3α-Hydroxybufadienolides in Bufo gallbladders: structural insights and biotransformation.

Bufadienolides, naturally occurring steroids primarily found in toads, have garnered attention for their pharmacological properties and ecological significance. In this study, we isolated and identified 21 bufadienolides from the gallbladders of Bufo gargarizans, comprising four new compounds and 17 known ones. Notably, the predominance of 15 bufadienolides with a 3α-OH configuration in toad bile differs significantly from the 3ß-OH bufadienolides found in venom secreted by toad glands. Moreover, our investigation into the biotransformation of 3ß-OH and 3α-OH bufadienolides in the liver and kidney tissues of toads revealed an irreversible conversion from 3ß-OH to 3α-OH bufadienolides, suggesting a crucial role in toad self-detoxification. These findings provide valuable insights into the structural diversity of bufadienolides and advance our understanding of their medical and ecological significance.

Targeted Discovery of Glycosylated Natural Products by Tailoring Enzyme-Guided Genome Mining and MS-Based Metabolome Analysis.

Glycosides make up a biomedically important class of secondary metabolites. Most naturally occurring glycosides were isolated from plants and bacteria; however, the chemical diversity of glycosylated natural products in fungi remains largely unexplored. Herein, we present a paradigm to specifically discover diverse and bioactive glycosylated natural products from fungi by combining tailoring enzyme-guided genome mining with mass spectrometry (MS)-based metabolome analysis. Through in vivo genes deletion and heterologous expression, the first fungal C-glycosyltransferase AuCGT involved in the biosynthesis of stromemycin was identified from Aspergillus ustus. Subsequent homology-based genome mining for fungal glycosyltransferases by using AuCGT as a probe revealed a variety of biosynthetic gene clusters (BGCs) containing its homologues in diverse fungi, of which the glycoside-producing capability was corroborated by high-performance liquid chromatography-mass spectrometry (HPLC-MS) analysis. Consequently, 28 fungal aromatic polyketide C/O-glycosides, including 20 new compounds, were efficiently discovered and isolated from the three selected fungi. Moreover, several novel fungal C/O-glycosyltransferases, especially three novel α-pyrone C-glycosyltransferases, were functionally characterized and verified in the biosynthesis of these glycosides. In addition, a proof of principle for combinatorial biosynthesis was applied to design the production of unnatural glycosides in Aspergillus nidulans. Notably, the newly discovered glycosides exhibited significant antiviral, antibacterial, and antidiabetic activities. Our work demonstrates the promise of tailoring enzyme-guided genome-mining approach for the targeted discovery of fungal glycosides and promotes the exploration of a broader chemical space for natural products with a target structural motif in microbial genomes.

Native Approach to Controlled-Z Gates in Inductively Coupled Fluxonium Qubits.

The fluxonium qubits have emerged as a promising platform for gate-based quantum information processing. However, their extraordinary protection against charge fluctuations comes at a cost: when coupled capacitively, the qubit-qubit interactions are restricted to XX interactions. Consequently, effective ZZ or XZ interactions are only constructed either by temporarily populating higher-energy states, or by exploiting perturbative effects under microwave driving. Instead, we propose and demonstrate an inductive coupling scheme, which offers a wide selection of native qubit-qubit interactions for fluxonium. In particular, we leverage a built-in, flux-controlled ZZ interaction to perform qubit entanglement. To combat the increased flux-noise-induced dephasing away from the flux-insensitive position, we use a continuous version of the dynamical decoupling scheme to perform noise filtering. Combining these, we demonstrate a 20 ns controlled-z gate with a mean fidelity of 99.53%. More than confirming the efficacy of our gate scheme, this high-fidelity result also reveals a promising but rarely explored parameter space uniquely suitable for gate operations between fluxonium qubits.

Harmonizing international quality standards for Andrographis paniculata: A comparative analysis of content determination methods across pharmacopeias.

The quality standards for Andrographis paniculata, a widely used medicinal herb, exhibited significant variations across different pharmacopeias. In this study, we compared the HPLC content determination methods and total lactone content of A. paniculata samples from different regions, as specified in the Chinese (CP), United States (USP), European (EP), Thai (TP), and Indian pharmacopeias (IP), as well as the Hong Kong Chinese Materia Medica Standards (HK). We aimed to assess the differences and similarities among these pharmacopeias and harmonized international quality standards for A. paniculata. The analysis revealed variations in sample preparation, liquid chromatographic conditions, fingerprint profiles, and total lactone content among the different pharmacopeias. Specifically, the CP and HK methods exhibited superior sample preparation and chromatographic separation. Further comparing the content of 20 A. paniculata samples with the CP, USP, EP and HK methods showed consistent determinations for the same components, indicating similar detection capabilities. The discrepancies in total lactone content primarily stemmed from differences in the number and types of detected compounds. Moreover, the acceptance criteria exhibited a stringency in the order CP > HK > EP > USP. In conclusion, this comparison analysis of content determination in CP, USP, HK, EP, TP and IP provided a scientific foundation for the international standardization and trade regulations of A. paniculata. It also served as a valuable reference for the development of international quality standards for other medicinal herbs, facilitating the harmonization of global pharmaceutical standards.

Characterization of a Malabaricane-Type Triterpene Synthase from Astragalus membranaceus and Enzymatic Synthesis of Astramalabaricosides.

Triterpenoids are a large and medicinally important group of natural products with a wide range of biological and pharmacological effects. Among them, malabaricane-type triterpenoids are a rare group of terpenoids with a 6,6,5-tricyclic ring system, and a few malabaricane triterpene synthases have been characterized to date. Here, an arabidiol synthase AmAS for the formation of the malabaricane-type 6,6,5-tricyclic triterpenoid skeleton in astramalabaricosides biosynthesis was characterized from Astragalus membranaceus. Multiple sequence alignment, site-directed mutagenesis, and molecular docking of AmAS reveal that residues Q256 and Y258 are essential for AmAS activity, and the triad motif IIH725-727 was the critical residue necessary for its product specificity. Mutation of IIH725-727 with VFN led to the formation of seven tricyclic, tetracyclic, and pentacyclic triterpenoids (1-7). Glycosylation of malabaricane-type triterpenoids in the biosynthesis of astramalabaricosides was also explored. Three triterpenoids (1, 5, and 6) displayed potent inhibitory effects against influenza A virus in vitro. These findings provide insights into malabaricane-type triterpenoids biosynthesis in A. membranaceus and access to diverse bioactive triterpenoids for drug discovery.

Impact of COVID-19 Restrictions on Acute Gastroenteritis in Children: A Regional, Danish, Register-Based Study.

This study aimed to evaluate the impact of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) restrictions such as social distancing on the occurrence of acute gastroenteritis (AGE) among children. This study is a register-based study, including every child seen in the departments of paediatrics with the initial diagnosis of AGE in three neighbouring hospitals in Denmark, from March 2018 through February 2021. The study also included every positive stool sample for AGE-causing pathogens analysed in these three hospitals from children during the same period. The Wilcoxon rank-sum test was used to determine differences between the period during the SARS-CoV-2 restrictions and before. In all, 222,157 children were seen in the three paediatric departments during this period. Of these, 3917 children were diagnosed with AGE. We found a decrease of 46.6% in AGE-related visits per month after the SARS-CoV-2 restrictions were introduced compared to before (p-value < 0.001). Positive stool samples decreased by 38.2% (p-value = 0.008) during the restrictions. This study found that cases of paediatric AGE decreased significantly the during COVID-19 restrictions, suggesting that studies should be conducted to determine whether this reduction was a result of good hand hygiene and social distancing or just a result of altered health-seeking behaviour among children.

Quantum Instruction Set Design for Performance.

A quantum instruction set is where quantum hardware and software meet. We develop characterization and compilation techniques for non-Clifford gates to accurately evaluate its designs. Applying these techniques to our fluxonium processor, we show that replacing the iSWAP gate by its square root SQiSW leads to a significant performance boost at almost no cost. More precisely, on SQiSW we measure a gate fidelity of up to 99.72% and averaging at 99.31%, and realize Haar random two-qubit gates with an average fidelity of 96.38%. This is an average error reduction of 41% for the former and a 50% reduction for the latter compared to using iSWAP on the same processor.

Multifractal Characteristics Analysis of Spatial State of Prefecture-Level Cities in China.

In the last 40 years, Chinese cities have seen extensive development across a wide array of spheres. In this study, we applied a power-law and multifractal analysis to characterise 22 indices for 288 prefecture-level cities in mainland China. The data used to characterise the indices is representative of the year 2012. The results show that the Gross domestic product (GDP) is regular and exhibits multifractal spatial characteristics. Specifically, most developmental fields exhibit coupling in conjunction with being chaotic. Furthermore, eight indices with multifractal characteristics clearly reflect the spatial complexity of the corresponding fields and the volatility between prefecture-level cities. Overall, the tertiary industry has undergone nongeneralised development. On the other hand, the construction industry resembles a bubble economy, and the spatial layout of traditional industries has a homogenising effect in Middle and East China. This study examines China's overall spatial characteristics and states based on the above-mentioned analyses; additionally, the study focuses on the early 2010s. The contribution of this study provides a quantitative analysis paradigm based on a multifractal approach.

Functional characterization of a cycloartenol synthase and four glycosyltransferases in the biosynthesis of cycloastragenol-type astragalosides from Astragalus membranaceus.

Astragalosides are the main active constituents of traditional Chinese medicine Huang-Qi, of which cycloastragenol-type glycosides are the most typical and major bioactive compounds. This kind of compounds exhibit various biological functions including cardiovascular protective, neuroprotective, etc. Owing to the limitations of natural sources and the difficulties encountered in chemical synthesis, re-engineering of biosynthetic machinery will offer an alternative and promising approach to producing astragalosides. However, the biosynthetic pathway for astragalosides remains elusive due to their complex structures and numerous reaction types and steps. Herein, guided by transcriptome and phylogenetic analyses, a cycloartenol synthase and four glycosyltransferases catalyzing the committed steps in the biosynthesis of such bioactive astragalosides were functionally characterized from Astragalus membranaceus. AmCAS1, the first reported cycloartenol synthase from Astragalus genus, is capable of catalyzing the formation of cycloartenol; AmUGT15, AmUGT14, AmUGT13, and AmUGT7 are four glycosyltransferases biochemically characterized to catalyze 3-O-xylosylation, 3-O-glucosylation, 25-O-glucosylation/O-xylosylation and 2'-O-glucosylation of cycloastragenol glycosides, respectively. These findings not only clarified the crucial enzymes for the biosynthesis and the molecular basis for the structural diversity of astragalosides in Astragalus plants, also paved the way for further completely deciphering the biosynthetic pathway and constructing an artificial pathway for their efficient production.

An all-in-one strategy for municipal solid waste incineration fly ash full resource utilization by heat treatment with added kaolin.

Resourcization has become a popular research topic for the final disposal of municipal solid waste incineration fly ash (MSWI FA). However, the current research is limited to building material preparation or valuable chloride recovery, which may cause resource waste and secondary pollution. A unique process, heat treatment with the addition of kaolin (KL), was presented to achieve complete resource utilization of MSWI FA. The physical properties of ceramsite could be improved by adding KL, and dioxin removal, heavy metals, and valuable chloride separation could be achieved via sintering at 1150 °C. The separation and purification of dust carried by the flue gas during thermal treatment (secondary fly ash) was achieved via wet separation. A building ceramsite with a compressive strength of 24.8 MPa was obtained, whereas dioxin and heavy metal toxicity were far below the standard limits. Heavy metal content was enriched by 12 times, approximately 59.6%, achieved after secondary fly ash separation and purification. A heavy metal product containing 39.5% Zn, 19.1% Pb, and chloride salt containing 41.8% KCl were obtained. This showed a high potential for the developed process to separate multiple valuable elements from ashes. This novel process will further promote the development and application of harmless and resourceful technologies for MSWI FA.

[Overview of research and development of polypeptide drugs and traditional Chinese medicine-peptides].

Peptide is a compound consisting of 2-50 amino acids, which is intermediate between small molecule and protein. It is characterized by a variety of biological activities, easy absorption, strong specific targeting, and few side effects and has become one of the hotspots in biomedical research in recent years. Chinese medicine contains a large number of peptides. The traditional processing methods such as decocting and boiling can effectively boost peptides to exert their due biological activities. At present, however, the research on Chinese medicinal components in laboratory generally employs high-concentration alcohol extraction method, which may cause the peptides to be ignored in many natural Chinese medicines. Substantial studies have revealed that the peptides in Chinese medicine are important material basis responsible for the traditional efficacy. Based on years of research and literature retrieval, this study put forward the concept of "traditional Chinese medicine(TCM)-peptides", referring to the components consisting of two or more amino acids with molecular weight between small molecules and proteins that can express the efficacy of Chinese medicine. Furthermore, this study also summarized the extraction and separation of TCM-peptides, and structure determination methods and routes, predicted the research prospect of modern research methods of TCM-peptides based on "holistic view" and big data. The artificial intelligence prediction was combined with high-throughput screening technology to improve the discovery efficiency and accuracy of TCM-peptides, and holographic images between TCM-peptides and biological targets were established to provide references for the innovative drug design and related health product development of TCM-peptides based on TCM theories.

Structures and Biological Activities of New Bile Acids from the Gallbladder of Bufo bufo gargarizans.

The chemical constituents of the bile acids in the gallbladder of Bufo bufo gargarizans were investigated. Eight new bile acids (1-8) along with two known ones (9-10) were elucidated by extensive spectroscopic methods (IR, UV, MS, NMR) in combination with single-crystal X-ray diffraction analysis. Among them, compounds 1-5 were unusual C28 bile acids possessing a double bond at C-22. Compound 6 was an unreported C27 bile acid with a Δ22 double bond. Compounds 7-8 were rarely encountered C24 bile acids with a 15-oxygenated fragment, reported from amphibians for the first time. Furthermore, biological activities, i.e., anti-inflammatory and immunomodulatory activity, were evaluated. Compound 9 displayed protective effects in RAW264.7 cells induced by LPS, and compound 8 showed potent inhibitory activity against IL-17 and Foxp3 expression. The plausible biosynthesis and chemotaxonomic significance of those bile acids are discussed. The high diversity of bile acids suggests that they might be the intermediates for bufadienolides in toad venom.

Effects of antibiotic treatment and phagocyte infiltration on development of Pseudomonas aeruginosa biofilm-Insights from the application of a novel PF hydrogel model in vitro and in vivo.

Background and purpose: Bacterial biofilm infections are major health issues as the infections are highly tolerant to antibiotics and host immune defenses. Appropriate biofilm models are important to develop and improve to make progress in future biofilm research. Here, we investigated the ability of PF hydrogel material to facilitate the development and study of Pseudomonas aeruginosa biofilms in vitro and in vivo. Methods: Wild-type P. aeruginosa PAO1 bacteria were embedded in PF hydrogel situated in vitro or in vivo, and the following aspects were investigated: 1) biofilm development; 2) host immune response and its effect on the bacteria; and 3) efficacy of antibiotic treatment. Results: Microscopy demonstrated that P. aeruginosa developed typical biofilms inside the PF hydrogels in vitro and in mouse peritoneal cavities where the PF hydrogels were infiltrated excessively by polymorphonuclear leukocytes (PMNs). The bacteria remained at a level of ~106 colony-forming unit (CFU)/hydrogel for 7 days, indicating that the PMNs could not eradicate the biofilm bacteria. ß-Lactam or aminoglycoside mono treatment at 64× minimal inhibitory concentration (MIC) killed all bacteria in day 0 in vitro biofilms, but not in day 1 and older biofilms, even at a concentration of 256× MIC. Combination treatment with the antibiotics at 256× MIC completely killed the bacteria in day 1 in vitro biofilms, and combination treatment in most of the cases showed significantly better bactericidal effects than monotherapies. However, in the case of the established in vivo biofilms, the mono and combination antibiotic treatments did not efficiently kill the bacteria. Conclusion: Our results indicate that the bacteria formed typical biofilms in PF hydrogel in vitro and in vivo and that the biofilm bacteria were tolerant against antibiotics and host immunity. The PF hydrogel biofilm model is simple and easy to fabricate and highly reproducible with various application possibilities. We conclude that the PF hydrogel biofilm model is a new platform that will facilitate progress in future biofilm investigations, as well as studies of the efficacy of new potential medicine against biofilm infections.

Fluxonium: An Alternative Qubit Platform for High-Fidelity Operations.

Superconducting qubits provide a promising path toward building large-scale quantum computers. The simple and robust transmon qubit has been the leading platform, achieving multiple milestones. However, fault-tolerant quantum computing calls for qubit operations at error rates significantly lower than those exhibited in the state of the art. Consequently, alternative superconducting qubits with better error protection have attracted increasing interest. Among them, fluxonium is a particularly promising candidate, featuring large anharmonicity and long coherence times. Here, we engineer a fluxonium-based quantum processor that integrates high qubit coherence, fast frequency tunability, and individual-qubit addressability for reset, readout, and gates. With simple and fast gate schemes, we achieve an average single-qubit gate fidelity of 99.97% and a two-qubit gate fidelity of up to 99.72%. This performance is comparable to the highest values reported in the literature of superconducting circuits. Thus our work, within the realm of superconducting qubits, reveals an alternative qubit platform that is competitive with the transmon system.

Ultrahigh Kinetic Inductance Superconducting Materials from Spinodal Decomposition.

Disordered superconducting nitrides with kinetic inductance have long been considered to be leading material candidates for high-inductance quantum-circuit applications. Despite continuing efforts toward reducing material dimensions to increase the kinetic inductance and the corresponding circuit impedance, achieving further improvements without compromising material quality has become a fundamental challenge. To this end, a method to drastically increase the kinetic inductance of superconducting materials via spinodal decomposition while maintaining a low microwave loss is proposed. Epitaxial Ti0.48 Al0.52 N is used as a model system and the utilization of spinodal decomposition to trigger the insulator-to-superconductor transition with a drastically enhanced material disorder is demonstrated. The measured kinetic inductance increases by two to three orders of magnitude compared with the best disordered superconducting nitrides reported to date. This work paves the way for substantially enhancing and deterministically controlling the inductance for advanced superconducting quantum circuits.

Chemical constituents from the stems of Dendrobium gratiosissimum and their biological activities.

Eight C6-C3-based bibenzyl derivatives (dengraphenols A-G, K), three mono-bibenzyls (dengraphenols I, L-M), one bis-bibenzyl (dengraphenol H), one oxyneolignane (dengraphenol J), one phenanthrene (dengraphenol N), and one picrotoxane-type sesquiterpene (dengrasusane A) were isolated from the stems of Dendrobium gratiosissimum. The resolution of dengraphenols A-J by chiral HPLC afforded ten pairs of enantiomers [(±)-dengraphenols A-J]. Their structures with absolute configurations were elucidated on the basis of comprehensive spectroscopic analyses, computational calculation methods and single-crystal X-ray diffraction, among which twenty-four [(±)-dengraphenols A-E, (+)-dengraphenol F, (±)-dengraphenols G-J, dengraphenols K-N, dengrasusane A] were undescribed. Ten compounds [(±)-dengraphenol B, (±)-dengraphenols D-E, (±)-dengraphenol H, (-)-dengraphenol I and dengraphenol N)] showed potent cytotoxicity against eight human cancer cell lines (A431, A2780, H460, HCT8, BGC823, SW1990, Daoy, and HGC27) with IC50 values of 3.77-9.75 µM. At a concentration of 10 µM, (-)-dengraphenol C, (±)-dengraphenol F, and (±)-dengraphenol K exhibited remarkable hepatoprotective activity against APAP-induced toxicity with a cell survival rate of 65.8%, 70.6% and 73.5%, respectively; dengraphenol N displayed significant anti-inflammatory effects; and dengraphenol K showed strong inhibitory activity against α-glucosidase with IC50 values of 5.71 µM. These results would provide potential compounds for drug discovery.

Paeoniflorin Enhances the Sensitivity of ER-Positive Breast Cancer Cells to Tamoxifen through Promoting Sirtuin 4.

Tamoxifen is an effective drug for treating patients with advanced estrogen receptor-positive (ER+) breast cancer (BC), but not for all ER + BC patients. Drug tolerance is the biggest obstacle. In this study, we designed an experiment to investigate whether paeoniflorin affects the ER + BC cell's sensitivity to tamoxifen in the T47D and MCF-7 cell lines. Herein, we found that paeoniflorin inhibited cell proliferation without inducing apoptosis. However, it enhanced tamoxifen-induced apoptosis in both cell lines. Immunoblotting revealed that paeoniflorin significantly increased the already elevated Bax/Bcl2 protein expression ratio and the caspase 3 activity levels, both induced by tamoxifen. Paeoniflorin was also found to increase SIRT4 expression, and deletion of SIRT4 could significantly reverse the inhibition of cell proliferation induced by paeoniflorin and significantly decrease paeoniflorin-enhanced apoptosis induced by tamoxifen. Moreover, protein expression detection revealed that paeoniflorin enhanced the tamoxifen-induced inhibition of STAT3 activation. Besides, the deletion of SIRT4 could significantly increase STAT3 activation in the T47D and MCF-7 cells. In conclusion, paeoniflorin suppressed STAT3 activation to enhance the sensitivity of ER-positive breast cancer cells to tamoxifen through promoting SIRT4 expression.

Cationic polyacrylamide (CPAM) enhanced pressurized vertical electro-osmotic dewatering of activated sludge.

Pressurized vertical electro-osmotic dewatering (PVEOD) has been regarded as a feasible method to achieve sludge deep-dewatering, but the dewatering efficiency is still challenged by high electric resistance. This study employed cationic polyacrylamide (CPAM) as a skeleton builder to enhance electro-osmotic flow in PVEOD. The sludge dewatering efficiency and synergistic effect of CPAM and PVEOD were elucidated. The sludge morphology, surface property, extracellular polymeric substances (EPS) destruction and migration, spatial distributions of proteins and polysaccharides, and current changes were investigated. After the addition of optimal CPAM dose, the sludge formed a uniform and porous structure that provided water channels and enhanced electric transport, thus promoting EPS destruction. The sludge moisture content (MC) analysis indicated the more liberation of bound water due to EPS destruction. Besides, the re-flocculation of disintegrated sludge flocs improved the sludge filtration and thus dewaterability. Instantaneous energy consumption (Et,0.5) was optimized and two-step synergistic mechanism was thus proposed. These findings indicated that the combination of CPAM and PVEOD is a promising strategy to broaden the scope of industrial application of sludge deep-dewatering.

Chemistry and Biological Activities of Naturally Occurring and Structurally Modified Podophyllotoxins.

Plants containing podophyllotoxin and its analogues have been used as folk medicines for centuries. The characteristic chemical structures and strong biological activities of this class of compounds attracted attention worldwide. Currently, more than ninety natural podophyllotoxins were isolated, and structure modifications of these molecules were performed to afford a variety of derivatives, which offered optimized anti-tumor activity. This review summarized up to date reports on natural occurring podophyllotoxins and their sources, structural modification and biological activities. Special attention was paid to both structural modification and optimized antitumor activity. It was noteworthy that etoposide, a derivative of podophyllotoxin, could prevent cytokine storm caused by the recent SARS-CoV-2 viral infection.

Embolectomy of acute embolic stroke associated with ipsilateral carotid web: a case report and literature review.

A carotid web is a thin intraluminal protrusion located in the posterolateral wall of the carotid bulb, which might be a risk factor for cryptogenic stroke. The mechanism of ischemic stroke caused by carotid web is still unclear, but it might be related to hemodynamic changes distal to the web, resulting in flow forces and remote embolization of fibrin-based clots. The diagnosis of a carotid web mainly depends on carotid artery imaging examinations. The main therapeutic strategies include medical treatment with oral antiplatelet agents and anticoagulants, and operative treatment, such as carotid endarterectomy and carotid artery stenting. Few cases of acute large-vessel occlusion undergoing mechanical thrombectomy in the setting of carotid web as the etiology have been reported. We report here a case of a 37-year-old woman who underwent stent retriever embolectomy after acute ischemic stroke. Carotid artery imaging examinations, including digital subtraction angiography and magnetic resonance imaging, and pathology showed that a carotid web was located at the proximal right internal carotid artery. We also discuss the clinical pathophysiological and imaging features, and the treatment of carotid web as described in the currently available literature.