Discovery and evaluation of HW161023 as a potent and orally active AAK1 inhibitor.

AAK1, also known as AP2-associated protein kinase 1, is an enzyme that belongs to the family of serine/threonine protein kinases. It regulates the assembly and disassembly of clathrin-coated pits and thereby protein endocytosis, by phosphorylating the μ2 subunit of the AP2 complex, which is a key component of clathrin-coated vesicles. LX9211 is currently the only selective small molecule AAK1 inhibitor at the clinical trial stage for diabetic peripheral neuropathic pain, which was found to be safe and well tolerated in healthy participants in phase I clinical trials.

Emerging role and function of Hippo-YAP/TAZ signaling pathway in musculoskeletal disorders.

Hippo pathway is an evolutionarily conservative key pathway that regulates organ size and tissue regeneration by regulating cell proliferation, differentiation and apoptosis. Yes-associated protein 1 (YAP)/ WW domain-containing transcription regulator 1 (TAZ) serves as a pivotal transcription factor within the Hippo signaling pathway, which undergoes negative regulation by the Hippo pathway. The expression of YAP/TAZ affects various biological processes, including differentiation of osteoblasts (OB) and osteoclasts (OC), cartilage homeostasis, skeletal muscle development, regeneration and quality maintenance.

Design method of transverse gradient coils based on nonuniform rational B-spline (NURBS) curves.

Purpose: To propose a hybrid transverse gradient coil design method that leverages current density-based methods and nonuniform rational B-spline (NURBS) curves to optimize the performance and manufacturability of gradient coils.

Methods: Our method begins by generating an initial wire configuration using a density-based method. Then, we fit NURBS curves to the configuration, and adjust the control parameters of these curves to meet performance requirements.

Enterovirus A71 infection-induced dry eye-like symptoms by damaging the lacrimal glands.

Purpose: To determine the effects of EV-A71 (Enterovirus A71) infection on ocular surface and its mechanism.

Methods: AG6 mice aged two to three weeks were randomly divided into control and EV-A71 infected groups. Slit-lamp observation, fluorescein staining, and phenol red thread test were used to assess symptoms of ocular surface at 4 dpi (days post infection).

Synthesis of tunable thickness-to-diameter ratio microcapsules a diffusion-controlled process for temperature-responsive release.

Designing microcapsules with a complicated functionalized shell to respond to an external stimulus has attracted much attention for triggered release; however, simplifying the synthesis process remains a significant challenge. Herein, we initially propose a novel, simple synthesis strategy that utilizes a mixed solvent as the organic phase to control the diffusion of common monomers during interfacial polymerization, resulting in the successful preparation of microcapsules with tunable thickness-to-diameter ratios (/). The morphology of microcapsules is confirmed by scanning electron microscopy.

Discovery of FLT3-targeting PROTACs with potent antiproliferative activity against acute myeloid leukemia cells harboring FLT3 mutations.

Acute myeloid leukemia (AML) patients harboring Fms-like tyrosine kinase 3 (FLT3) mutations often suffer from poor prognosis and relapse. Targeted protein degradation utilizing proteolysis targeting chimeras (PROTACs) is considered as a novel therapeutic strategy in drug discovery and may be a promising modality to target FLT3 mutations for the development of potent anti-AML drugs. Herein, a kind of FLT3-targeting PROTACs was rationally developed based on a FLT3 inhibitor previously reported by us.

Mechanical strain regulates osteogenesis via Antxr1/LncRNA H19/Wnt/β-catenin axis.

Alleviating bone loss is an essential way to prevent osteoporotic fractures. Proper exercise improves bone density without the side effects of long-term medications, but the mechanism is unclear. Our study explored the role of Antxr1/LncRNA H19/Wnt/β-catenin axis in the process of exercise-mediated alleviation of bone loss.

Discovery of Potent and Oral Bioavailable MAT2A Inhibitors for the Treatment of MTAP-Deleted Tumors.

Inhibition of methionine adenosyltransferase 2A (MAT2A) has received significant interest because of its implication as a synthetic lethal target in methylthioadenosine phosphorylase (MTAP)-deleted cancers. Here, we report the discovery of a series of 3-pyrido[1,2-]pyrimidin-3-one derivatives as novel MAT2A inhibitors. The selected compound exhibited high potency for MAT2A inhibition and a favorable pharmacokinetic profile.

m6A demethylase FTO and osteoporosis: potential therapeutic interventions.

Osteoporosis is a common bone disease, characterized by a descent in bone mass due to the dysregulation of bone homeostasis. Although different studies have identified an association between osteoporosis and epigenetic alterations in osteogenic genes, the mechanisms of osteoporosis remain unclear. N6-methyladenosine (m6A) modification is a methylated adenosine nucleotide, which regulates the translocation, exporting, translation, and decay of RNA.

Exercise improved bone health in aging mice: a role of SIRT1 in regulating autophagy and osteogenic differentiation of BMSCs.

Introduction: This study was designed to investigate the effect of running exercise on improving bone health in aging mice and explore the role of the SIRT1 in regulating autophagy and osteogenic differentiation of Bone marrow Mesenchymal Stem Cells (BMSCs).

Methods: Twelve-month-old male C57BL/6J mice were used in this study as the aging model and were assigned to treadmill running exercise for eight weeks. Non-exercise male C57BL/6J mice of the same old were used as aging control and five-month-old mice were used as young controls.

Dual ultrasound-guided totally implantable venous access ports via the right internal jugular vein in pediatric patients with cancer: a preliminary experience in a single institution.

Objective: To assess the efficacy and safety of dual ultrasound-guided (DUG) totally implantable venous access port (TIVAP) implantation (namely, using ultrasound-guided percutaneous puncture with transesophageal echocardiography-guided catheterization) via the right internal jugular vein (IJV) in pediatric patients with cancer.

Methods: Fifty-five children with cancer requiring chemotherapy underwent DUG-TIVAP implantation via the right IJV. Clinical data were recorded, including the procedure success rate, first attempt success rate, and perioperative and postoperative complications.

Epigallocatechin-3-gallate restores mitochondrial homeostasis impairment by inhibiting HDAC1-mediated NRF1 histone deacetylation in cardiac hypertrophy.

Decompensated cardiac hypertrophy is accompanied by impaired mitochondrial homeostasis, whether histone acetylation is involved in this process is yet to be determined. The role of HDAC1-mediated NRF1 histone deacetylation was investigated in transverse aortic constriction (TAC)-induced hypertrophy in rats and phenylephrine (PE)-induced hypertrophic cardiomyocytes. Administration of epigallocatechin-3-gallate (EGCG), an inhibitor of HDAC1, restored cardiac function, decreased heart/body weight and fibrosis, increased the ratio of mtDNA/nDNA and the percentage of LysoTracker CMs in TAC, compared with TAC without receiving EGCG.

Synthesis of Acrylate Dual-Tone Resists and the Effect of Their Molecular Weight on Lithography Performance and Mechanism: An Investigation.

Acrylate photoresists have gained considerable attention in recent years owing to their high resolution, high sensitivity, and versality. In this work, a series of thermally stable copolymers are synthesized by introducing an isobornyl group, and well characterized using Fourier transform infrared spectroscopy (FT-IR) and nuclear magnetic resonance spectra (H-NMR). The effects of polymerization conditions on the molecular weight and their further influence on lithography are explored.

The effects on type 2 diabetes mellitus mouse femoral bone achieved by anti-osteoporosis exercise interventions.

Purpose: Exercise therapy and key regulators of bone quality exert anti-hyperglycemic effects on type 2 diabetes mellitus (T2DM) mice. A number of programs have been reported to have an effect on bone disease in T2DM. Major unanswered questions concern the potential correlation of exercise with the improvement of bone quality in T2DM mice and how the nonlinear optical properties of bone are correlated with changes to its crystal structure.

Role of Sostdc1 in skeletal biology and cancer.

Sclerostin domain-containing protein-1 (Sostdc1) is a member of the sclerostin family and encodes a secreted 28-32 kDa protein with a cystine knot-like domain and two N-linked glycosylation sites. Sostdc1 functions as an antagonist to bone morphogenetic protein (BMP), mediating BMP signaling. It also interacts with LRP6, mediating LRP6 and Wnt signaling, thus regulating cellular proliferation, differentiation, and programmed cell death.

Identification of Candidate Genes and Regulatory Competitive Endogenous RNA (ceRNA) Networks Underlying Intramuscular Fat Content in Yorkshire Pigs with Extreme Fat Deposition Phenotypes.

Intramuscular fat (IMF) content is vital for pork quality, serving an important role in economic performance in pig industry. Non-coding RNAs, with mRNAs, are involved in IMF deposition; however, their functions and regulatory mechanisms in porcine IMF remain elusive. This study assessed the whole transcriptome expression profiles of the muscle of pigs with high (H) and low (L) IMF content to identify genes implicated in porcine IMF adipogenesis and their regulatory functions.

The Effects of Asprosin on Exercise-Intervention in Metabolic Diseases.

Fibrillin is the major constituent of extracellular microfibrils, which are distributed throughout connective tissues. Asprosin is derived from the C-terminal region of the FBN1 gene, which encodes profibrillin that undergoes cleavage by furin protein. In response to fasting with low dietary glucose, asprosin is released as a secreted factor from white adipose tissue, and is transported to the liver for the mediation of glucose release into the blood circulation.

Co(NO)/covalent organic framework nanoparticles for high-efficiency photocatalytic oxidation of thioanisole.

Herein, we demonstrated a highly efficient photocatalytic sulfide oxidation reaction at ambient conditions without a sacrificial reagent or redox mediator, by using Co(NO)/covalent organic framework nanoparticles as a photocatalyst.

Classification of gastric cancerous tissues by a residual network based on optical coherence tomography images.

Optical coherence tomography (OCT) is a noninvasive, radiation-free, and high-resolution imaging technology. The intraoperative classification of normal and cancerous tissue is critical for surgeons to guide surgical operations. Accurate classification of gastric cancerous OCT images is beneficial to improve the effect of surgical treatment based on the deep learning method.

Metabolomics-based comparative study of breast colostrum and mature breast milk.

Breast milk is the safest and most complete natural food for babies. Although breast milk is crucial to the health and development of infants, the metabolites in breast milk during lactation period have not been characterized. Therefore, we examined and compared the metabolites in breast colostrum and mature breast milk using gas chromatography-time-of-flight-mass spectrometry-based metabolomics.

Treg/Th17 Ratio Regulation May Play an Important Role in Epigallocatechin-3-Gallate-Mediated Attenuation of Increased Afterload-Induced Cardiac Hypertrophy.

The aim of this study was to investigate whether Treg/Th17 ratio regulation plays an important role in epigallocatechin-3-gallate (EGCG) in attenuating increased afterload-induced cardiac hypertrophy. Three-month-old male C57BL/6 mice were divided into sham + vehicle, abdominal aortic constriction (AAC) + vehicle, and AAC + EGCG groups. Intraperitoneal EGCG (50 mg/kg/d) administration was conducted.

m6A Methylation Regulates Osteoblastic Differentiation and Bone Remodeling.

Osteoporosis is a prevalent bone disease of the aging population, which is characterized by a decrease in bone mass because of the imbalance of bone metabolism. Although the prevention and treatment of osteoporosis have been explored by different researchers, the mechanisms underlying osteoporosis are not clear exactly. N6 methyladenosine (m6A) is a methylated adenosine nucleotide, which functions through its interaction with the proteins called "writers," "readers" and "erasers.

Effects of exercise on the expression of long non-coding RNAs in the bone of mice with osteoporosis.

Physical activity or exercise are known to promote bone formation and decrease bone resorption to maintain skeletal and bone health both in animal models and in humans with osteoporosis. Previous studies have indicated that long non-coding RNAs (lncRNAs) are able to regulate bone metabolism. Therefore, the present study aimed to evaluate whether lncRNAs responded to exercise by regulating the balance of bone metabolism in order to prevent osteoporosis.

The Role of Long Non-coding RNA, Nuclear Enriched Abundant Transcript 1 (NEAT1) in Cancer and Other Pathologies.

Nuclear enriched abundant transcript 1 (NEAT1), consisting of two kinds of lncRNAs of 3.7 kB NEAT1-1 and 23 kB NEAT1-2, can be highly expressed in organs and tissues such as the ovary, prostate, colon, and pancreas, and is involved in paraspeckle formation and mRNA editing and gene expression. Therefore, NEAT1 is a potential biomarker for the treatment of a variety of diseases, which may be caused by two factors (isoforms of NEAT1 and NEAT1 sponging miRNA as ceRNA).