L</i>. <i>edodes</i> cultivation.</p></div

The ideogram showing the genomic features of <i>Lentinula edodes</i>.

<p>(a) Scaffolds: the diagram represents 41 scaffolds of <i>L</i>. <i>edodes</i>, half of the genome size. (b) GC content was calculated as the percentage of G+C in 20-kb non-overlapping windows. (c) Gene number was calculated in 20-kb non-overlapping windows, and the maximum value of the axis is 15. (d) Gene expression of 2 samples with red (FPKM > = 100), orange (FPKM > = 10), green (FPKM > = 0) and black (FPKM = 0) colors. The out ring presents the gene expression of mycelia cultured by medium with cellulose as the main carbon source, and the inner ring presents the gene expression of mycelia cultured by medium with glucose as the main carbon source. (e) Large segmental duplications: regions sharing more than 90% sequence similarity are connected by orange (sequence length > = 5kb) and grey (sequence length > = 2kb) lines.</p