Effects of Chemical Composition and Cross-Linking Degree on the Thermo-Mechanical Properties of Bio-Based Thermosetting Resins: A Molecular Dynamics Simulation Study.

Bio-based epoxy resins have received significant attention in terms of concerns regarding carbon emission. Epoxidized soybean oil (ESO) derived from sustainable feedstock has been widely used to blend with traditional diglycidyl ether of bisphenol-A (DGEBA) to replace some of the petroleum-based components. In this work, molecular dynamics (MD) simulations were applied to track the network formation and predict the performance of methyl hexahydrophthalic anhydride (MHHPA)-cured ESO/DGEBA blend systems. The effects of ESO content and cross-linking degree on the mass density, volumetric shrinkage, glass transition temperature (Tg), coefficient of thermal expansion (CTE), Young's modulus, yield strength, and Poisson's ratio of the epoxy resin were systematically investigated. The results show that systems with high ESO content achieve gelation at low cross-linking degree. The Tg value, Young's modulus, and yield strength increase with the increase in cross-linking degree, but the CTE at the glassy state and Poisson's ratio decrease. The comparison results between the simulated and experimental data demonstrated that the MD simulations can accurately predict the thermal and mechanical properties of ESO-based thermosets. This study gains insight into the variation in thermo-mechanical properties of anhydride-cured ESO/DGEBA-based epoxy resins during the cross-linking process and provides a rational strategy for optimizing bio-based epoxy resins.

Aphid alarm pheromone mimicry in transgenic Chrysanthemum morifolium: insights into the potential of (E)-ß-farnesene for aphid resistance.

(E)-ß-Farnesene (EBF) serves as the primary component of the alarm pheromone used by most aphid pest species. Pyrethrum (Tanacetum cinerariifolium) exhibits tissue-specific regulation of EBF accumulation and release, effectively mimicking the aphid alarm signal, deterring aphid attacks while attracting aphid predators. However, cultivated chrysanthemum (Chrysanthemum morifolium), a popular and economically significant flower, is highly vulnerable to aphid infestations. In this study, we investigated the high expression of the pyrethrum EBF synthase (TcEbFS) gene promoter in the flower head and stem, particularly in the parenchyma cells. Subsequently, we introduced the TcEbFS gene, under the control of its native promoter, into cultivated chrysanthemum. This genetic modification led to increased EBF accumulation in the flower stem and young flower bud, which are the most susceptible tissues to aphid attacks. Analysis revealed that aphids feeding on transgenic chrysanthemum exhibited prolonged probing times and extended salivation durations during the phloem phase, indicating that EBF in the cortex cells hindered their host-location behavior. Interestingly, the heightened emission of EBF was only observed in transgenic chrysanthemum flowers after mechanical damage. Furthermore, we explored the potential of this transgenic chrysanthemum for aphid resistance by comparing the spatial distribution and storage of terpene volatiles in different organs and tissues of pyrethrum and chrysanthemum. This study provides valuable insights into future trials aiming for a more accurate replication of alarm pheromone release in plants. It highlights the complexities of utilizing EBF for aphid resistance in cultivated chrysanthemum and calls for further investigations to enhance our understanding of this defense mechanism.

The phytochemistry, pharmacology, pharmacokinetics, quality control, and toxicity of Forsythiae Fructus: An updated systematic review.

Forsythiae Fructus (FF), the dried fruit of F. suspensa, is commonly used to treat fever, inflammation, etc in China or other Asian countries. FF is usually used as the core herb in traditional Chinese medicine preparations for the treatment of influenza, such as Shuang-huang-lian oral liquid and Yin-qiao powder, etc. Since the wide application and core role of FF, its research progress was summarized in terms of traditional uses, phytochemistry, pharmacology, pharmacokinetics, quality control, and toxicity. Meanwhile, the anti-influenza substances and mechanism of FF were emphasized. Till now, a total of 290 chemical components are identified in F. suspensa, and among them, 248 components were isolated and identified from FF, including 42 phenylethanoid glycosides, 48 lignans, 59 terpenoids, 14 flavonoids, 3 steroids, 24 cyclohexyl ethanol derivatives, 14 alkaloids, 26 organic acids, and 18 other types. FF and their pure compounds have the pharmacological activities of anti-virus, anti-inflammation, anti-oxidant, anti-bacteria, anti-tumor, neuroprotection, hepatoprotection, etc. Inhibition of TLR7, RIG-I, MAVS, NF-κB, MyD88 signaling pathway were the reported anti-influenza mechanisms of FF and phenylethanoid glycosides and lignans are the main active groups. However, the bioavailability of phenylethanoid glycosides and lignans of FF in vivo was low, which needed to be improved. Simultaneously, the un-elucidated compounds and anti-influenza substances of FF strongly needed to be explored. The current quality control of FF was only about forsythoside A and phillyrin, more active components should be taken into consideration. Moreover, there are no reports of toxicity of FF yet, but the toxicity of FF should be not neglected in clinical applications.

Ultralong-life and high-capacity magnesium/sodium hybrid-ion battery using a ternary CoSe/NiSe2/CuSe2 cathode and dual-ion electrolyte.

An ultrahigh-performance magnesium/sodium hybrid-ion battery (MNHB) is developed using ternary CoSe/NiSe2/CuSe2 (CNCS) "micro-flowers" as cathode materials, working with a coordinative [Mg2Cl2][AlCl4]2 and bis(trifluoroethylsulfonyl)imide anionic sodium salt in triglyme electrolyte. After 2000 cycles at 2.0 A g-1, the MNHB shows a stable capacity of 115.5 mA h g-1 and a high Coulombic efficiency exceeding 99.8%. The battery shows very rapid charging, and good stability in extreme environments, providing new opportunities to develop other hybrid-ion systems.

Jolkinolide B inhibits the progression of hepatocellular carcinoma by regulating Musashi-2 protein.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths. However, the HCC treatment is still challenging. Herein, we aimed to reveal the anti-tumor effect of Jolkinolide B in HCC cell lines Huh-7 and SK-Hep-1. The results showed that Jolkinolide B inhibited the migration, invasion, and epithelial-to-mesenchymal transition(EMT) of HCC cells. In addition, Jolkinolide B induced HCC cell apoptosis by upregulating Bax and downregulating BCL-2 expressions. Furthermore, we demonstrated that Jolkinolide B inactivated the ß-catenin signaling and reduced Musashi-2 expression. Finally, we revealed that Musashi-2 overexpression reversed the Jolkinolide B-induced anti-HCC effect. Overall, we proved that Jolkinolide B is a potential candidate for treating HCC.

Influences of Polyphenols on the Properties of Crosslinked Acellular Fish Swim Bladders: Experiments and Molecular Dynamic Simulations.

Acellular fish swim bladders (AFSBs) are a promising biomaterial in tissue engineering, however, they may suffer from rapid degradation due to enzyme invasion. In this work, natural polyphenols, including epigallocatechin gallate (EGCG), proanthocyanidin (PC), tannic acid (TA) and protocatechuic acid (PCA), were utilized to improve the properties of AFSBs through crosslinking modifications. Fourier transform infrared (FTIR) results indicate that the triple helix of the collagen in AFSBs is well preserved after crosslinking. The differential scanning calorimetry (DSC), water contact angle (WCA) and in vitro degradation tests indicate that the polyphenol-crosslinked AFSBs exhibit improved thermal stability, enzymatic stability, hydrophilicity and mechanical properties. Among them, EGCG with multiple phenolic hydroxyl groups and low potential resistance is more favorable for the improvement of the mechanical properties and enzymatic stability of AFSBs, as well as their biocompatibility and integrity with the collagen triple helix. Moreover, the crosslinking mechanism was demonstrated to be due to the hydrogen bonds between polyphenols and AFSBs, and was affected by the molecular size, molecular weight and the hydroxyl groups activity of polyphenol molecules, as clarified by molecular dynamic (MD) simulations. The approach presented in this work paves a path for improving the properties of collagen materials.

Short-term reproductive outcomes analysis and prediction of the modified uterine stent treatment for mild to moderate intrauterine adhesions: experience at a single institution.

BACKGROUND: To evaluate the efficacy of modified uterine stent in the treatment of mild-to-moderate intrauterine adhesions and explore the relative indicators affecting prognosis prediction. METHODS: A total of 115 patients with mild-to-moderate intrauterine adhesions received a modified uterine stent placement after hysteroscopy adhesiolysis. The second-look hysteroscopy operated after 3 months surgery, and the third-look hysteroscopy operated after 6 months surgery if necessary. The stent was removed when the cavity shape was repaired, then the reproductive outcomes were followed up one year. RESULTS: Menstrual blood volume, endometrial thickness and volume had increased significantly after 3 months surgery. The rates of cavity repaired were 86.96% (100/115) after 3 months surgery and 100% (115/115) after 6 months surgery cumulatively. Endometrial thickness after 3-months surgery was positively associated with uterine cavity shape repaired (P<0.01). The receive operating characteristic (ROC) curve showed the rate of uterine cavity shape repaired predicted by the model was 0.92, based on the endometrial thickness after 3-months surgery. The rate of pregnancy was 86.09% (99/115) in one year, while the rate of miscarriage accounted for 26.26% (26/99). The median time interval between stent removal and subsequent conception was 3 months. It showed adhesion recurrence was the risk factor for subsequent pregnancy (P<0.01). CONCLUSIONS: A modified uterine stent placement under hysteroscopy was an effective approach for mild-to-moderate intrauterine adhesions, which is easy to operate and worthy for clinical promotion. Endometrial thickness measured by ultrasonography probably has predictive value in adhesion recurrence and subsequent pregnancy. TRIAL REGISTRATION: ChiCTR2100051524. Date of registration (retrospectively registered): 26/09/2021.

Multi-omics and chemical profiling approaches to understand the material foundation and pharmacological mechanism of sophorae tonkinensis radix et rhizome-induced liver injury in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Sophorae tonkinensis Radix et Rhizoma (STR) is an extensively applied traditional Chinese medicine (TCM) in southwest China. However, its clinical application is relatively limited due to its hepatotoxicity effects. AIM OF THE STUDY: To understand the material foundation and liver injury mechanism of STR. MATERIALS AND METHODS: Chemical compositions in STR and its prototypes in mice were profiled by ultra-performance liquid chromatography coupled quadrupole-time of flight mass spectrometry (UPLC-Q/TOF MS). STR-induced liver injury (SILI) was comprehensively evaluated by STR-treated mice mode. The histopathologic and biochemical analyses were performed to evaluate liver injury levels. Subsequently, network pharmacology and multi-omics were used to analyze the potential mechanism of SILI in vivo. And the target genes were further verified by Western blot. RESULTS: A total of 152 compounds were identified or tentatively characterized in STR, including 29 alkaloids, 21 organic acids, 75 flavonoids, 1 quinone, and 26 other types. Among them, 19 components were presented in STR-medicated serum. The histopathologic and biochemical analysis revealed that hepatic injury occurred after 4 weeks of intragastric administration of STR. Network pharmacology analysis revealed that IL6, TNF, STAT3, etc. were the main core targets, and the bile secretion might play a key role in SILI. The metabolic pathways such as taurine and hypotaurine metabolism, purine metabolism, and vitamin B6 metabolism were identified in the STR exposed groups. Among them, taurine, hypotaurine, hypoxanthine, pyridoxal, and 4-pyridoxate were selected based on their high impact value and potential biological function in the process of liver injury post STR treatment. CONCLUSIONS: The mechanism and material foundation of SILI were revealed and profiled by a multi-omics strategy combined with network pharmacology and chemical profiling. Meanwhile, new insights were taken into understand the pathological mechanism of SILI.

Genomic basis of the distinct biosynthesis of ß-glucogallin, a biochemical marker for hydrolyzable tannin production, in three oak species.

Hydrolyzable tannins (HTs), predominant polyphenols in oaks, are widely used in grape wine aging, feed additives, and human healthcare. However, the limited availability of a high-quality reference genome of oaks greatly hampered the recognition of the mechanism of HT biosynthesis. Here, high-quality reference genomes of three Asian oak species (Quercus variabilis, Quercus aliena, and Quercus dentata) that have different HT contents were generated. Multi-omics studies were carried out to identify key genes regulating HT biosynthesis. In vitro enzyme activity assay was also conducted. Dual-luciferase and yeast one-hybrid assays were used to reveal the transcriptional regulation. Our results revealed that ß-glucogallin was a biochemical marker for HT production in the cupules of the three Asian oaks. UGT84A13 was confirmed as the key enzyme for ß-glucogallin biosynthesis. The differential expression of UGT84A13, rather than enzyme activity, was the main reason for different ß-glucogallin and HT accumulation. Notably, sequence variations in UGT84A13 promoters led to different trans-activating activities of WRKY32/59, explaining the different expression patterns of UGT84A13 among the three species. Our findings provide three high-quality new reference genomes for oak trees and give new insights into different transcriptional regulation for understanding ß-glucogallin and HT biosynthesis in closely related oak species.

SnS2 quantum dots-coated VO2@carbon nanorods for secondary battery displaying high capacity and rate-performance.

Electrode materials optimization is one of the keys to improving the energy storage characteristics of secondary batteries. Herein, a VO2@carbon@SnS2 composite is developed by coating SnS2 quantum dots (QDs) on lamellar VO2@carbon nanorods, yielding a high-performance aluminum-ion battery cathode. SnS2 QDs embedded in VO2@carbon accelerate electron transport, while the in situ coating of carbon improves cycling stability. When cycling at 0.5 A g-1, capacity is maintained at 157.6 mA h g-1 after 200 cycles. Even at 1.0 A g-1, the cathode can be stably cycled 1000 times. Capacity remains at 176.3 mA h g-1 and coulombic efficiency is 99.1% at temperatures below -10 °C after 100 cycles. These findings provide new ideas for the development of QD-modified composites for application in secondary batteries.

Murepavadin promotes the killing efficacies of aminoglycoside antibiotics against Pseudomonas aeruginosa by enhancing membrane potential.

Murepavadin is a peptidomimetic that specifically targets the lipopolysaccharide transport protein LptD of Pseudomonas aeruginosa. Here, we found that murepavadin enhances the bactericidal efficacies of tobramycin and amikacin. We further demonstrated that murepavadin enhances bacterial respiration activity and subsequent membrane potential, which promotes intracellular uptake of aminoglycoside antibiotics. In addition, the murepavadin-amikacin combination displayed a synergistic bactericidal effect in a murine pneumonia model.

Comparative Analysis of Characteristic Volatile Compounds in Five Types of Infant Nutrition Powders by HS-GC-IMS and GC-MS.

This study employed the headspace-gas chromatography-ion migration spectrum (HS-GC-IMS) in conjunction with the gas chromatography-mass spectrometer (GC-MS) technique for the assessment of the flavor quality of complementary food powder intended for infants and young children. A total of 62 volatile compounds were identified, including aldehydes, esters, alcohols, ketones, pyrazines, and furans, among which aldehydes were the most abundant compounds. Based on the principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) models, infant nutritional powder (YYB) from different manufacturers could be clearly distinguished. Among them, 2-hydroxybenzaldehyde, 1, 2-dimethoxyethane, 2-isobutyl-3-methoxypyrazine, and methyl butyrate were the four most critical differential volatiles. In addition, these differences were also manifested in changes in fatty acids. The reason for this phenomenon can be attributed to the difference in the proportion of raw materials used in nutrition powder, micronutrient content, and the packaging process. In conclusion, this study provides comprehensive information on the flavor quality of YYB, which can be used as a basis for quality control of YYB.

A review of the ethnopharmacology, phytochemistry, pharmacology, pharmacokinetics and toxicology of Abri Herba (Ji-Gu-Cao).

Abri Herba (AH, known as 'Ji-Gu-Cao' in China) has a long-term medicinal history of treating cholecystitis, acute and chronic hepatitis and non-alcoholic fatty liver (NAFL) in China or other Asian countries. This review aimed to provide a comprehensive analysis of AH in terms of ethnopharmacology, phytochemistry, pharmacology, pharmacokinetics and toxicology. The information involved in the study was collected from a variety of electronic resources, and >100 scientific studies have been used since 1962. Until now, 95 chemical compounds have been isolated and identified from AH and the seeds of Abrus cantoniensis Hance (ACH), including 47 terpenoids, 26 flavonoids and 4 alkaloids. The pharmacological activities of AH extracts and their pure compounds have been explored in the aspects of anti-hyperlipidaemia, hepatoprotection, anti-tumour, anti-viral, anti-bacterial, anti-inflammatory and analgesic, immunomodulation, antioxidant and others. The pharmacokinetics and excretion kinetics of AH in vivo and 15 traditional and clinical prescriptions containing AH have been sorted out, and the potential therapeutic mechanism and drug metabolism pattern were also summarised. The pods of ACH are toxic, with a median lethal dose (LD50) of 10.01 ± 2.90 g/kg (i.g.) in mice. Interestingly, the toxicity of ACH's pods and seeds decreased after boiling. However, the toxicity mechanism of pods of ACH is unclear, limiting its clinical application. Clinical trials in the future should be used to explore its safety. Meanwhile, as one of the relevant pharmacological activities, the effects and mechanism of AH on anti-hyperlipidaemia and hepatoprotection should be further studied, which is of great significance for understanding its mechanism of action in the treatment of NAFL disease and improving its clinical application.

Advanced gastrointestinal stromal tumor: reliable classification of imatinib plasma trough concentration via machine learning.

AIM: Patients with advanced gastrointestinal stromal tumors (GISTs) exhibiting an imatinib plasma trough concentration (IM Cmin) under 1100 ng/ml may show a reduced drug response rate, leading to the suggestion of monitoring for IM Cmin. Consequently, the objective of this research was to create a customized IM Cmin classification model for patients with advanced GISTs from China. METHODS: Initial data and laboratory indicators from patients with advanced GISTs were gathered, and the above information was segmented into a training set, validation set, and testing set in a 6:2:2 ratio. Key variables associated with IM Cmin were identified to construct the classification model using the least absolute shrinkage and selection operator (LASSO) regression and forward stepwise binary logistic regression. Within the training and validation sets, nine ML classification models were constructed via the resampling method and underwent comparison through the Brier scores, the areas under the receiver-operating characteristic curve (AUROC), the decision curve, and the precision-recall (AUPR) curve to determine the most suitable model for this dataset. Two methods of internal validation were used to assess the most suitable model's classification performance: tenfold cross-validation and random split-sample validation (test set), and the value of the test set AUROC was used to evaluate the model's classification performance. RESULTS: Six key variables (gender, daily IM dose, metastatic site, red blood cell count, platelet count, and percentage of neutrophils) were ultimately selected to construct the classification model. In the validation set, it is found by comparison that the Extreme Gradient Boosting (XGBoost) model has the largest AUROC, the lowest Brier score, the largest area under the decision curve, and the largest AUPR value. Furthermore, as evaluated via internal verification, it also performed well in the test set (AUROC = 0.725). CONCLUSION: For patients with advanced GISTs who receive IM, initial data and laboratory indicators could be used to accurately estimate whether the IM Cmin is below 1100 ng/ml. The XGBoost model may stand a chance to assist clinicians in directing the administration of IM.

Bioinformatics and Integrative Experimental Method to Identifying and Validating Co-Expressed Ferroptosis-Related Genes in OA Articular Cartilage and Synovium.

Purpose: Osteoarthritis (OA) is the most common joint disease worldwide and is the primary cause of disability and chronic pain in older adults.Ferroptosis is a type of programmed cell death characterized by aberrant iron metabolism and reactive oxygen species accumulation; however, its role in OA is not known. Methods: To identify ferroptosis markers co-expressed in articular cartilage and synovium samples from patients with OA, in silico analysis was performed.Signature genes were analyzed and the results were evaluated using a ROC curve prediction model.The biological function, correlation between Signature genes, immune cell infiltration, and ceRNA network analyses were performed. Signature genes and ferroptosis phenotypes were verified through in vivo animal experiments and clinical samples. The expression levels of non-coding RNAs in samples from patients with OA were determined using qRT-PCR. ceRNA network analysis results were confirmed using dual-luciferase assays. Results: JUN, ATF3, and CDKN1A were identified as OA- and ferroptosis-associated signature genes. GSEA analysis demonstrated an enrichment of these genes in immune and inflammatory responses, and amino acid metabolism. The CIBERSORT algorithm showed a negative correlation between T cells and these signature genes in the cartilage, and a positive correlation in the synovium. Moreover, RP5-894D12.5 and FAM95B1 regulated the expression of JUN, ATF3, and CDKN1A by competitively binding to miR-1972, miR-665, and miR-181a-2-3p. In vivo, GPX4 was downregulated in both OA cartilage and synovium; however, GPX4 and GSH were downregulated, while ferrous ions were upregulated in patient OA cartilage and synovium samples, indicating that ferroptosis was involved in the pathogenesis of OA. Furthermore, JUN, ATF3, and CDKN1A expression was downregulated in both mouse and human OA synovial and cartilage tissues. qRT-PCR demonstrated that miR-1972, RP5-894D12.5, and FAM95B1 were differentially expressed in OA tissues. Targeted interactions between miR-1972 and JUN, and a ceRNA regulatory mechanism between RP5-894D12.5, miR-1972, and JUN were confirmed by dual-luciferase assays. Conclusion: This study identified JUN, ATF3, and CDKN1A as possible diagnostic biomarkers and therapeutic targets for joint synovitis and OA. Furthermore, our finding indicated that RP5-894D12.5/miR-1972/JUN was a potential ceRNA regulatory axis in OA, providing an insight into the connection between ferroptosis and OA.

The comparative analysis of Lonicerae Japonicae Flos and Lonicerae Flos: A systematical review.

ETHNOPHARMACOLOGICAL RELEVANCE: Lonicerae Japonicae Flos (LJF) and Lonicerae Flos (LF) were once used as the same herb in China, but they were distinguished by Chinese Pharmacopoeia in 2005 in terms of their medicinal history, plant morphology, medicinal properties and chemical constituents. However, their functions, flavor, and meridian tropism are the same according to the Chinese pharmacopoeia 2020 edition, making researchers and customers confused. AIM OF THE REVIEW: This review aimed to provide a comparative analysis of LJF and LF in order to provide a rational application in future research. MATERIALS AND METHODS: The information was gathered from China National Knowledge Infrastructure (CNKI), SciFinder, Google Scholar, PubMed, Web of Science, and Chinese Masters and Doctoral Dissertations (all chosen articles were reviewed attentively from 1980.1 to 2023.8). RESULTS: Till now, 507 chemical compounds have been isolated and identified in LJF, while 223 ones (79 overlapped compounds) are found in LF, including organic acids and derivatives, flavonoids, triterpenoids, iridoids, and essential oil components, etc. In addition, the pharmacological activities of LJF and LF, especially for their anti-influenza efficacy and mechanism, and their difference in terms of pharmacokinetic parameters, toxicology, and clinical applications were also summarized. CONCLUSION: The current work offers comparative information between LJF and LF in terms of botany, traditional uses, phytochemistry, ethnopharmacology, pharmacokinetics, toxicology, and pharmacology, especially their anti-influenza activities. Despite the same clinical applications and similar chemical components in LJF and LF, differentiated components were still existed, resulting in differentiated pharmacological activities and pharmacokinetics parameters. Moreover, the research about anti-influenza mechanism and functional substances of LJF and LF is dramatically limited, restricting their clinical applications. In addition, few studies have investigated the metabolism feature of LF in vivo, which is one of the important bases for revealing the pharmacological mechanism of LF. At the same time, the toxicity of LJF and LF is not fully studied, and the toxic compounds of LJF and LF need to be screened out in order to standardize the drug use and improve their rational applications.

Enhanced Anti/De-Icing Performance on Rough Surfaces Based on The Synergistic Effect of Fluorinated Resin and Embedded Graphene.

Icing negatively impacts various industrial sectors and daily life, often leading to severe safety problems and substantial economic losses. In this work, a fluorinated resin coating with embedded graphene nanoflakes is prepared using a spin-coating curing process. The results shows that the ice adhesion strength is reduced by ≈97.0% compared to the mirrored aluminum plate, and the icing time is delayed by a factor of 46.3 under simulated solar radiation power of 96 mW cm-2 (1 sun) at an ambient temperature of -15 °C. The superior anti/de-icing properties of the coating are mainly attributed to the synergistic effect of the fluorinated resin with a low surface energy, the rough structure of the sandblasted aluminum plate, which reduces the contact area, and the embedded graphene nanoflakes with a superior photothermal effect. Furthermore, the hydrogen bonding competition effect between the exposed-edge oxygen-containing functional groups of the embedded graphene nanoflakes and water molecules further improves the anti-icing properties. This work proposes a facile preparation method to prepare coatings with excellent anti/de-icing properties, offering significant potential for large-scale engineering applications.

Multitasking Pharmacophores Support Cabotegravir-Based Long-Acting HIV Pre-Exposure Prophylaxis (PrEP).

Cabotegravir is an integrase strand transfer inhibitor (INSTI) for HIV treatment and prevention. Cabotegravir-based long-acting pre-exposure prophylaxis (PrEP) presents an emerging paradigm for infectious disease control. In this scheme, a combination of a high efficacy and low solubility of anti-infection drugs permits the establishment of a pharmaceutical firewall in HIV-vulnerable groups over a long period. Although the structure-activity-relationship (SAR) of cabotegravir as an INSTI is known, the structural determinants of its low solubility have not been identified. In this work, we have integrated multiple experimental and computational methods, namely X-ray diffraction, solid-state NMR (SSNMR) spectroscopy, solution NMR spectroscopy, automated fragmentation (AF)-QM/MM and density functional theory (DFT) calculations, to address this question. The molecular organization of cabotegravir in crystal lattice has been determined. The combination of very-fast magic-angle-sample-spinning (VF MAS) SSNMR and solution NMR, as supported by AF-QM/MM and DFT calculations, permits the identification of structural factors that contribute to the low aqueous solubility of cabotegravir. Our study reveals the multitasking nature of pharmacophores in cabotegravir, which controls the drug solubility and, meanwhile, the biological activity. By unraveling these function-defining molecular features, our work could inspire further development of long-acting HIV PrEP drugs.

Exploring the co-operativity of secretory structures for defense and pollination in flowering plants.

MAIN CONCLUSION: In flowers multiple secretory systems cooperate to deliver specialized metabolites to support specific roles in defence and pollination. The collective roles of cell types, enzymes, and transporters are discussed. The interplay between reproductive strategies and defense mechanisms in flowering plants has long been recognized, with trade-offs between investment in defense and reproduction predicted. Glandular trichomes and secretory cavities or ducts, which are epidermal and internal structures, play a pivotal role in the secretion, accumulation, and transport of specialized secondary metabolites, and contribute significantly to defense and pollination. Recent investigations have revealed an intricate connection between these two structures, whereby specialized volatile and non-volatile metabolites are exchanged, collectively shaping their respective ecological functions. However, a comprehensive understanding of this profound integration remains largely elusive. In this review, we explore the secretory systems and associated secondary metabolism primarily in Asteraceous species to propose potential shared mechanisms facilitating the directional translocation of these metabolites to diverse destinations. We summarize recent advances in our understanding of the cooperativity between epidermal and internal secretory structures in the biosynthesis, secretion, accumulation, and emission of terpenes, providing specific well-documented examples from pyrethrum (Tanacetum cinerariifolium). Pyrethrum is renowned for its natural pyrethrin insecticides, which accumulate in the flower head, and more recently, for emitting an aphid alarm pheromone. These examples highlight the diverse specializations of secondary metabolism in pyrethrum and raise intriguing questions regarding the regulation of production and translocation of these compounds within and between its various epidermal and internal secretory systems, spanning multiple tissues, to serve distinct ecological purposes. By discussing the cooperative nature of secretory structures in flowering plants, this review sheds light on the intricate mechanisms underlying the ecological roles of terpenes in defense and pollination.

Effect of alfalfa supplementary change dietary non-fibrous carbohydrate (NFC) to neutral detergent fiber (NDF) ratio on rumen fermentation and microbial function in Gansu alpine fine wool sheep (Ovis aries).

Bodyweight loss and rumen microbial dysfunction of grazing sheep was a challenge for the sheep production industry during cold season, which were considered to correlated with under-roughage-feeding. Alfalfa is a good roughage supplementary for ruminants, which can improve grazing sheep bodyweight-loss and rumen microbial dysfunction during grass-withering period. This study evaluated the effects of alfalfa hay supplementary change dietary non-fibrous carbohydrate/neutral detergent fiber (NFC/NDF) ratios on rumen fermentation and microbial function of Gansu alpine fine wool sheep during extreme cold season. 120 ewes (3-4 yrs) with an average body weight of 28.71 ± 1.22 kg were allocated randomly into three treatments, and fed NFC/NDF of 1.92 (H group), 1.11 (M group), and 0.68 (L group), respectively. This study was conducted for 107 d, including 7 d of adaption to the diets. The rumen fermentation parameters and microbial characteristics were measured after the end of feeding trials. The results showed that the concentrations of sheep body weight, nitrogen components (Total-N, Soluble protein-N and Ammonia-N), blood biochemical indices (LDH, BUN and CHO) and ruminal volatile fatty acids (TVFA and propionate) significantly increased with an increase in the proportion of NFC/NDF ratios (p < .05), and the acetate and acetate/propionat ratio presented a contrary decreasing trend (p < .05). A total of 1018 OTUs were obtained with 97% consistency. Ruminococcus, Ruminococcaceae and Prevotella were observed as the predominant phyla in ruminal fluid microbiota. Higher NFC/NDF ratios with Alfalfa supplementary increased the richness and diversity of ruminal fluid microbiota, and decreased ruminal fluid microbiota beta-diversity. Using clusters of orthologous groups (COG), the ruminal fluid microbiota of alfalfa supplementary feeding showed low immune pathway and high carbohydrate metabolism pathway. In summary, the study suggested that there was an increasing tendency in dietary NFC/NDF ratio of 1.92 in body weight, ruminal fermentation, microbial community composition and fermentation characteristics through developing alfalfa supplementary system.