Pexidartinib hydrochloride exposure induces developmental toxicity and immunotoxicity in zebrafish embryos via activation of Wnt signaling.

Pexidartinib, a macrophage colony-stimulating factor receptor (CSF-1R) inhibitor, is indicated for the treatment of tendon sheath giant cell tumor (TGCT). However, few studies on the toxicity mechanisms of pexidartinib for embryonic development. In this study, the effects of pexidartinib on embryonic development and immunotoxicity in zebrafish were investigated. Zebrafish embryos at 6 h post fertilization (6 hpf) were exposed to 0, 0.5, 1.0, and 1.5 µM concentrations of pexidartinib, respectively. The results showed that different concentrations of pexidartinib induced the shorter body, decreased heart rate, reduced number of immune cells and increase of apoptotic cells. In addition, we also detected the expression of Wnt signaling pathway and inflammation-related genes, and found that these genes expression were significantly upregulated after pexidartinib treatment. To test the effects of embryonic development and immunotoxicity due to hyperactivation of Wnt signaling after pexidartinib treatment, we used IWR-1, Wnt inhibitor, for rescue. Results show that IWR-1 could not only rescue developmental defects and immune cell number, but also downregulate the high expression of Wnt signaling pathway and inflammation-related caused by pexidartinib. Collectively, our results suggest that pexidartinib induces the developmental toxicity and immunotoxicity in zebrafish embryos through hyperactivation of Wnt signaling, providing a certain reference for the new mechanisms of pexidartinib function.

Identification and functional analysis of two GJA8 variants in Chinese families with eye anomalies.

In this study, we report on two different GJA8 variants related to congenital eye anomalies in two unrelated families, respectively. GJA8 (or Cx50) encoding a transmembrane protein to form lens connexons has been known as a common causative gene in congenital cataracts and its variants have recently been reported related to a wide phenotypic spectrum of eye defects. We identified two GJA8 variants, c.134G>T (p.Try45Leu, W45L) detected in a cataract family by Sanger sequencing and c.281G>A (p.Gly94Glu, G94E) found in a family with severe eye malformations including microphthalmia by whole-exome sequencing. These two variants were absent in healthy population and predicted deleterious by bioinformatic analysis. Furthermore, we compared the expression in cell lines between these mutants and the wildtype to explore their potential mechanism. Cell counting kit-8 assay showed that overexpression of either W45L or G94E decreased cell viability compared with wild-type Cx50 and the control. A lower protein level in W45L found by western blotting and fewer punctate fluorescent signals showed by fluorescence microscopy suggested that W45L may have less protein expression. A higher G94E protein level and abundant dotted distribution indicated that G94E may cause aberrant protein degradation and accumulation. Such results from in vitro assays confirmed the impact of these two variants and gave us a hint about their different pathogenic roles in different phenotypes. In conclusion, our study is the first to have the functional analysis of two GJA8 variants c.134G>T and c.281G>A in Chinese pedigrees and explore the impact of these variants, which can help in prenatal diagnosis and genetic counseling as well in basic studies on GJA8.

Access to Monomeric Lead(II) Hydrides with Remarkable Thermostability and Their Use in Catalytic Hydroboration of Carbonyl Derivatives.

We report on the remarkable stability of unprecedented, monomeric lead(II) hydrides M+[LPb(II)H]- (M[1-H]), where L = 2,6-bis(3,5-diphenylpyrrolyl)pyridine and M = (18-crown-6)potassium or ([2.2.2]-cryptand)potassium. The half-life of [K18c6][1-H] of ∼2 days in tetrahydrofuran at 25 °C is significantly longer than those reported for dimeric lead(II) hydrides supported by bulky terphenyl ligands (few hours at low temperatures), which are the only examples known for lead(II) hydride compounds. The presence of a Pb-H bond in [1-H]- was unambiguously identified by multinuclear NMR spectroscopy. Remarkably, a 1H resonance of the hydride ligand was found at δ = 41.43 ppm (1JPbH = 1312 Hz). For reactivity study, [1-H]- serves as an excellent hydroboration catalyst with high turnover numbers and turnover frequencies for several carbonyl compounds.

Origin and Structural Characteristics of Tri-coordinated Extra-framework Aluminum Species in Dealuminated Zeolites.

Post-synthetic dealumination treatment is a common tactic adopted to improve the catalytic performance of industrialized zeolitic catalysts through enhancements in acidity and stability. However, among the possible extra-framework aluminum (EFAL) species in dealuminated zeolites such as Al3+, Al(OH)2+, Al(OH)2+, AlO+, AlOOH, and Al(OH)3, the presence of tri-coordinated EFAL-Al3+ species, which exhibit large quadrupolar effect due to the lack of hydrogen-bonding species, was normally undetectable by conventional one- and two-dimensional 1H and/or 27Al solid-state nuclear magnetic resonance (SSNMR) techniques. By combining density functional theory (DFT) calculations with experimental 31P SSNMR using trimethylphosphine (TMP) as the probe molecule, we report herein a comprehensive study to certify the origin, fine structure, and possible location of tri-coordinated EFAL-Al3+ species in dealuminated HY zeolite. The spatial proximities and synergies between the Brønsted and various Lewis acid sites were clearly identified, and the origin for the observed EFAL-Al3+ species with ultra-strong Lewis acidity was deduced to be at the expense of adjacent Brønsted acid sites. The excellent performance of such tri-coordinated EFAL species was furthermore confirmed by glucose isomerization reactions.

Electrochemical immunosensor for detection of epidermal growth factor reaching lower detection limit: toward oxidized glutathione as a more efficient blocking reagent for the antibody functionalized silver nanoparticles and antigen interaction.

Blocking reagent is of vital importance for an immunosensor because it ensures the antifouling of the sensing interface and thus selective determination of the target. This Letter investigates a small inactive peptide, oxidized glutathione (GSSG), to replace the commonly used bovine serum albumin (BSA) as blocking reagent for immunosensor fabrication to lower the detection limit of electrochemical immunosensors. The EGF (epidermal growth factor) detection as an example is used here to compare the blocking effects from GSSG and BSA, respectively. The relatively big size of BSA sterically hinders EGF and antibody functionalized silver nanoparticles (Ab-AgNPs) binding. By comparison, GSSG cannot hinder EGF and Ab-AgNPs binding since it is much smaller than EGF, verified by scanning electron microscopy (SEM) results. The established GSSG blocking-based immunosensor for EGF reaches a very low detection limit of 0.01 pM, exhibits wide linearity range between 0.1 pM and 0.1 µM and is more sensitive than the BSA blocking strategy. The proposed GSSG-blocking strategy in the immunoassay paves an attractive platform for other biomolecules to reach a lower detection limit.

Hexagonal cobalt oxyhydroxide-carbon dots hybridized surface: high sensitive fluorescence turn-on probe for monitoring of ascorbic acid in rat brain following brain ischemia.

In this study, we report a novel and efficient fluorescence probe synthesized by Tris(hydroxymethyl)aminomethane-derived carbon dots (CDs)-modified hexagonal cobalt oxyhydroxide(CoOOH) nanoflakes (Tris-derived CDs-CoOOH) for monitoring of cerebral ascorbic acid (AA) in brain microdialysate. The as-prepared Tris-derived CDs with the fluorescence quantum yield of 7.3% are prepared by a one-step pyrolysis strategy of the sole precursor and used as the signal output. After being hybridized with CoOOH nanoflakes to form Tris-derived CDs-CoOOH, the luminescence of the Tris-derived CDs can be efficiently quenched by CoOOH via fluorescence resonance energy transfer (FRET). Due to the specific redox reaction between the enediol group of AA and hexagonal CoOOH nanoflakes, AA can reduce the hexagonal CoOOH nanoflakes in the Tris-derived CDs-CoOOH and lead to collapse of the hybrized structure, then the release of Tris-derived CDs, and thus finally the fluorescence recovery. Moreover, cobalt ions (II), generated by CoOOH nanoflakes oxidizing AA, almost have no obvious interference on the fluorescence probe, i.e., Tris-derived CDs, which could be ascribed to the surface of Tris-derived CDs containing a few strong chelation groups such as amino/carboxyl/thiol groups, instead of plenty of -OH groups with weak chelation with Co(2+). On the basis of this feature, the Tris-derived CDs-CoOOH fluorescent probe demonstrates a linear range from 100 nM to 20 µM with the detection limit of ∼50 nM, i.e., with an improved sensitivity toward AA detection. Compared with other turn-on fluorescent methods using convenient fluorophore-nitroxide fluorescent probes for detection of AA, the method demonstrated here possesses a facial synthesis route, lower limit of detection, and wider linear range, which validates sensing of AA in the cerebral systems during the calm/ischemia process. This study provides a fluorescence assay for the simple yet facial detection of AA in the cerebral systems and assists in the understanding of the biological processes in the physiological and pathological study.

Explainable machine-learning predictions for catalysts in CO2-assisted propane oxidative dehydrogenation.

Propylene is an important raw material in the chemical industry that needs new routes for its production to meet the demand. The CO2-assisted oxidative dehydrogenation of propane (CO2-ODHP) represents an ideal way to produce propylene and uses the greenhouse gas CO2. The design of catalysts with high efficiency is crucial in CO2-ODHP research. Data-driven machine learning is currently of great interest and gaining popularity in the heterogeneous catalysis field for guiding catalyst development. In this study, the reaction results of CO2-ODHP reported in the literature are combined and analyzed with varied machine learning algorithms such as artificial neural network (ANN), k-nearest neighbors (KNN), support vector regression (SVR) and random forest regression (RF)and were used to predict the propylene space-time yield. Specifically, the RF method serves as a superior performing algorithm for propane conversion and propylene selectivity prediction, and SHapley Additive exPlanations (SHAP) based on the Shapley value performs fine model interpretation. Reaction conditions and chemical components show different impacts on catalytic performance. The work provides a valuable perspective for the machine learning in light alkane conversion, and helps us to design catalyst by catalytic performance hidden in the data of literatures.

Recent Advances in Carbon Nanotube-Based Energy Harvesting Technologies.

There has been enormous interest in technologies that generate electricity from ambient energy such as solar, thermal, and mechanical energy, due to their potential for providing sustainable solutions to the energy crisis. One driving force behind the search for new energy-harvesting technologies is the desire to power sensor networks and portable devices without batteries, such as self-powered wearable electronics, human health monitoring systems, and implantable wireless sensors. Various energy harvesting technologies have been demonstrated in recent years. Among them, electrochemical, hydroelectric, triboelectric, piezoelectric, and thermoelectric nanogenerators have been extensively studied because of their special physical properties, ease of application, and sometimes high obtainable efficiency. Multifunctional carbon nanotubes (CNTs) have attracted much interest in energy harvesting because of their exceptionally high gravimetric power outputs and recently obtained high energy conversion efficiencies. Further development of this field, however, still requires an in-depth understanding of harvesting mechanisms and boosting of the electrical outputs for wider applications. Here, various CNT-based energy harvesting technologies are comprehensively reviewed, focusing on working principles, typical examples, and future improvements. The last section discusses the existing challenges and future directions of CNT-based energy harvesters.

High-performance peptide and disulfide mapping by direct injection of intact proteins using on-line coupled UV-liquid chromatography microdroplet mass spectrometry (UVLC-MMS).

Microdroplet mass spectrometry (MMS), achieving ultra-fast enzyme digestion in the ionization source, holds great promises for innovating protein analysis. Here, in-depth protein characterization is demonstrated by direct injection of intact protein mixtures via on-line coupling MMS with capillary C4 liquid chromatography (LC) containing UV windows (UVLC-MMS) through an enzyme introduction tee. We showed complete sets of peptides of individual proteins (hemoglobin, bovine serum albumin, and ribonuclease A) in a mixture could be obtained in one injection. Such full (100%) sequence coverage, however, could not be achieved by conventional nanoLC-MS method using bottom-up approach with single enzyme. Moreover, direct injection of a chaperone α-crystalline (α-Cry) complex yielded identification of post-translational modifications including novel sites and semi-quantitative characterization including 3:1 stoichiometry ratio of αA- and αB-Cry sub-units and ∼1.4 phosphorylation/subunit on S45 (novel site) and S122 (main site) of αA-Cry, ∼0.7 phosphorylation/subunit on S19 (main site) and S45 of αB-Cry, as well as 100% acetylation on both N-termini of each subunits by matching the mass and retention time of the intact and its digested peptides. Furthermore, trifluoroacetic acid was able to be used in the mobile phase with UVLC-MMS to improve the separation of differentially reduced intact species and detectability of the droplet-digested products. This allowed us to completely map four disulfide linkages of ribonuclease A based on collision-induced dissociation of disulfide clusters, some of which would otherwise not be detected, preventing scrambling or shuffling errors arising from lengthy bulk solution digestion by the bottom-up approach. Integration of UVLC and MMS greatly improves droplet digestion efficiency and MS detection, enabling highly efficient workflow for in-depth and accurate protein characterization.

Cysteamine affects skeletal development and impairs motor behavior in zebrafish.

Cysteamine is a kind of feed additive commonly used in agricultural production. It is also the only targeted agent for the treatment of cystinosis, and there are some side effects in clinical applications. However, the potential skeletal toxicity remains to be further elucidated. In this study, a zebrafish model was for the first time utilized to synthetically appraise the skeletal developmental defects induced by cysteamine. The embryos were treated with 0.35, 0.70, and 1.05 mM cysteamine from 6 h post fertilization (hpf) to 72 hpf. Substantial skeletal alterations were manifested as shortened body length, chondropenia, and abnormal somite development. The results of spontaneous tail coiling at 24 hpf and locomotion at 120 hpf revealed that cysteamine decreased behavioral abilities. Moreover, the level of oxidative stress in the skeleton ascended after cysteamine exposure. Transcriptional examination showed that cysteamine upregulated the expression of osteoclast-related genes but did not affect osteoblast-related genes expression. Additionally, cysteamine exposure caused the downregulation of the Notch signaling and activating of Notch signaling partially attenuated skeletal defects. Collectively, our study suggests that cysteamine leads to skeletal developmental defects and reduces locomotion activity. This hazard may be associated with cysteamine-mediated inhibition of the Notch signaling and disorganization of notochordal cells due to oxidative stress and apoptosis.

DotFAN: A Domain-Transferred Face Augmentation Net.

The performance of a convolutional neural network (CNN) based face recognition model largely relies on the richness of labeled training data. However, it is expensive to collect a training set with large variations of a face identity under different poses and illumination changes, so the diversity of within-class face images becomes a critical issue in practice. In this paper, we propose a 3D model-assisted domain-transferred face augmentation network (DotFAN) that can generate a series of variants of an input face based on the knowledge distilled from existing rich face datasets of other domains. Extending from StarGAN's architecture, DotFAN integrates with two additional subnetworks, i.e., face expert model (FEM) and face shape regressor (FSR), for latent facial code control. While FSR aims to extract face attributes, FEM is designed to capture a face identity. With their aid, DotFAN can separately learn facial feature codes and effectively generate face images of various facial attributes while keeping the identity of augmented faces unaltered. Experiments show that DotFAN is beneficial for augmenting small face datasets to improve their within-class diversity so that a better face recognition model can be learned from the augmented dataset.

Tunable Fluorescent Silica-Coated Carbon Dots: A Synergistic Effect for Enhancing the Fluorescence Sensing of Extracellular Cu²âº in Rat Brain.

Carbon quantum dots (CDs) combined with self-assembly strategy have created an innovative way to fabricate novel hybrids for biological analysis. This study demonstrates a new fluorescence platform with enhanced selectivity for copper ion sensing in the striatum of the rat brain following the cerebral calm/sepsis process. Here, the fabrication of silica-coated CDs probes is based on the efficient hybridization of APTES which act as a precursor of organosilane self-assembly, with CDs to form silica-coated CDs probes. The fluorescent properties including intensity, fluorescence quantum yield, excitation-independent region, and red/blue shift of the emission wavelength of the probe are tunable through reliable regulation of the ratio of CDs and APTES, realizing selectivity and sensitivity-oriented Cu(2+) sensing. The as-prepared probes (i.e., 3.33% APTES-0.9 mg mL(-1) CDs probe) show a synergistic amplification effect of CDs and APTES on enhancing the fluorescence signal of Cu(2+) detection through fluorescent self-quenching. The underlying mechanism can be ascribed to the stronger interaction including chelation and electrostatic attraction between Cu(2+) and N and O atoms-containing as well as negatively charged silica-coated CDs than other interference. Interestingly, colorimetric assay and Tyndall effect can be observed and applied to directly distinguish the concentration of Cu(2+) by the naked eye. The proposed fluorescent platform here has been successfully applied to monitor the alteration of striatum Cu(2+) in rat brain during the cerebral calm/sepsis process. The versatile properties of the probe provide a new and effective fluorescent platform for the sensing method in vivo sampled from the rat brain.

Fe(3+)-functionalized carbon quantum dots: A facile preparation strategy and detection for ascorbic acid in rat brain microdialysates.

This study reports an Fe(3+)-functionalized carbon quantum dots (Fe(3+)-functionalized CQDs) for the highly sensitive and selective detection of ascorbic acid (AA) in rat brain microdialysates based on the specific redox reaction between iron(III) ions and AA. The carbon quantum dots (CQDs) were synthesized by one-step pyrolysis of a small organic molecules i.e. tris(hydroxymethyl)aminomethane (Tris). Fe(3+) can tightly chelate to the surface of CQDs by the hydroxyl group to form Fe(3+)-functionalized CQDs while the fluorescence of CQDs can be effectively quenched by Fe(3+) via Fluorescence resonance energy transfer (FRET). The fluorescence of the Fe(3+)-functionalized CQDs can be sensitively turned on by AA to give an "on-off-on" fluorescence response through the oxidation-reduction between Fe(3+) and AA since the produced Fe(2+) has much lower chelating ability to CQDs and the fluorescence of CQDs can be restored. This Fe(3+)-functionalized CQDs based nanoprobe shows high selective and sensitive response in the concentration of AA ranging from 0.1 µM to 50 µM with the detection limit as lower as 9.1 nM, which is lower than other assays. Finally, the proposed fluorescent probe was successfully applied to direct analysis of AA in biological fluids, i.e. rat brain microdialysates, and may pave a new route to the design of effective carbon quantum dots-based fluorescence probes for other bioassay.