A Selective FGFR1/2 PROTAC Degrader with Antitumor Activity.

The aberrant activation of FGFR acts as a potent driver of multiple types of human cancers. Despite the development of several conventional small-molecular FGFR inhibitors, their clinical efficacy is largely compromised because of low selectivity and side effects. In this study, we report the selective FGFR1/2-targeting proteolysis-targeting chimera BR-cpd7 that displays significant isoform specificity to FGFR1/2 with half maximal degradation concentration values around 10 nmol/L while sparing FGFR3. The following mechanistic investigation reveals the reduced FGFR signaling, through which BR-cpd7 induces cell-cycle arrest and consequently blocks the proliferation of multiple FGFR1/2-dependent tumor cells. Importantly, BR-cpd7 has almost no antiproliferative activity against cancer cells without FGFR aberrations, furtherly supporting its selectivity. In vivo, BR-cpd7 exhibits robust antitumor effects in FGFR1-dependent lung cancer at well-tolerated dose schedules, accompanied by complete FGFR1 depletion. Overall, we identify BR-cpd7 as a promising candidate for developing a selective FGFR1/2-targeted agent, thereby offering a new therapeutic strategy for human cancers in which FGFR1/2 plays a critical role.

A selective Fibroblast Growth Factor Receptor 1/2 PROTAC degrader with antitumor activity.

The aberrant activation of fibroblast growth factor receptor (FGFR) acts as a potent driver of multiple types of human cancers. Despite the development of several conventional small-molecular FGFR inhibitors, their clinical efficacy is largely compromised due to low selectivity and side effects. Here, we report the selective FGFR1/2-targeting proteolysis targeting chimeric (PROTAC), BR-cpd7 that displays significant isoform specificity to FGFR1/2 with DC50 values around 10 nM, while sparing FGFR3. The following mechanistic investigation reveals the reduced FGFR signaling, through which BR-cpd7 induces cell cycle arrest and consequently blocks the proliferation of multiple FGFR1/2-dependent tumor cells. Importantly, BR-cpd7 has almost no anti-proliferative activity against cancer cells without FGFR aberrations, furtherly supporting its selectivity. In vivo, BR-cpd7 exhibits robust antitumor effects in FGFR1-dependent lung cancer at well-tolerated dose schedules, accompanied by complete FGFR1 depletion. Overall, we identify BR-cpd7 as a promising candidate for developing a selective FGFR1/2-targeted agent, thereby offering a new therapeutic strategy for human cancers in which FGFR1/2 plays a critical role.

Investigating the mechanism of cornel iridoid glycosides on type 2 diabetes mellitus using serum and urine metabolites in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Cornel iridoid glycosides (CIG) are extracted from Corni fructus, a herbal medicine used in traditional Chinese medicine to treat diabetes. However, the antidiabetic effects of CIG and the underlying metabolic mechanisms require further exploration. AIM OF THE STUDY: This study aimed to assess the antidiabetic effects and metabolic mechanism of CIG by performing metabolomic analyses of serum and urine samples of rats. MATERIALS AND METHODS: A rat model of type 2 diabetes mellitus (T2DM) was established by administering a low dose of streptozotocin (30 mg/kg) intraperitoneally after 4 weeks of feeding a high-fat diet. The model was evaluated based on several parameters, including fasting blood glucose (FBG), random blood glucose (RBG), urine volume, liver index, body weight, histopathological sections, and serum biochemical parameters. Subsequently, serum and urine metabolomics were analyzed using ultra-high-pressure liquid chromatography coupled with linear ion trap-Orbitrap tandem mass spectrometry (UHPLC-LTQ-Orbitrap-MS). Data were analyzed using unsupervised principal component analysis (PCA) and supervised orthogonal partial least squares discriminant analysis (OPLS-DA). Differential metabolites were examined by the Kyoto Encyclopedia of Genes and Genomes (KEGG) metabolic pathways to explore the underlying mechanisms. RESULTS: After 4 weeks of treatment with different doses of CIG, varying degrees of antidiabetic effects were observed, along with reduced liver and pancreatic injury, and improved oxidative stress levels. Compared with the T2DM group, 19 and 23 differential metabolites were detected in the serum and urine of the CIG treatment group, respectively. The key metabolites involved in pathway regulation include taurine, chenodeoxycholic acid, glycocholic acid, and L-tyrosine in the serum and glycine, hippuric acid, phenylacetylglycine, citric acid, and D-glucuronic acid in the urine, which are related to lipid, amino acid, energy, and carbohydrate metabolism. CONCLUSIONS: This study confirmed the antidiabetic effects of CIG and revealed that CIG effectively controlled metabolic disorders in T2DM rats. This seems to be meaningful for the clinical application of CIG, and can benefit further studies on CIG mechanism.

Immune cell receptor-specific nanoparticles as a potent adjuvant for nasal split influenza vaccine delivery.

Mucosal delivery systems have gained much attention as effective way for antigen delivery that induces both systemic and mucosal immunity. However, mucosal vaccination faces the challenges of mucus barrier and effective antigen uptake and presentation. In particular, split, subunit and recombinant protein vaccines that do not have an intact pathogen structure lack the efficiency to stimulate mucosal immunity. In this study, poly (lactic acid-co-glycolic acid-polyethylene glycol) (PLGA-PEG) block copolymers were modified by mannose to form a PLGA-PEG-Man conjugate (mannose modified PLGA-PEG), which were characterized. The novel nanoparticles (NPs) prepared with this material had a particle size of about 150 nm and a zeta potential of -15 mV, and possessed ideal mucus permeability, immune cell targeting, stability and low toxicity. Finally, PLGA-PEG-Man nanoparticles (PLGA-PEG-Man NPs) were successfully applied for intranasal delivery of split influenza vaccine in rat for the first time, which triggered strong systemic and mucosal immune responses. These studies suggest that PLGA-PEG-Man NPs could function as competitive potential nano-adjuvants to address the challenge of inefficient mucosal delivery of non-allopathogenic antigens.

Coated Porous Microneedles for Effective Intradermal Immunization with Split Influenza Vaccine.

In order to alleviate the pain associated with subcutaneous injections, microneedles (MNs) are gaining increasing attention as a novel transdermal drug delivery modality. Among them, porous microneedles (pMNs) are particularly suitable for the delivery of drugs and vaccines whose activity is sensitive to the microneedle preparation process. They can carry drugs actively to achieve an effective load and deliver drugs into the skin. In this study, the biocompatible cellulose acetate (CA) microporous MNs with a large pore size of 1.13 µm ± 0.45 and a high porosity of 74.8% ± 2.8% were prepared by using a safe nonsolvent-induced phase separation (NIPS) method. The MN patches prepared after adsorption of appropriate concentrations of split influenza vaccine fully met the dose loading requirements. A biocompatible carboxymethyl cellulose (CMC) solution was used in the pMN coating to strengthen their mechanical properties, with an average maximum stress of 32.89 N, and to act as a medium for the dispersion of an adjuvant in the coating layer. The influenza vaccine adsorbed in the micropore and the adjuvant dispersed in the coating were released intradermally to exert synergistic effects with different release patterns and rates. The coated pMNs induced an efficient immune response in Wistar rats with a hemagglutination inhibition (HI) titer of ≥1024, which was comparable to that of intramuscular injection. The research is organized around the goal of engineering exploration of innovative technologies, suggesting that pMNs have a tantalizing prospect for future applications. It opens up the possibility of eventually obtaining a simple, easy-to-use, and efficient application technology for the prevention of global epidemics like influenza.

Quantifying the Two-Dimensional Driving Patterns of Chemisorbed Oxygen and Particle Size on NO Reduction Activity and Mechanism.

Quantification in the driving patterns of activity descriptors on structure-activity relationships and reaction mechanisms over heterogeneous catalysts is still a great challenge and needs to be addressed urgently. Herein, with the example of typical Mn-based catalysts, based on the activity regularity and many characterizations, the chemisorbed oxygen density (ρOß) and particle size (dTEM) have been proposed as the two-dimensional descriptors for selective catalytic reduction of NO, whose role is in quantifying the contents of vacancy defects and the amounts of active sites located on terraces or interfaces, respectively. They can be utilized to construct and quantify the driving patterns for the structure-activity relationships and reaction mechanisms of NO reduction. As a consequence, a complementary modulation for Ea by ρOß and dTEM is described quantitatively in terms of the fitted functions. Moreover, based on the structure-activity relationships and the quantification laws of in situ diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS), the reaction efficiency (RE) of the specific combined NOx-intermediate is identified as the trigger to drive the Langmuir-Hinshelwood mechanism and modulated by the descriptors complementally and collaboratively following the fitted quantification functions. Either of the two descriptors at its lower values plays a dominant role in regulating Ea and RE, and the dominant factor evolves progressively: dTEM ↔ coupling dTEM with ρOß â†” ρOß, when the dependency of Ea and RE on the descriptors is adopted to identify the dominant factor and domains. Therefore, this work has quantitatively accounted for the essence of activity modulation and may provide insight into the quantitative driving patterns for reaction activity and mechanism.

StarmapVis: An interactive and narrative visualisation tool for single-cell and spatial data.

Current single-cell visualisation techniques project high dimensional data into 'map' views to identify high-level structures such as cell clusters and trajectories. New tools are needed to allow the transversal through the high dimensionality of single-cell data to explore the single-cell local neighbourhood. StarmapVis is a convenient web application displaying an interactive downstream analysis of single-cell expression or spatial transcriptomic data. The concise user interface is powered by modern web browsers to explore the variety of viewing angles unavailable to 2D media. Interactive scatter plots display clustering information, while the trajectory and cross-comparison among different coordinates are displayed in connectivity networks. Automated animation of camera view is a unique feature of our tool. StarmapVis also offers a useful animated transition between two-dimensional spatial omic data to three-dimensional single cell coordinates. The usability of StarmapVis is demonstrated by four data sets, showcasing its practical usability. StarmapVis is available at: https://holab-hku.github.io/starmapVis.

Porous Microneedles for Therapy and Diagnosis: Fabrication and Challenges.

The use of microneedles (MNs), an innovative transdermal technology, enables efficient, convenient, painless, and controlled-release drug delivery. Porous microneedles (pMNs), special MNs with abundant interconnected pores that can produce capillary action, are gaining increasing attention as a novel MNs technology. pMNs can actively adsorb bioactive ingredients from solutions of drugs or vaccines for in vivo delivery or from interstitial skin fluids (ISFs) for wearable and point-of-care testing (POCT) products. Different pore sizes and porosities of pMNs can be achieved with different materials and preparation processes, which makes the application of pMNs adaptable to multiple scenarios. In addition, easier and faster detection will be accomplished by the smart combination of pMNs with other detection technologies. This paper aims to summarize the recent research progress of pMNs, focusing on the influence of various materials and their corresponding preparation methods on its structure and function display, discussing the key issues and looking forward to the future development.

An Improved Mixture Density Network for 3D Human Pose Estimation with Ordinal Ranking.

Estimating accurate 3D human poses from 2D images remains a challenge due to the lack of explicit depth information in 2D data. This paper proposes an improved mixture density network for 3D human pose estimation called the Locally Connected Mixture Density Network (LCMDN). Instead of conducting direct coordinate regression or providing unimodal estimates per joint, our approach predicts multiple possible hypotheses by the Mixture Density Network (MDN). Our network can be divided into two steps: the 2D joint points are estimated from the input images first; then, the information of human joints correlation is extracted by a feature extractor. After the human pose feature is extracted, multiple pose hypotheses are generated via the hypotheses generator. In addition, to make better use of the relationship between human joints, we introduce the Locally Connected Network (LCN) as a generic formulation to replace the traditional Fully Connected Network (FCN), which is applied to a feature extraction module. Finally, to select the most appropriate 3D pose result, a 3D pose selector based on the ordinal ranking of joints is adopted to score the predicted pose. The LCMDN improves the representation capability and robustness of the original MDN method notably. Experiments are conducted on the Human3.6M and MPII dataset. The average Mean Per Joint Position Error (MPJPE) of our proposed LCMDN reaches 50 mm on the Human3.6M dataset, which is on par or better than the state-of-the-art works. The qualitative results on the MPII dataset show that our network has a strong generalization ability.

A Nuclear Export Signal Is Required for cGAS to Sense Cytosolic DNA.

The cyclic GMP-AMP (cGAMP) synthase (cGAS) is a key DNA sensor that initiates STING-dependent signaling to produce type I interferons through synthesizing the secondary messenger 2'3'-cGAMP. In this study, we confirm previous studies showing that cGAS is located both in the cytoplasm and in the nucleus. Nuclear accumulation is observed when leptomycin B is used to block the exportin, CRM1 protein. As a result, leptomycin B impairs the production of interferons in response to DNA stimulation. We further identify a functional nuclear export signal (NES) in cGAS, 169LEKLKL174. Mutating this NES leads to the sequestration of cGAS within the nucleus and the loss of interferon response to cytosolic DNA treatment, and it further determines the key amino acid to L172. Collectively, our data demonstrate that the cytosolic DNA-sensing function of cGAS depends on its presence within the cytoplasm, which is warranted by a functional NES.

Classification of Electromyographic Hand Gesture Signals Using Modified Fuzzy C-Means Clustering and Two-Step Machine Learning Approach.

Understanding and classifying electromyogram (EMG) signals is of significance for dexterous prosthetic hand control, sign languages, grasp recognition, human-machine interaction, etc.. The existing research of EMG-based hand gesture classification faces the challenges of unsatisfied classification accuracy, insufficient generalization ability, lack of training data and weak robustness. To address these problems, this paper combines unsupervised and supervised learning methods to classify an EMG dataset consisting of 10 classes of hand gestures. To lessen the difficulty of classification, clustering methods including subtractive clustering and fuzzy c-means (FCM) clustering algorithms are employed first to obtain the initial partition of the inputs. In particular, modified FCM algorithm is proposed to accustom the conventional FCM to the multi-class classification problem. Based on the grouping information obtained from clustering, a type of two-step supervised learning approach is proposed. Specifically, a top-classifier and three sub-classifiers integrated with windowing method and majority voting are employed to accomplish the two-step classification. The results demonstrate that the proposed method achieves 100% test accuracy and the strongest robustness compared to the conventional machine learning approaches, which shows the potential for industrial and healthcare applications, such as movement intention detection, grasp recognition and dexterous prostheses control.

An Allosteric PRC2 Inhibitor Targeting EED Suppresses Tumor Progression by Modulating the Immune Response.

Aberrant activity of polycomb repressive complex 2 (PRC2) is involved in a wide range of human cancer progression. The WD40 repeat-containing protein EED is a core component of PRC2 and enhances PRC2 activity through interaction with H3K27me3. In this study, we report the discovery of a class of pyrimidone compounds, represented by BR-001, as potent allosteric inhibitors of PRC2. X-ray co-crystallography showed that BR-001 directly binds EED in the H3K27me3-binding pocket. BR-001 displayed antitumor potency in vitro and in vivo. In Karpas422 and Pfeiffer xenograft mouse models, twice daily oral dosing with BR-001 resulted in robust antitumor activity. BR-001 was also efficacious in syngeneic CT26 colon tumor-bearing mice; oral dosing of 30 mg/kg of BR-001 led to 59.3% tumor growth suppression and increased frequency of effector CD8+ T-cell infiltrates in tumors. Pharmacodynamic analysis revealed that CXCL10 was highly upregulated, suggesting that CXCL10 triggers the trafficking of CD8+ T cells toward tumor sites. Our results demonstrate for the first time that inhibition of EED modulates the tumor immune microenvironment to induce regression of colon tumors and therefore has the potential to be used in combination with immune-oncology therapy. SIGNIFICANCE: BR-001, a potent inhibitor of the EED subunit of the PRC2 complex, suppresses tumor progression by modulating the tumor microenvironment.

Tensile Properties and Corrosion Behavior of Extruded Low-Alloyed Mg⁻1Sn⁻1Al⁻1Zn Alloy: The Influence of Microstructural Characteristics.

A low-alloyed Mg⁻Sn⁻Al⁻Zn system was developed and successfully fabricated through the extrusion process. The dependence of tensile properties and corrosion behavior on microstructural characteristics of the studied alloy has been investigated. After extrusion, the alloy consists of fine dynamically recrystallized (DRXed) grains of ~2.65 μm and strongly textured coarse unDRXed grains. As a consequence, the extruded alloy showed a high-tensile yield strength (YS) of 259 MPa, ultimate tensile strength (UTS) of 297 MPa and elongation (EL) of 19.0%. The strengthening response was discussed in terms of grain size, texture and solutes. The as-extruded alloy presented severe pitting corrosion and the dependence of corrosion properties on the crystallographic orientation and the formation of corrosion products was analyzed.

Influence of Equal Channel Angular Pressing Passes on the Microstructures and Tensile Properties of Mg-8Sn-6Zn-2Al Alloy.

An I-phase containing Mg-8Sn-6Zn-2Al (wt %; TZA862) alloy was fabricated and subjected to different number of passes of equal channel angular pressing (ECAP) processing at 300 °C. The results showed that the alloys exhibited a bimodal microstructure, which consisted of fine dynamically recrystallized (DRX) grains and coarse non-DRX grains. When increasing the number of ECAP passes from 2 to 6, the fraction of DRX grains and the dispersed second phase particles subsequently increase. However, the fraction and particles then decrease once the number of ECAP passes increases to 8. After 6 ECAP passes, remarkable grain refinement was achieved and increasing the number of passes to 8 cannot further refine the microstructure. Furthermore, the alloys having undergone ECAP exhibited a strong ED-tilted texture, the intensity of which increased with an increase in the number of ECAP passes. The ultimate tensile strength (UTS; 338 MPa) and elongation (El.; 14.2%) of the alloy processed with 6 ECAP passes were considerably higher compared to those of the other materials that had undergone ECAP. These significant enhancements were attributed to extensive grain boundary strengthening, precipitation strengthening and a higher work-hardening capacity.

The Ubiquitin Ligase RNF125 Targets Innate Immune Adaptor Protein TRIM14 for Ubiquitination and Degradation.

Tripartite motif-containing 14 (TRIM14) is a mitochondrial adaptor that facilitates innate immune signaling. Upon virus infection, the expression of TRIM14 is significantly induced, which stimulates the production of type-I IFNs and proinflammatory cytokines. As excessive immune responses lead to harmful consequences, TRIM14-mediated signaling needs to be tightly balanced. In this study, we identify really interesting new gene-type zinc finger protein 125 (RNF125) as a negative regulator of TRIM14 in the innate antiviral immune response. Overexpression of RNF125 inhibits TRIM14-mediated antiviral response, whereas knockdown of RNF125 has the opposite effect. RNF125 interacts with TRIM14 and acts as an E3 ubiquitin ligase that catalyzes TRIM14 ubiquitination. RNF125 promotes K48-linked polyubiquitination of TRIM14 and mediates its degradation via the ubiquitin-proteasome pathway. Consequently, wild-type mouse embryonic fibroblasts show significantly reduced TRIM14 protein levels in late time points of viral infection, whereas TRIM14 protein is retained in RNF125-deficient mouse embryonic fibroblasts. Collectively, our data suggest that RNF125 plays a new role in innate immune response by regulating TRIM14 ubiquitination and degradation.

An enantioselective synthesis of (+)-(S)-[n]-gingerols via the L-proline-catalyzed aldol reaction.

An enantioselective approach to (+)-(S)-[n]-gingerols (1a-c) has been developed. The requisite stereogenic centers of target molecules are facilely constructed by the proline-catalyzed cross-aldol reaction from readily available achiral starting materials.

[Studies on anti-hyperglycemic effect and its mechanism of Clinopodium chinense].

OBJECTIVE: To investigate the anti-hyperglycemic effect and its mechanism of ethanol extraction from Calamintha chinensis (EJCT). METHOD: Fasting serum glucose (FSG) in normal mice was determined after oral administration of EJCT. Effects of EJCT on hyperglycemia mice induced by adrenaline were investigated by observing the contents of FSG and liver glucogen. Effect of EJCT on the diabetic mice induced by alloxan was investigated by observing the contents of FSG and the injured degree of pancreatic islet. The antilipid-peroxidation of EJCT on liver homogenate was measured by determination of malondiadehyde (MDA) induced by Fe2+/Cys. RESULT: EJCT showed no obvious effect on FSG in normal mice. However, EJCT 300, 600 mg x kg(-1) could remarkably decrease the contents of FSG and increase liver glucogen in hyperglycemia mice induced by adrenaline. In diabetic mice induced by alloxan, EJCT 150, 300, 600 mg x kg(-1) could remarkably decrease the contents of FSG. The damage of pancreatic islet induced by alloxan was also significantly attenuated by EJCT. Furthermore, EJCT 30, 60, 90, 120 mg x L(-1) inhibited lipid peroxidation initiated by Fe2+/Cys in liver homogenate. CONCLUSION: These results suggest that EJCT can significantly attenuate hyperglycemia in diabetic mice, which is probably due to decreasing the decomposition of liver glucogen, increasing the synthesis of liver glucogen, antioxidation and amelioration of damaged pancreatic islet.