Glycomic Analysis Reveals That Sialyltransferase Inhibition Is Involved in the Antiviral Effects of Arbidol.

Due to the high mutation rate of influenza virus and the rapid increase of drug resistance, it is imperative to discover host-targeting antiviral agents with broad-spectrum antiviral activity. Considering the discrepancy between the urgent demand of antiviral drugs during an influenza pandemic and the long-term process of drug discovery and development, it is feasible to explore host-based antiviral agents and strategies from antiviral drugs on the market. In the current study, the antiviral mechanism of arbidol (ARB), a broad-spectrum antiviral drug with potent activity at early stages of viral replication, was investigated from the aspect of hemagglutinin (HA) receptors of host cells. N-glycans that act as the potential binding receptors of HA on 16-human bronchial epithelial (16-HBE) cells were comprehensively profiled for the first time by using an in-depth glycomic approach based on TiO2-PGC chip-Q-TOF MS. Their relative levels upon the treatment of ARB and virus were carefully examined by employing an ultra-high sensitive qualitative method based on Chip LC-QQQ MS, showing that ARB treatment led to significant and extensive decrease of sialic acid (SA)-linked N-glycans (SA receptors), and thereby impaired the virus utilization on SA receptors for rolling and entry. The SA-decreasing effect of ARB was demonstrated to result from its inhibitory effect on sialyltransferases (ST), ST3GAL4 and ST6GAL1 of 16-HBE cells. Silence of STs, natural ST inhibitors, as well as sialidase treatment of 16-HBE cells, resulted in similar potent antiviral activity, whereas ST-inducing agent led to the diminished antiviral effect of ARB. These observations collectively suggesting the involvement of ST inhibition in the antiviral effect of ARB. IMPORTANCE This study revealed, for the first time, that ST inhibition and the resulted destruction of SA receptors of host cells may be an underlying mechanism for the antiviral activity of ARB. ST inhibition has been proposed as a novel host-targeting antiviral approach recently and several compounds are currently under exploration. ARB is the first antiviral drug on the market that was found to possess ST inhibiting function. This will provide crucial evidence for the clinical usages of ARB, such as in combination with neuraminidase (NA) inhibitors to exert optimized antiviral effect, etc. More importantly, as an agent that can inhibit the expression of STs, ARB can serve as a novel lead compound for the discovery and development of host-targeting antiviral drugs.

Photoacoustic laser streaming with non-plasmonic metal ion implantation in transparent substrates.

Photoacoustic laser streaming provides a versatile technique to manipulate liquids and their suspended objects with light. However, only gold was used in the initial demonstrations. In this work, we first demonstrate that laser streaming can be achieved with common non-plasmonic metals such as Fe and W by their ion implantations in transparent substrates. We then investigate the effects of ion dose, substrate material and thickness on the strength and duration of streaming. Finally, we vary laser pulse width, repetition rate and power to understand the observed threshold power for laser streaming. It is found that substrate thickness has a negligible effect on laser streaming down to 0.1 mm, glass and quartz produce much stronger streaming than sapphire because of their smaller thermal conductivity, while quartz exhibits the longest durability than glass and sapphire under the same laser intensity. Compared with Au, Fe and W with higher melting points show a longer lifetime although they require a higher laser intensity to achieve a similar speed of streaming. To generate a continuous laser streaming, the laser must have a minimum pulse repetition rate of 10 Hz and meet the minimum pulse width and energy to generate a transient vapor layer. This vapor layer enhances the generation of ultrasound waves, which are required for observable fluid jets. Principles of laser streaming and temperature simulation are used to explain these observations, and our study paves the way for further materials engineering and device design for strong and durable laser streaming.

Comprehensive Glycomic Profiling of Respiratory Tract Tissues of Tree Shrews by TiO2-PGC Chip Mass Spectrometry.

Due to its relatively small size, homology to humans, and susceptibility to human viruses, the tree shrew becomes an ideal alternative animal model for the study of human viral infectious diseases. However, there is still no report for the comprehensive glycan profile of the respiratory tract tissues in tree shrews. In this study, we characterized the structural diversity of N-glycans in the respiratory tract of tree shrews using our well-established TiO2-PGC chip-Q-TOF-MS method. As a result, a total of 219 N-glycans were identified. Moreover, each identified N-glycan was quantitated by a high sensitivity and accurate MRM method, in which 13C-labeled internal standards were used to correct the inherent run-to-run variation in MS detection. Our results showed that the N-glycan composition in the turbinate and lung was significantly different from the soft palate, trachea, and bronchus. Meanwhile, 28 high-level N-glycans in turbinate were speculated to be correlated with the infection of H1N1 virus A/California/04/2009. This study is the first to reveal the comprehensive glycomic profile of the respiratory tract of tree shrews. Our results also help to better understand the role of glycan receptors in human influenza infection and pathogenesis.

Spatial modulation and cofactor engineering of key pathway enzymes for fumarate production in Candida glabrata.

Fumarate is a naturally occurring organic acid that is an intermediate of the tricarboxylic acid (TCA) cycle and has numerous applications in food, pharmaceutical, and chemical industries. However, microbial fumarate production from renewable feedstock is limited by the intrinsic inefficiency of its synthetic pathway caused by week metabolites transportation and cofactor imbalance. In this study, spatial modulation and cofactor engineering of key pathway enzymes in the reductive TCA pathway were performed for the development of a Candida glabrata strain capable of efficiently producing fumarate. Specifically, DNA-guided scaffold system was first constructed and optimized to modulate pyruvate carboxylase, malate dehydrogenase, and fumarase, increasing the fumarate titer from 0.18 to 11.3 g/L. Then, combinatorially tuning cofactor balance by controlling the expression strengths of adenosine diphosphate-dependent phosphoenolpyruvate carboxykinase and NAD+ -dependent formate dehydrogenase led to a large increase in fumarate production up to 18.5 g/L. Finally, the engineered strain T.G-4G-S(1:1:2) -P(M) -F(H) was able to produce 21.6 g/L fumarate in a 5-L batch bioreactor. This strategy described here, paves the way to develop efficient cell factories for the production of the other industrially useful chemicals.

LC-MS based sphingolipidomic study on A549 human lung adenocarcinoma cell line and its taxol-resistant strain.

BACKGROUND: Resistance to chemotherapy drugs (e.g. taxol) has been a major obstacle in successful cancer treatment. In A549 human lung adenocarcinoma, acquired resistance to the first-line chemotherapy taxol has been a critical problem in clinics. Sphingolipid (SPL) controls various aspects of cell growth, survival, adhesion, and motility in cancer, and has been gradually regarded as a key factor in drug resistance. To better understand the taxol-resistant mechanism, a comprehensive sphingolipidomic approach was carried out to investigate the sphingolipid metabolism in taxol-resistant strain of A549 cell (A549T). METHODS: A549 and A549T cells were extracted according to the procedure with optimal condition for SPLs. Sphingolipidomic analysis was carried out by using an UHPLC coupled with quadrupole time-of-flight (Q-TOF) MS system for qualitative profiling and an UHPLC coupled with triple quadrupole (QQQ) MS system for quantitative analysis. The differentially expressed sphingolipids between taxol-sensitive and -resistant cells were explored by using multivariate analysis. RESULTS: Based on accurate mass and characteristic fragment ions, 114 SPLs, including 4 new species, were clearly identified. Under the multiple reaction monitoring (MRM) mode of QQQ MS, 75 SPLs were further quantified in both A549 and A549T. Multivariate analysis explored that the levels of 57 sphingolipids significantly altered in A549T comparing to those of A549 (p < 0.001 and VIP > 1), including 35 sphingomyelins (SMs), 14 ceramides (Cers), 3 hexosylceramides (HexCers), 4 lactosylceramides (LacCers) and 1 sphingosine. A significant decrease of SM and Cer levels and overall increase of HexCer and LacCer represent the major SPL metabolic characteristic in A549T. CONCLUSIONS: This study investigated sphingolipid profiles in human lung adenocarcinoma cell lines, which is the most comprehensive sphingolipidomic analysis of A549 and A549T. To some extent, the mechanism of taxol-resistance could be attributed to the aberrant sphingolipid metabolism, "inhibition of the de novo synthesis pathway" and "activation of glycosphingolipid pathway" may play the dominant role for taxol-resistance in A549T. This study provides insights into the strategy for clinical diagnosis and treatment of taxol resistant lung cancer.

Novel tricyclic pyrazolo[1,5-d][1,4]benzoxazepin-5(6H)-one: Design, synthesis, model and use as hMAO-B inhibitors.

Based on our recently reported selective hMAO-A inhibitors, on which, the intramolecular cyclization led to a very interesting change of isoform selectivity. A series of selective hMAO-B inhibitors (3a-3u) with novel scaffold of tricyclic pyrazolo[1,5-d][1,4]benzoxazepin-5(6H)-one were designed and synthesized. Compound 3u (IC50=221 nM) exhibited the best inhibitory activity and isoform selectivity against hMAO-B, superior to selegiline (IC50=321 nM), which is a commercial selective hMAO-B inhibitor used to Parkinson's disease. Modeling study indicated that the selectivity of our compounds to hMAO-B is determined by at least two residues, i.e., Ile 199 and Cys 172 (or corresponded Phe 208 and Asn 181 of hMAO-A). These data support further studies to assess rational design of more efficiently selective hMAO-B inhibitors.

Design and synthesis of novel 2-pyrazoline-1-ethanone derivatives as selective MAO inhibitors.

Thirty seven novel 2-pyrazoline-1-ethanone derivatives were designed, synthesized and evaluated as selective hMAO inhibitors. Among them, compounds 7h (IC50=2.40 µM) and 12c (IC50=2.00 µM) exhibited best inhibitory activity and selectivity against hMAO-A, surpassing that of the positive control Clorgyline (IC50=2.76 µM). Based on selective activity of hMAO-A, SAR analysis showed that the order of N1 substituent contribution was bromo (3)>piperidinyl (4)>morpholinyl (5)>imidazolyl (6), and compounds with electron-withdrawing substituents (-F, -Cl) at C3 or C5 phenyl ring of 2-pyrazoline nucleus dedicated stronger MAO-A inhibitory activity. Molecular docking showed that compounds 7h and 12c were nicely bound to hMAO-A via two hydrogen bonds (SER209, GLU216), one Pi-Pi interaction and three hydrogen bonds (SER209, GLU216, TYR69), one Sigma-Pi interaction, respectively. In addition, the substituent at C3 position of 2-pyrazoline with the N1 acetyl has little effect on MAO-A inhibitory activity. These data support further studies to assess rational design of more efficiently selective hMAO inhibitors in the future.

Spinning a Liquid Wheel and Driving Surface Thermomagnetic Convection with Light.

A typical Tesla thermomagnetic engine employs a solid magnetic wheel to convert thermal energy into mechanical energy, while thermomagnetic convection in ferrofluid is still challenging to observe because it is a volume convection that occurs in an enclosed space. Using a water-based ferrofluid, a liquid Tesla thermomagnetic engine is demonstrated and reports the observation of thermomagnetic convection on a free surface. Both types of fluid motions are driven by light and observed by simply placing ferrofluid on a cylindrical magnet. The surface thermomagnetic convection on the free surface is made possible by eliminating the Marangoni effect, while the spinning of the liquid wheel is achieved through the solid-like behavior of the ferrofluid under a strong magnetic field. Increasing the magnetic field reveals a transition from simple thermomagnetic convection to a combination of the central spin of the spiky wheel surrounded by thermomagnetic convection in the outer region of the ferrofluid. The coupling between multiple ferrofluid wheels through a fluid bridge is further demonstrated. These demonstrations not only unveil the unique properties of ferrofluid but also provide a new platform for studying complex fluid dynamics and thermomagnetic convection, opening up exciting opportunities for light-controlled fluid actuation and soft robotics.

In Situ Observation of Electron-Beam-Induced NaH Decomposition in Graphene Nanoreactors by Transmission Electron Microscopy.

Sodium hydride (NaH) was unprecedently embedded inside graphene nanobubbles via the discovered reaction between NaH and CO. With the graphene nanobubble as a nanoreactor for NaH, we directly observed the electron-beam-induced decomposition process of graphene-covered NaH by in situ high-resolution transmission electron microscopy with energy dispersive spectrometry and electron energy loss spectroscopy, revealing its decomposition mechanism. This can provide guidance for the design of hydrogen storage materials.

Turning dead leaves into an active multifunctional material as evaporator, photocatalyst, and bioplastic.

Large numbers of leaves fall on the earth each autumn. The current treatments of dead leaves mainly involve completely destroying the biocomponents, which causes considerable energy consumption and environmental issues. It remains a challenge to convert waste leaves into useful materials without breaking down their biocomponents. Here, we turn red maple dead leaves into an active three-component multifunctional material by exploiting the role of whewellite biomineral for binding lignin and cellulose. Owing to its intense optical absorption spanning the full solar spectrum and the heterogeneous architecture for effective charge separation, films of this material show high performance in solar water evaporation, photocatalytic hydrogen production, and photocatalytic degradation of antibiotics. Furthermore, it also acts as a bioplastic with high mechanical strength, high-temperature tolerance, and biodegradable features. These findings pave the way for the efficient utilization of waste biomass and innovations of advanced materials.

Hydroxyapatite-based nano-drug delivery system for nicotinamide mononucleotide (NMN): significantly enhancing NMN bioavailability and replenishing in vivo nicotinamide adenine dinucleotide (NAD+) levels.

OBJECTIVES: This study addresses the bioavailability challenges associated with oral nicotinamide mononucleotide (NMN) administration by introducing an innovative NMN formulation incorporated with hydroxyapatite (NMN-HAP). METHODS: The NMN-HAP was developed using a wet chemical precipitation and physical adsorption method. To assess its superiority over conventional free NMN, we examined NMN, nicotinamide adenine dinucleotide (NAD+), and nicotinamide riboside (NR) levels in mouse plasma and tissues following oral administration of NMN-HAP. KEY FINDINGS: NMN-HAP nanoparticles demonstrated a rod-shaped morphology, with an average size of ~50 nm, along with encapsulation efficiency and drug loading capacity exceeding 40%. In vitro, drug release results indicated that NMN-HAP exhibited significantly lower release compared with free NMN. In vivo studies showed that NMN-HAP extended circulation time, improved bioavailability compared with free NMN, and elevated plasma levels of NMN, NAD+, and NR. Moreover, NMN-HAP administration displayed tissue-specific distribution with a substantial accumulation of NMN, NAD+, and NR in the brain and liver. CONCLUSION: NMN-HAP represents an ideal formulation for enhancing NMN bioavailability, enabling tissue-specific delivery, and ultimately elevating in vivo NAD+ levels. Considering HAP's biocompatible nature and versatile characteristics, we anticipate that this system has significant potential for various future applications.

ScRNAPip: A systematic and dynamic pipeline for single-cell RNA sequencing analysis.

With the advancement of sequencing technology, cell separation, and whole-genome amplification techniques, single cell technology for genome sequencing is emerging gradually. In comparison to traditional genome sequencing at the multi-cellular level, single-cell sequencing can not only measure the gene expression level more accurately but also can detect a small amount of gene expression or rare noncoding RNA. This technology has garnered increasing interest among researchers engaged in single-cell studies in recent years. Here, we developed a reproducible computational workflow for scRNA-seq data analysis which including tasks like quality control, normalization, data correction, pseudotime analysis, copy number analysis, etc. We illustrate the application of these steps using publicly available datasets and provide practical recommendations for their implementation. This study serves as a comprehensive tutorial for researchers keen on single-cell data analysis, aiding users in constructing and refining their own analysis pipelines.

Enhanced Electron Correlation and Significantly Suppressed Thermal Conductivity in Dirac Nodal-Line Metal Nanowires by Chemical Doping.

Enhancing electron correlation in a weakly interacting topological system has great potential to promote correlated topological states of matter with extraordinary quantum properties. Here, the enhancement of electron correlation in a prototypical topological metal, namely iridium dioxide (IrO2 ), via doping with 3d transition metal vanadium is demonstrated. Single-crystalline vanadium-doped IrO2 nanowires are synthesized through chemical vapor deposition where the nanowire yield and morphology are improved by creating rough surfaces on substrates. Vanadium doping leads to a dramatic decrease in Raman intensity without notable peak broadening, signifying the enhancement of electron correlation. The enhanced electron correlation is further evidenced by transport studies where the electrical resistivity is greatly increased and follows an unusual T $\sqrt T $ dependence on the temperature (T). The lattice thermal conductivity is suppressed by an order of magnitude via doping even at room temperature where phonon-impurity scattering becomes less important. Density functional theory calculations suggest that the remarkable reduction of thermal conductivity arises from the complex phonon dispersion and reduced energy gap between phonon branches, which greatly enhances phase space for phonon-phonon Umklapp scattering. This work demonstrates a unique system combining 3d and 5d transition metals in isostructural materials to enrich the system with various types of interactions.

Identification of Cannabidivarin Metabolites in Different Mouse Organs Using Ultra-Performance Liquid Chromatography Coupled to a Quadrupole Time-of-Flight Mass Spectrometer.

Background and Objectives: As a natural analog of cannabidiol (CBD), nonpsychoactive cannabidivarin (CBDV) has therapeutic potential. However, the precise metabolism of CBDV either in vivo or in vitro has not been fully understood. Objective and Experimental Approach: Therefore, mice were intragastrically administered CBDV, and metabolite-rich and potential target organs and tissues were collected and analyzed by ultrahigh-performance liquid chromatography-quadrupole time-of-flight mass spectrometry. The metabolic pathways of CBDV in mice were illustrated more comprehensively for the first time. Results: Twenty-one metabolites were found, all of which, except decarbonylated CBDV, were initially identified. Compared with CBD, the newly identified metabolic pathways were single dehydrogenation, combined decarbonylation and monohydroxylation, and glutathione conjugations of CBDV and its phase I metabolite. Conclusions: According to the very low response in plasma and the extremely high response in intestinal contents 1 h later after the administration, it was assumed that the oral bioavailability of CBDV was as poor as that of CBD, and the major forms to excrete were conjugates of glutathione and glucuronic acid. In contrast to CBDV, decarbonylated CBDV in the keto form and enol form had considerable responses in plasma and preferred to target fatty tissues and organs owing to their higher lipophilicity. Whether these forms can function as genuine active substances in vivo instead of CBDV is worthy of investigation. These results and supposes contribute notable information regarding the pharmacokinetics and pharmacodynamics of CBDV.

Critical role of tetracycline's self-promotion effects in its visible-light driven photocatalytic degradation over ZnO nanorods.

Zinc oxide (ZnO), which is widely applied for ultraviolet-light driven photocatalysis, has no activity in visible-light photocatalytic process due to its large band gap of ∼3.2 eV. Herein, however, we demonstrated the multiple self-promotion effects of tetracycline as band adjuster, photo-sensitizer, and charge transfer promoter for ZnO nanorods, realizing its visible-light photocatalytic degradation with an excellent removal efficiency up to 91.1% within only 2 h. Besides, the influence of complex realistic factors on this unique process was evaluated together with tests with realistic water matrices. Furthermore, the active species and degradation products were identified. Both acute and developmental toxicities were found to be reduced as the degradation proceeds. These results pave the path for the brand-new self-driven visible-light photocatalysis.

Photoluminescence and Raman Spectra of One-Dimensional Lead-free Perovskite CsCu2I3 Single-Crystal Wires.

Lead-free highly luminescent CsCu2I3 perovskite has attracted much attention recently, but agreements on basic optical properties have remained unsettled. By correlating X-ray diffraction with the photoluminescence (PL) of CsCu2I3 single-crystal wires, we first show that blue PL at 420 nm originates from CuI. We then exclude defect states as a source for the broadband emission centered at 570 nm from the lack of defect absorption, PL under sub-bandgap photoexcitation, observations of a linear dependence of PL intensity on excitation laser power, and a strong spectral blueshift under mild hydrostatic pressure. Finally, using a model of the self-trapped exciton and the associated coordinate configuration diagram, we explain pressure evolutions of PL energy, intensity, and lifetime. Single-crystal wires also enable us to obtain polarization-dependent Raman spectra down to 10 cm-1 and confirm their respective ambient crystal structure of orthorhombic Cmcm and phase transition to Pbnm at ∼5 GPa.

Improvement of tissue-specific distribution and biotransformation potential of nicotinamide mononucleotide in combination with ginsenosides or resveratrol.

Decreased Nicotinamide adenine dinucleotide (NAD+ ) level has received increasing attention in recent years since it plays a critical role in many diseases and aging. Although some research has proved that supplementing nicotinamide mononucleotide (NMN) could improve the level of NAD+ , it is still uncertain whether the NAD+ level in specific tissues could be improved in combination with other nutrients. So far, a variety of nutritional supplements have flooded the market, which contains the compositions of NMN coupled with natural products. However, the synergy and transformation process of NMN has not been fully elucidated. In this study, oral administration of NMN (500 mg/kg) combined with resveratrol (50 mg/kg) or ginsenoside Rh2&Rg3 (50 mg/kg) was used to validate the efficacy of appropriate drug combinations in mice. Compared with NMN alone, NMN combined with resveratrol could increase the levels of NAD+ in the heart and muscle by about 1.6 times and 1.7 times, respectively, whereas NMN coupled with ginsenoside Rh2&Rg3 could effectively improve the level of NAD+ in lung tissue for approximately 2.0 times. Our study may provide new treatment ideas for aging or diseases in cardiopulmonary caused by decreased NAD+ levels.

Characterization of deglycosylated metabolites of platycosides reveals their biotransformation after oral administration.

Platycodon grandiflorus is a well-known edible and medicinal plant that has been developed for dietary supplements or functional foods to relieve pulmonary disorders. Platycosides are the main active constituents of P. grandiflorus with multiple pharmacological activities. However, their metabolic fates after dietary consumption are still unclear. Herein, 25 deglycosylated metabolites of platycosides were identified, most of which were identified in vivo for the first time. Notably, 3-O-ß-d-glucopyranosyl platycosides could be absorbed into the bloodstream, and their structures were unambiguously characterized with the aid of chemically prepared standards, including two new compounds (M3 and M11). These findings reveal that both intestinal bacterial metabolism and hydrolysis of ester linkage at C-28 by carboxylesterases in liver are the possible in vivo deglycosylation metabolism pathway of platycosides. This study greatly facilitated our understanding of the fate of the platycosides after dietary consumption of P. grandiflorus products.

Telehealth readiness and its influencing factors among Chinese clinical nurses: A cross-sectional study.

AIM/OBJECTIVE: This study aimed to assess telehealth readiness among clinical nurses in China and explore the factors that affect their telehealth readiness and the relationships of telehealth readiness and telehealth practice-related variables. BACKGROUND: Telehealth is a new service model that uses information and communication technology to provide professional health care services for resource-poor areas. With the global spread of COVID-19, nurses urgently need to adapt and apply telehealth technology to replace conventional face-to-face treatment. However, nurse-led telehealth services in China are currently only in the pilot phase and the readiness of clinical nurses needs to be assessed to facilitate successful telehealth implementation. DESIGN: A cross-sectional, multicentre study was undertaken with the questionnaire survey method. METHODS: Data were collected in October-December 2020 used online questionnaires. A convenience sample of 3386 nurses from 19 hospitals in China completed the Chinese version of Telehealth Readiness Assessment Tools. RESULTS: The mean score of the telehealth readiness was in the category between 61 and 80 points (mean 61.23, SD 11.61). The percentages of nurses meeting the following levels of telehealth readiness were as follows: low (49.9%), moderate (42.0%) and high (8.1%). Significantly higher domain scores were recorded for nurses in the unmarried, head of responsible nursing group. Moreover, there were positive correlations between telehealth readiness level and service experience, service willingness, mode cognition, manpower allocation and policy guidance. CONCLUSIONS: There are still many factors hindering the successful implementation of telehealth. Nursing educators should formulate telehealth education curriculum and service standards to improve the telehealth readiness of nurses.

High ambipolar mobility in cubic boron arsenide revealed by transient reflectivity microscopy.

Semiconducting cubic boron arsenide (c-BAs) has been predicted to have carrier mobility of 1400 square centimeters per volt-second for electrons and 2100 square centimeters per volt-second for holes at room temperature. Using pump-probe transient reflectivity microscopy, we monitored the diffusion of photoexcited carriers in single-crystal c-BAs to obtain their mobility. With near-bandgap 600-nanometer pump pulses, we found a high ambipolar mobility of 1550 ± 120 square centimeters per volt-second, in good agreement with theoretical prediction. Additional experiments with 400-nanometer pumps on the same spot revealed a mobility of >3000 square centimeters per volt-second, which we attribute to hot electrons. The observation of high carrier mobility, in conjunction with high thermal conductivity, enables an enormous number of device applications for c-BAs in high-performance electronics and optoelectronics.