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Abstract Ionizable lipid nanoparticles (LNPs) are seeing widespread use in mRNA delivery, notably in SARS-CoV-2 mRNA vaccines. However, the expansion of mRNA therapies beyond COVID-19 is impeded by the absence of LNPs tailored for diverse cell types. In this study, we present the AI-Guided Ionizable Lipid Engineering (AGILE) platform, a synergistic combination of deep learning and combinatorial chemistry. AGILE streamlines ionizable lipid development with efficient library design, in silico lipid screening via deep neural networks, and adaptability to diverse cell lines. Using AGILE, we rapidly design, synthesize, and evaluate ionizable lipids for mRNA delivery, selecting from a vast library. Intriguingly, AGILE reveals cell-specific preferences for ionizable lipids, indicating tailoring for optimal delivery to varying cell types. These highlight AGILE’s potential in expediting the development of customized LNPs, addressing the complex needs of mRNA delivery in clinical practice, thereby broadening the scope and efficacy of mRNA therapies.

In order to find culturable bacteria resources and antibacterial activity strain in the rhizosphere soil of mangrove plants from the Maowei Sea, the rhizosphere soil of five mangrove plants(Rhizophora stylosa, Talipariti tiliaceum, Sonneratia apetala, Aegiceras corniculatum, and Pluchea indica) was cultured by enrichment media and then isolated the culturable bacteria. The culturable bacteria were purified by six different isolation media. The diversity of culturable bacteria was analyzed by the 16S rRNA gene sequence information. Antimicrobial activities (Staphylococcus epidermidis, methicillin-resistant S. aureus, and Pseudomonas aeruginosa) of the culturable bacteria were analyzed by disk diffusion method. The results were as follows: (1) A total of 120 strains were isolated from seven rhizosphere soil samples of mangrove plants which could be classified into 35 families and 47 genera, among which five potential new species were obtained. The dominant genus was Streptomyces (14.2%). (2) It was found that the crude extracts of nine strains had antibacterial activity against at least one pathogen. The results indicate that there are abundant culturable bacteria and potential new antibiotics resources in the mangrove rhizosphere soils from the Maowei Sea.

Chitosan is a fining agent used in winemaking, although its use in juice and wine beyond fining has been limited until now. Therefore, this study's first aim was to determine if chitosan derived from Agaricus bisporus (button mushrooms) could reduce caffeic and caftaric acid concentrations in Pinot noir grape juice (Study A). The second aim was to determine if chitosan, when added to base wine, could influence the synthesis of furan-derived compounds during storage (Study B). In Study A, Pinot noir grape juice was stored at 10 °C for 18 hours after the following treatments: control (no addition), bentonite/activated charcoal (BAC), low molecular weight (

Traditional Method sparkling wine production requires a sugar addition to the base wine to initiate the second alcoholic fermentation in bottles. This study aimed to identify differences in “fruity” volatile aroma compounds (VOCs) in Traditional Method sparkling wines produced from the addition of either cane sugar or beet sugar to Auxerrois base wines. Wines underwent a second fermentation in bottles inoculated with IOC 18-2007 yeast and fermented at 15 °C. Standard chemical analysis was carried out on base wines and sparkling wines. The concentrations of fourteen “fruity” volatile aroma compounds representing five classes of compounds were analysed by Headspace-Solid-Phase Micro-Extraction-Gas Chromatography-Mass Spectrometry (HS-SPME-GC-MS). Cane and beet sugars were analysed in de-aromatised wine and distilled water to establish the concentrations of VOCs present in the sugar products prior to addition to wine. Wines were analysed on the day of inoculation and bottling and again after the second fermentation. Beet sugar significantly (Pt

Abstract Background LncRNA can regulate gene at various levels such as apparent genetics, alternative splicing, and regulation of mRNA degradation. However, the molecular mechanism of LncRNA in cholangiocarcinoma is still unclear. This deserves further exploration. Methods We investigated the expression of AGAP2-AS1 in 32 CCA tissues and two CCA cell lines. We found a LncRNA AGAP2-AS1 which induced by SP1 has not been reported in CCA, and Knockdown and overexpression were used to investigate the biological role of AGAP2-AS1 in vitro. CHIP and RIP were performed to verify the putative targets of AGAP2-AS1. Results AGAP2-AS1 was significantly upregulated in CCA tumor tissues. SP1 induced AGAP2-AS1 plays an important role in tumorigenesis. AGAP2-AS1 knockdown significantly inhibited proliferation and caused apoptosis in CCA cells. In addition, we demonstrated that AGAP2-AS1 promotes the proliferation of CCA. Conclusions We conclude that the long non-coding RNA AGAP2-AS1 plays a role in promoting the proliferation of cholangiocarcinoma.

The aim of this study was to determine the influence of caffeic and caftaric acid, fructose, and storage temperature on the formation of furan-derived compounds during storage of base wines. Base wines produced from Chardonnay grapes were stored at 15 and 30 °C for 90 days with additions of fructose, caffeic acid, and caftaric acid independently or in combinations. Wines were analyzed following 90 days of storage for: total hydroxycinnamic acids, degree of browning, caffeic acid and caftaric acid concentrations, and nine furan-derived compounds. Caffeic and caftaric acid additions increased homofuraneol concentration by 31% and 39%, respectively, at 15 °C (p < 0.05). Only the addition of caffeic acid increased furfural by 15% at 15 °C (p < 0.05). Results demonstrate that some furan derivatives over 90 days at 15 °C increased slightly with 5 mg/L additions of caffeic and caftaric acid. This is the first time the influence of hydroxycinnamic acids on furan-derived compounds has been reported during short-term aging of base wine at cellar temperature.

Background: Long non-coding RNAs modulate tumor occurrence through different molecular mechanisms. It had been reported that HNF1A-AS1 (HNF1A Antisense RNA 1) was differently expressed in multiple tumors. The role of HNF1A-AS1 in colorectal cancer was less analyzed, and the mechanism of regulating the cell cycle has not been completely elucidated. Methods: Differentially expressed lncRNAs were screened out from the TCGA database. HNF1A-AS1 was examined in CRC clinical samples and cell lines by RT-qPCR. CCK8 assay, colony formation assay, flow cytometry, transwell assays, tube forming assay and vivo experiments were performed to study the function of HNF1A-AS1 in CRC tumor progression. Bioinformatic analysis, luciferase report assay, RNA pull-down and RIP assays were carried out to explore proteins binding HNF1A-AS1 and the potential downstream targets. Results: Our results showed that HNF1A-AS1 was upregulated in CRC and associated with unfavorable prognosis. HNF1A-AS1 promoted proliferation, migration and angiogenesis, accelerated cell cycle and reduced cell apoptosis in CRC. Bioinformatics prediction and further experiments proved that HNF1A-AS1 could promote CCND1 expression by suppressing PDCD4 or competitively sponging miR-93-5p. Meanwhile, METTL3 mediated HNF1A-AS1 m6A modification and affected its RNA stability. HNF1A-AS1/IGF2BP2/CCND1 may act as a complex to regulate the stability of CCND1. Conclusion: In summary, our result reveals the novel mechanism in which m6A-mediated HNF1A-AS1/IGF2BP2/CCND1 axis promotes CRC cell cycle progression, along with competitively sponging miR-93-5p to upregulate CCND1, demonstrating its significant role in cell cycle regulation and suggesting that HNF1A-AS1 may act as a potential prognostic marker of colorectal cancer in the future.

Objective To test the antifibrotic effect of dermatan sulphate in a bleomycin-induced mouse model of pulmonary fibrosis. Methods C57 mice were randomly divided into four experimental groups: saline-treated control group, bleomycin-induced fibrosis group, prednisolone acetate group and dermatan sulphate group. Lungs were assessed using the lung index, and the extent of interstitial fibrosis was graded using histopathological observation of haematoxylin & eosin-stained lung tissue. Lung tissue hydroxyproline levels and blood fibrinogen levels were measured using a hydroxyproline colorimetric kit and the Clauss fibrinogen assay, respectively. Tissue-type plasminogen activator (tPA) was measured using a chromogenic tPA assay kit. Results Lung index values were significantly lower in the dermatan sulphate group versus the fibrosis group. Histopathological analyses revealed that dermatan sulphate treatment ameliorated the increased inflammatory cell infiltration, and attenuated the reduction in interstitial thickening, associated with bleomycin-induced fibrosis. Hydroxyproline and fibrinogen levels were decreased in the dermatan sulphate group versus the fibrosis model group. Dermatan sulphate treatment was associated with increased tPA levels versus controls and the fibrosis group. Conclusions Damage associated with bleomycin-induced pulmonary fibrosis was alleviated by dermatan sulphate.

The purpose of this study was to investigate the effect of wine style and cane sugar addition in the liqueur d’expedition (dosage) solution on volatile aroma compounds (VOCs) in traditional method sparkling wine. There were 24 bottles of each treatment produced. Treatments were sparkling wine zero dosage (ZD); NV sparkling wine + sugar (BS); unoaked still Chardonnay wine + sugar (UC); Pinot noir 2009 sparkling wine + sugar (PN); Niagara produced Brandy + sugar (B) and Icewine (IW). The control treatment in the sensory analysis was an oaked still Chardonnay wine + sugar (OC) because the zero-dosage wine was not suitable for a difference test that compared wines with sugar to one without. Standard wine chemical parameters were analysed before disgorging and after liqueur d’expedition was added and included; pH, titratable acidity (TA g/L), alcohol (v/v %), residual sugar (RS g/L), free and total SO2 and total phenolics (A.U.). Volatile aroma compounds (VOCs) analysed by Headspace Solid- Phase Micro-Extraction Gas Chromatography-Mass Spectrometry (HS-SPME-GC-MS) included two alcohols, and six ethyl esters. ZD wines had the highest foam height and highest dissolved oxygen level. Sugar affected VOC concentrations in all treatments at five weeks post-disgorging, but by 15 weeks after liqueur d’expedition addition, the wine with added sugar had similar VOC concentrations to the ZD wines. The type of wines used in the dosage solutions had more influence on VOC concentrations than sugar addition.

Ionizable lipid nanoparticles (LNPs) pivotal to the success of COVID-19 mRNA (messenger RNA) vaccines hold substantial promise for expanding the landscape of mRNA-based therapies. Nevertheless, the risk of mRNA delivery to off-target tissues highlights the necessity for LNPs with enhanced tissue selectivity. The intricate nature of biological systems and inadequate knowledge of lipid structure-activity relationships emphasize the significance of high-throughput methods to produce chemically diverse lipid libraries for mRNA delivery screening. Here, we introduce a streamlined approach for the rapid design and synthesis of combinatorial libraries of biodegradable ionizable lipids. This led to the identification of iso-A11B5C1, an ionizable lipid uniquely apt for muscle-specific mRNA delivery. It manifested high transfection efficiencies in muscle tissues, while significantly diminishing off-targeting in organs like the liver and spleen. Moreover, iso-A11B5C1 also exhibited reduced mRNA transfection potency in lymph nodes and antigen-presenting cells, prompting investigation into the influence of direct immune cell transfection via LNPs on mRNA vaccine effectiveness. In comparison with SM-102, while iso-A11B5C1' s limited immune transfection attenuated its ability to elicit humoral immunity, it remained highly effective in triggering cellular immune responses after intramuscular administration, which is further corroborated by its strong therapeutic performance as cancer vaccine in a melanoma model. Collectively, our study not only enriches the high-throughput toolkit for generating tissue-specific ionizable lipids but also encourages a reassessment of prevailing paradigms in mRNA vaccine design. This study encourages rethinking of mRNA vaccine design principles, suggesting that achieving high immune cell transfection might not be the sole criterion for developing effective mRNA vaccines. [ABSTRACT FROM AUTHOR]

Misregulation of vascular endothelial growth factor A (VEGF-A) has been implicated in numerous types of ovarian disease, such as polycystic ovarian syndrome, ovarian hyperstimulation syndrome, endometriosis and ovarian cancer. VEGF regulates blood vessel permeability and angiogenesis. In our previous study, VEGF-regulated gene expression was profiled in the uterus of a transgenic mouse model with repressed VEGF expression, which indicated that VEGF is an important regulator in controlling gene expression in the uterus. The anti-Müllerian hormone (AMH) is expressed by ovarian granulosa cells (GCs) and acts through its type 2 receptor, AMH receptor 2 (AMHR2). Serum AMH levels are used to predict ovarian reserves and the small antral follicles contribute markedly to the serum AMH level. AMH recruits primordial follicles and inhibits excessive follicular development by follicular stimulating hormone (FSH). However, AMH may be influenced by suppression of gonadotrophin secretion and VEGF inhibition. In the current study, human primary ovarian GCs were isolated from ovarian follicle fluid of in vitro fertilization/intracytoplasmic sperm injection cycles (IVF/ICSI). It was identified that the FSH receptor was consistently expressed in the isolated cells. VEGF-A treatment stimulated AMHR2 overexpression at the gene and protein levels. In addition, VEGF induced AMHR2 expression on the surface of the isolated GCs from mature follicles. The VEGF treatment was also performed in an ovarian granulosa-like cell line, KGN. AMH and AMHR2 are co-expressed in normal GCs; however, as a result of VEGF misregulation, AMHR2 overexpression increases AMH binding, which may attenuate follicular or oocyte maturation. However, the associated function and underlying mechanism requires further investigation. [ABSTRACT FROM AUTHOR]

A two-step synthesis of N-heterocyclic carbene (NHC) precatalysts by diastereoselective or enantioselective lithiation of pyrrolo[1,2-c]imidazol-3-ones followed by POCl3-induced salt formation is described. The resulting 3-chloro-pyrroloimidazol(in)ium salts may be coordinated to palladium(II) upon NHC generation with t-BuLi at low temperature. The method may facilitate exploitation of these compounds as chiral organocatalysts or ligands in metal catalysis. [ABSTRACT FROM AUTHOR]