An SNR Enhancement Method for Φ-OTDR Vibration Signals Based on the PCA-VSS-NLMS Algorithm.

To improve the signal-to-noise ratio (SNR) of vibration signals in a phase-sensitive optical time-domain reflectometer (Φ-OTDR) system, a principal component analysis variable step-size normalized least mean square (PCA-VSS-NLMS) denoising method was proposed in this study. First, the mathematical principle of the PCA-VSS-NLMS algorithm was constructed. This algorithm can adjust the input signal to achieve the best filter effect. Second, the effectiveness of the algorithm was verified via simulation, and the simulation results show that compared with the wavelet denoising (WD), Wiener filtering, variational mode decomposition (VMD), and variable step-size normalized least mean square (VSS-NLMS) algorithms, the PCA-VSS-NLMS algorithm can improve the SNR to 30.68 dB when the initial SNR is -1.23 dB. Finally, the PCA-VSS-NLMS algorithm was embedded into the built Φ-OTDR system, an 11.22 km fiber was measured, and PZT was added at 10.19-10.24 km to impose multiple sets of fixed-frequency disturbances. The experimental results show that the SNR of the vibration signal is 8.77 dB at 100 Hz and 0.07 s, and the SNR is improved to 26.17 dB after PCA-VSS-NLMS filtering; thus, the SNR is improved by 17.40 dB. This method can improve the SNR of the system's position information without the need to change the existing hardware conditions, and it provides a new scheme for the detection and recognition of long-distance vibration signals.

Combined toxicity of polyethylene microplastics and nickel oxide nanoparticle on earthworm (Eisenia andrei): oxidative stress responses, bioavailability and joint effect.

The co-occurrence of heavy metals and microplastics (MPs) is an emerging issue that has attracted considerable attention. However, the interaction of nickel oxide nanoparticle (nano-NiO) combined with MPs in soil was poorly researched. Here, experiments were conducted to study the influence of nano-NiO (200 mg/kg) and polyethylene (PE) MPs with different concentrations (0.1, 1, and 10%) and sizes (13, 50, and 500 µm) on earthworms for 28 days. Compared to control, the damage was induced by PE and nano-NiO, which was evaluated by biomarker Integrated Biomarker Response index: version 2 (IBRv2) based on six biomarkers including SOD, POD, CAT, MDA, AChE, Na+/K+-ATPase and cellulase. The majority of the chosen biomarkers showed significant but complicated responses with increasing contaminant concentrations after 28 days of exposure. Moreover, the joint effect was assessed as antagonism by the effect addition index (EAI). Overall, this work expands our understanding of the combined toxicity of PE and nano-NiO in soil ecosystems.

Full-length transcriptome profiling of Acanthopanax gracilistylus provides new insight into the kaurenoic acid biosynthesis pathway.

Acanthopanax gracilistylus is a deciduous plant in the family Araliaceae, which is commonly used in Chinese herbal medicine, as the root bark has functions of nourishing the liver and kidneys, removing dampness and expelling wind, and strengthening the bones and tendons. Kaurenoic acid (KA) is the main effective substance in the root bark of A. gracilistylus with strong anti-inflammatory effects. To elucidate the KA biosynthesis pathway, second-generation (DNA nanoball) and third-generation (Pacific Biosciences) sequencing were performed to analyze the transcriptomes of the A. gracilistylus leaves, roots, and stems. Among the total 505,880 isoforms, 408,954 were annotated by seven major databases. Sixty isoforms with complete open reading frames encoding 11 key enzymes involved in the KA biosynthesis pathway were identified. Correlation analysis between isoform expression and KA content identified a total of eight key genes. Six key enzyme genes involved in KA biosynthesis were validated by real-time quantitative polymerase chain reaction. Based on the sequence analysis, the spatial structure of ent-kaurene oxidase was modeled, which plays roles in the three continuous oxidations steps of KA biosynthesis. This study greatly enriches the transcriptome data of A. gracilistylus and facilitates further analysis of the function and regulation mechanism of key enzymes in the KA biosynthesis pathway. Supplementary Information: The online version contains supplementary material available at 10.1007/s12298-024-01436-7.

Spatially and Temporally Resolved Dynamic Response of Co-Based Composite Interface during the Oxygen Evolution Reaction.

Interfacial interaction dictates the overall catalytic performance and catalytic behavior rules of the composite catalyst. However, understanding of interfacial active sites at the microscopic scale is still limited. Importantly, identifying the dynamic action mechanism of the "real" active site at the interface necessitates nanoscale, high spatial-time-resolved complementary-operando techniques. In this work, a Co3O4 homojunction with a well-defined interface effect is developed as a model system to explore the spatial-correlation dynamic response of the interface toward oxygen evolution reaction. Quasi in situ scanning transmission electron microscopy-electron energy-loss spectroscopy with high spatial resolution visually confirms the size characteristics of the interface effect in the spatial dimension, showing that the activation of active sites originates from strong interfacial electron interactions at a scale of 3 nm. Multiple time-resolved operando spectroscopy techniques explicitly capture dynamic changes in the adsorption behavior for key reaction intermediates. Combined with density functional theory calculations, we reveal that the dynamic adjustment of multiple adsorption configurations of intermediates by highly activated active sites at the interface facilitates the O-O coupling and *OOH deprotonation processes. The dual dynamic regulation mechanism accelerates the kinetics of oxygen evolution and serves as a pivotal factor in promoting the oxygen evolution activity of the composite structure. The resulting composite catalyst (Co-B@Co3O4/Co3O4 NSs) exhibits an approximately 70-fold turnover frequency and 20-fold mass activity than the monomer structure (Co3O4 NSs) and leads to significant activity (η10 ∼257 mV). The visual complementary analysis of multimodal operando/in situ techniques provides us with a powerful platform to advance our fundamental understanding of interfacial structure-activity relationships in composite structured catalysts.

Full-length transcriptome sequencing provides new insights into the complexity of flavonoid biosynthesis in Glechoma longituba.

Glechoma longituba has been frequently used in treating urolithiasis and cholelithiasis due to the presence of flavonoids, which are its major bioactive constituents. However, research on the molecular background of flavonoid biosynthesis in G. longituba is limited. In this study, we used single-molecule real-time combined with next-generation sequencing technologies to construct the complete transcriptome of G. longituba. We identified 404,648 non-redundant transcripts, including 249,697 coding sequences, 197,811 simple sequence repeats, 174,846 long noncoding RNA, and 176,554 coding RNA. Moreover, we functionally annotated 346,218 isoforms (85.56%) and identified 86,528 differentially expressed genes. We also identified 55 non-redundant full-length isoforms related to the flavonoid biosynthetic pathway. Pearson correlation analysis revealed that the expression levels of some key genes of the flavonoid biosynthesis pathway were significantly positively correlated with the flavonoid metabolites. Furthermore, we performed bioinformatics analysis (sequence and structural) of isoform_47029 (encoding flavanone 3-hydroxylase) and isoform_53692 (encoding flavonol synthase) to evaluate their potential biological functions. Finally, we validated gene expression levels of 12 flavonoid-related key enzyme genes using quantitative real-time PCR. Overall, this study provides full-length transcriptome information on G. longituba for the first time and valuable molecular resources for further research on the medicinal properties of this plant.

A Markov model-based cost-effectiveness analysis comparing zanubrutinib to ibrutinib for treating relapsed and refractory chronic lymphocytic leukemia.

OBJECTIVE: This article examined the cost-effectiveness of zanubrutinib and ibrutinib for managing relapsed and refractory chronic lymphocytic leukemia from the viewpoint of payers in China and the US. METHODS: Markov models were employed to conduct comparisons. Baseline characteristics and clinical data were extracted from the ALPINE study. The cost-effectiveness outcome indicators encompassed cost, quality-adjusted life years, and the incremental cost-effectiveness ratio. RESULTS: The Markov model analysis revealed that the zanubrutinib group incurred an incremental cost per patient of $-24,586.53 compared to the ibrutinib group. The zanubrutinib group exhibited an incremental utility per capita of 0.28 quality-adjusted life years, resulting in an incremental cost-effectiveness ratio of $-88,068.16 per quality-adjusted life year, which is lower than the payment threshold in China. The willingness-to-pay value in China for 2022 was three times the country's gross domestic product per capita. In the US, patients in the zanubrutinib group experienced per capita incremental costs of $-79,421.56, per capita incremental utility of 0.28 quality-adjusted life years, and an incremental cost-effectiveness ratio of $-284,485.45 per quality-adjusted life year. CONCLUSION: For Chinese payers, zanubrutinib exhibited superior cost-effectiveness compared to ibrutinib. Zanubrutinib proved to be a more affordable option for US payers when considering the payment threshold.

Comparative transcriptome analysis of different tissues of Solanum khasianum reveals candidate genes involved in steroidal glycoalkaloid biosynthesis.

Fruits and leaves of Solanum khasianum C. B. Clarke have long been used as a common Chinese herbal medicine. Steroidal glycoalkaloids (SGAs), the main active ingredient in S. khasianum, exhibit various pharmacological effects. However, genes involved in the SGA biosynthetic pathway in S. khasianum have not yet been identified. Genes encoding potential key SGA biosynthesis enzymes were identified through comprehensive RNA sequencing analysis (RNA-seq) of S. khasianum leaves, stems, and fruits. A total of 123,704 unigenes were obtained, of which 109,775 (88.74%) were annotated in seven public databases. Among these, 54 unigenes potentially involved in SGA biosynthesis were identified. Additionally, 23,636 differentially expressed genes were identified by comparing gene expression levels among the fruits, stems, and leaves of S. khasianum. The structural characteristics and phylogenetic relationship of cycloartenol synthase involved in SGA biosynthesis were further analyzed. Solasodine constituent was detected by high-performance liquid chromatography. This is the first study to report the comparative transcriptome analysis of different tissues of S. khasianum that identifies valuable genes potentially involved in SGA biosynthesis in this species.

Harnessing the Lysosomal Sorting Signals of the Cation-Independent Mannose-6-Phosphate Receptor for Targeted Degradation of Membrane Proteins.

Membrane proteins are a crucial class of therapeutic targets that remain challenging to modulate using traditional occupancy-driven inhibition strategies or current proteolysis-targeting degradation approaches. Here, we report that the inherent endolysosomal sorting machinery can be harnessed for the targeted degradation of membrane proteins. A new degradation technique, termed signal-mediated lysosome-targeting chimeras (SignalTACs), was developed by genetically fusing the signaling motif from the cation-independent mannose-6-phosphate receptor (CI-M6PR) to a membrane protein binder. Antibody-based SignalTACs were constructed with the CI-M6PR signal peptides fused to the C-terminus of both heavy and light chains of IgG. We demonstrated the scope of this platform technology by degrading five pathogenesis-related membrane proteins, including HER2, EGFR, PD-L1, CD20, and CD71. Furthermore, two simplified constructs of SignalTACs, nanobody-based and peptide-based SignalTACs, were created and shown to promote the lysosomal degradation of target membrane proteins. Compared to the parent antibodies, SignalTACs exhibited significantly higher efficiency in inhibiting tumor cell growth both in vitro and in vivo. This work provides a simple, general, and robust strategy for degrading membrane proteins with molecular precision and may represent a powerful platform with broad research and therapeutic applications.

Full-length transcriptome analysis provides insights into flavonoid biosynthesis in Ranunculus japonicus.

Ranunculus japonicus Thunb. is a traditional Chinese herb. Plants in the genus Ranunculus are generally rich in flavonoids, which have antibacterial, anti-infective, and other pharmacological effects. However, owing to the lack of reference genomes, little is known about the flavonoid biosynthetic pathway in R. japonicus. In this study, PacBio isoform sequencing (PacBio iso-seq) and DNA nanoball sequencing (DNB-seq) were combined to build a full-length transcriptome database for three different tissues of R. japonicus. A total of 395,402 full-length transcripts were obtained, of which 308,474 were successfully annotated. A Kyoto Encyclopedia of Genes and Genomes analysis identified 29 differentially expressed genes encoding nine key enzymes for flavonoid biosynthesis. Correlation analysis indicated that flavanone 3-hydroxylase and flavonol synthase genes might have key roles in the accumulation of flavonoid substances in the different tissues of R. japonicus. The structures of chalcone synthase and chalcone isomerase enzymes were spatially modeled. Reverse-transcription quantitative PCR was used to verify gene expression levels of key enzymes associated with flavonoid biosynthesis. In addition, 22 MYB transcription factors involved in flavonoid biosynthesis and phenylpropanoid biosynthesis were discovered. The reliable transcriptomic data from this study provide genetic information about R. japonicus as well as insights into the molecular mechanism of flavonoid biosynthesis. The results also provide a basis for developing the medicinal value R. japonicus.

Synergistic activation of AMPK by AdipoR1/2 agonist and inhibitor of EDPs-EBP interaction recover NAFLD through enhancing mitochondrial function in mice.

Nonalcoholic fatty liver disease (NAFLD), especially nonalcoholic steatohepatitis (NASH), is a common hepatic manifestation of metabolic syndrome. However, there are no effective therapy to treat this devastating disease. Accumulating evidence suggests that the generation of elastin-derived peptides (EDPs) and the inhibition of adiponectin receptors (AdipoR)1/2 plays essential roles in hepatic lipid metabolism and liver fibrosis. We recently reported that the AdipoR1/2 dual agonist JT003 significantly degraded the extracellular matrix (ECM) and ameliorated liver fibrosis. However, the degradation of the ECM lead to the generation of EDPs, which could further alter liver homeostasis negatively. Thus, in this study, we successfully combined AdipoR1/2 agonist JT003 with V14, which acted as an inhibitor of EDPs-EBP interaction to overcome the defect of ECM degradation. We found that combination of JT003 and V14 possessed excellent synergistic benefits on ameliorating NASH and liver fibrosis than either alone since they compensate the shortage of each other. These effects are induced by the enhancement of the mitochondrial antioxidant capacity, mitophagy, and mitochondrial biogenesis via AMPK pathway. Furthermore, specific suppression of AMPK could block the effects of the combination of JT003 and V14 on reduced oxidative stress, increased mitophagy and mitochondrial biogenesis. These positive results suggested that this administration of combination of AdipoR1/2 dual agonist and inhibitor of EDPs-EBP interaction can be recommended alternatively for an effective and promising therapeutic strategy for the treatment of NAFLD and NASH related fibrosis.

[Identification of key enzyme genes involved in biosynthesis pathways of lignan and lignin in Eucommia ulmoides based on transcriptome assembly].

Lignan is the main medicinal component of Eucommia ulmoides, and lignin is involved in the defense of plants against diseases and insect pests.They are synthesized from coniferyl alcohol with the help of dirigent(DIR) and peroxidase(POD), respectively.In this study, transcriptome assembly of stems and leaves of E.ulmoides was performed, yielding 112 578 unigenes.Among them, 70 459 were annotated in seven databases.A total of 59 unigenes encodes 11 key enzymes in the biosynthesis pathways of lignin and lignin, of which 11 encode POD and 8 encode DIR.A total of 13 unigenes encoding transcription factors are involved in phenylpropanoid metabolism. Compared with leaves of E.ulmoides, 7 575 unigenes were more highly expressed in stems, of which 462 were involved in phenylpropanoid biosynthesis.Our results extend the public transcriptome dataset of E.ulmoides, which provide valuable information for the analysis of biosynthesis pathways of lignan and lignin in E.ulmoides and lay a foundation for further study on the functions and regulation mechanism of key enzymes in lignan and lignin biosynthesis pathways.

Indole-Based Long-Wavelength Fluorescent Probes for Bioimaging of S-Nitrosylation in Mitochondria.

S-Nitrosylation has been found to play an important role in regulating mitochondrial function. However, probes for detection of protein S-nitrosylation in mitochondria remain unexplored. Herein, a novel 4-(pyridin-4-yl)vinyl-substituted indole was designed, exhibiting a long-wavelength emission and a high fluorescent quantum yield. Functionalization of the 7-position of the indole ring with an arylphosphine ester resulted with probes with efficient mitochondria-targeting ability. Furthermore, the indole-arylphosphine displayed a significant fluorescence enhancement upon exposure to S-nitrosoglutathione (GSNO) at low micromolar concentrations in A431 cells. Taken together, this study provides a new indole-based fluorescent probe with a unique long-wavelength emission for direct detection of S-nitrosylation in mitochondria, which may represent a powerful tool for understanding the critical roles of S-nitrosylation within mitochondria of living organisms.

Probing the transcriptome of Boehmeria nivea reveals candidate genes associated with the biosynthesis of chlorogenic acid.

Boehmeria nivea (L.) Gaudich is used in traditional Chinese medicine. Chlorogenic acids are major medically active components of Boehmeria nivea, which can be used clinically to treat hyperglycemia, pneumonia, and cancer. To identify the genes involved in chlorogenic acid biosynthesis, we analyzed transcriptome data from leaf, root, and stem tissues of Boehmeria nivea using the Illumina Hi-Seq 4000 platform. A total of 146,790 unigenes were obtained from Boehmeria nivea, of which 106,786 were annotated in public databases. In analyses of the KEGG (Kyoto Encyclopedia of Genes and Genome) database, 484 unigenes that encode the five key enzymes involved in chlorogenic acid biosynthesis were identified, and shikimate O-hydroxycinnamoyl transferase was spatially simulated. Some of these key enzyme unigenes expression levels were verified by RT-qPCR (real-time quantitative Polymerase Chain Reaction). Furthermore, multiple genes encoding plant resistance proteins or transcription factors were identified and analyzed. Differentially expressed genes were identified by performing pairwise comparison of genes between tissues. This study increases the number of public transcript datasets of this species and identifies candidate genes related to the biosynthesis of chlorogenic acid, laying a foundation for the further exploration of this pathway in Boehmeria nivea.

Accurate and Efficient SIMS Oxygen Isotope Analysis of Composition-Variable Minerals: Online Matrix Effect Calibration for Dolomite.

High-quality oxygen isotope analysis of composition-variable minerals (e.g., ubiquitous carbonates) using secondary ion mass spectrometry (SIMS) is extremely challenging. The classical off-line procedure, which requires additional electron probe microanalyzer (EPMA) chemical compositions for calibrating instrumental mass fractionation (IMF), is inherently inaccurate and analytically inefficient. In this study, the first accurate and paired SIMS analysis of δ18O and Fe# [molar Fe/(Mg + Fe)] in dolomite is reported. Based on five newly developed dolomite O-isotopic standards with an Fe# range of 0.01-0.35 obtained by SIMS, a novel accurate and rapid online matrix effect calibration method for dolomite O-isotope analysis was developed using concurrent SIMS 18O-16O-56Fe16O-24Mg16O measurements without additional chemical electron probe microanalysis. A logistic equation was proposed as the best-fit curve to represent the δ18O matrix effect based on the 56Fe16O/24Mg16O ratios. For CTD-4 carbonatitic dolomite with variable Fe# but homogeneous oxygen isotopes, the off-line method exhibited highly variable apparent δ18O values in the range of 5.74-10.11‰. The online method yielded a homogeneous δ18O value of 7.94 ± 0.34‰ (2SD, n = 40), which is comparable with that of bulk analysis (7.94 ± 0.20‰; 2SD). Comprehensive analyses validated the online method as the best strategy for performing accurate δ18O analysis of samples with highly heterogeneous compositions. Based on its accuracy, simplicity, and economic feasibility, this method has potential applications in the analysis of composition-complex dolomites, detrital dolomites, and other precious terrestrial and extraterrestrial materials.

Light oxygen isotopes in mantle-derived magmas reflect assimilation of sub-continental lithospheric mantle material.

Oxygen isotope ratios in mantle-derived magmas that differ from typical mantle values are generally attributed to crustal contamination, deeply subducted crustal material in the mantle source or primordial heterogeneities. Here we provide an alternative view for the origin of light oxygen-isotope signatures in mantle-derived magmas using kimberlites, carbonate-rich magmas that assimilate mantle debris during ascent. Olivine grains in kimberlites are commonly zoned between a mantle-derived core and a magmatic rim, thus constraining the compositions of both mantle wall-rocks and melt phase. Secondary ion mass spectrometry (SIMS) analyses of olivine in worldwide kimberlites show a remarkable correlation between mean oxygen-isotope compositions of cores and rims from mantle-like 18O/16O to lower 'crustal' values. This observation indicates that kimberlites entraining low-18O/16O olivine xenocrysts are modified by assimilation of low-18O/16O sub-continental lithospheric mantle material. Interaction with geochemically-enriched domains of the sub-continental lithospheric mantle can therefore be an important source of apparently 'crustal' signatures in mantle-derived magmas.

Visible-Light-Driven Redox Neutral Direct C-H Amination of Glycine Derivatives and Peptides with N-Acyloxyphthalimides.

A room temperature, visible-light-promoted and redox neutral direct C-H amination of glycine and peptides has been firstly accomplished by using N-acyloxyphthalimide or -succinimide as nitrogen-radical precursor. The present strategy provides ways to introduce functionalities such as N-acyloxyphthalimide or -succinimide specifically to terminal glycine segment of peptides. Herein, mild conditions and high functional-group tolerance allow the preparation of non-natural α-amino acids and modification of corresponding peptides in this way.

A CDR-based approach to generate covalent inhibitory antibody for human rhinovirus protease.

Covalent target modulation with small molecules has been emerging as a promising strategy for drug discovery. However, covalent inhibitory antibody remains unexplored due to the lack of efficient strategies to engineer antibody with desired bioactivity. Herein, we developed an intracellular selection method to generate covalent inhibitory antibody against human rhinovirus 14 (HRV14) 3C protease through unnatural amino acid mutagenesis along the heavy chain complementarity-determining region 3 (CDR-H3). A library of antibody mutants was thus constructed and screened in vivo through co-expression with the target protease. Using this screening strategy, six covalent antibodies with proximity-enabled bioactivity were identified, which were shown to covalently target HRV14-3C protease with high inhibitory potency and exquisite selectivity. Compared to structure-based rational design, this library-based screening method provides a simple and efficient way for the discovery and engineering of covalent antibody for enzyme inhibition.

Role of Acupuncture in Amblyopia Treatment.

CONTEXT: Amblyopia is an ophthalmological developmental disorder that occurs during early childhood due to disrupted binocular vision. It leads to reduced best-corrected visual acuity in one eye (seldom in both eyes) in which the visual acuity of one eye is 2 rows weaker than the other eye on a Snellen vision testing chart. Many studies have reported the outcomes of acupuncture in the treatment of amblyopia. Evidence suggests that acupuncture improves outcomes in children with amblyopia, but these studies are associated with several limitations which may affect the evaluation of the efficacy and reproducibility of studies on acupuncture. One important limitation is the lack of sham acupuncture as a control which has not been used in any clinical trial. The use of nonacupoint acupuncture is suggested as a placebo to improve the quality of evidence and comparability?

The Relationship between Urinary Stones and Gut Microbiomeby 16S Sequencing.

OBJECTIVE: To understand the relationship between urinary stones and the gut microbiome and to screen for microbial species that may be involved in stone formation. METHODS: Stool samples were collected from patients with urolithiasis and healthy patients between March and December 2017. The samples were analyzed by 16S sequencing to determine differences in the microbiome profiles between the two groups. The mouse model was established and was divided into two groups. Fecal samples were collected from the mice before gavage and three weeks postgavage for microbiome analysis. The microbial population of each group was analyzed to screen for microbial species that may affect the formation of urinary stones. Differences in the number of crystals in the renal tubules of the mice were examined by necropsy. RESULTS: The microbial composition was different between urolithiasis patients and healthy controls. The urolithiasis patients had significantly reduced microbial abundance; however, increased proportions of Bacteroidetes and Actinobacteria were detected compared to healthy controls. Furthermore, the abundance of Alistipesindistinctus and Odoribactersplanchnicus was significantly increased in the urolithiasis patients compared to the healthy controls. In addition, the incidence of urolithiasis was much higher in the experimental mouse group (stone solution + urolithiasis patient stool) than in the control mouse group. However, the microbial abundance before gavage was not significantly different from that seen three weeks postgavage. CONCLUSION: Theurolithiasis patients in this study had a different gut microbiome when compared with that of healthy individuals. The altered microbiome increased the rate of crystal formation in renal tubules and accelerated urinary stone formation in the mouse model of urolithiasis.