Dendritic-cell-targeting virus-like particles as potent mRNA vaccine carriers.

Messenger RNA vaccines lack specificity for dendritic cells (DCs)-the most effective cells at antigen presentation. Here we report the design and performance of a DC-targeting virus-like particle pseudotyped with an engineered Sindbis-virus glycoprotein that recognizes a surface protein on DCs, and packaging mRNA encoding for the Spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or for the glycoproteins B and D of herpes simplex virus 1. Injection of the DC-targeting SARS-CoV-2 mRNA vaccine in the footpad of mice led to substantially higher and durable antigen-specific immunoglobulin-G titres and cellular immune responses than untargeted virus-like particles and lipid-nanoparticle formulations. The vaccines also protected the mice from infection with SARS-CoV-2 or with herpes simplex virus 1. Virus-like particles with preferential uptake by DCs may facilitate the development of potent prophylactic and therapeutic vaccines.

Unraveling the Dynamic Molecular Motions of a Twin-Cavity Cage with Slow Configurational but Rapid Conformational Interconversions.

Featuring diverse structural motions/changes, dynamic molecular systems hold promise for executing complex tasks. However, their structural complexity presents formidable challenge in elucidating their kinetics, especially when multiple structural motions are intercorrelated. We herein introduce a twin-cavity cage that features interconvertible C3- and C1-configurations, each configuration exhibiting interchangeable P- and M-conformations. This molecule is therefore composed of four interconnected chiral species (P)-C3, (M)-C3, (P)-C1, (M)-C1. We showcase an effective methodology to decouple these sophisticated structural changes into two kinetically distinct pathways. Utilizing time-dependent 1H NMR spectroscopy at various temperatures, which disregards the transition between mirror-image conformations, we first determine the rate constant (kc) for C3- to C1-configuration interconversion; while time-dependent circular dichroism spectroscopy at different temperatures quantifies the observed rate constant (kobs) of ensemble of all structural changes. As kobs >> kc, it allows us to decouple the overall molecular motions into a slow configurational transformation and rapid conformational interconversions, the latter further dissected into two independent conformational interchanges, namely (P)-C3 ⇄ (M)-C3 and (P)-C1 ⇄ (M)-C1. This work therefore sheds light on comprehensive kinetic study of complex molecular dynamics, offering valuable insights for the rational design of smart dynamic materials for applications of sensing, separation, catalysis, molecular machinery, etc.

New Pyranone Derivatives and Sesquiterpenoid Isolated from the Endophytic Fungus Xylaria sp. Z184.

The fungus Xylaria sp. Z184, harvested from the leaves of Fallopia convolvulus (L.) Á. Löve, has been isolated for the first time. Chemical investigation on the methanol extract of the culture broth of the titles strain led to the discovery of three new pyranone derivatives, called fallopiaxylaresters A-C (1-3), and a new bisabolane-type sesquiterpenoid, named fallopiaxylarol A (4), along with the first complete set of spectroscopic data for the previously reported pestalotiopyrone M (5). Known pyranone derivatives (6-11), sesquiterpenoids (12-14), isocoumarin derivatives (15-17), and an aromatic allenic ether (18) were also co-isolated in this study. All new structures were elucidated by the interpretation of HRESIMS, 1D, 2D NMR spectroscopy, and quantum chemical computation approach. The in vitro antimicrobial, anti-inflammatory, and α-glucosidase-inhibitory activities of the selected compounds and the crude extract were evaluated. The extract was shown to inhibit nitric oxide (NO) production induced by lipopolysaccharide (LPS) in murine RAW264.7 macrophage cells, with an inhibition rate of 77.28 ± 0.82% at a concentration of 50 µg/mL. The compounds 5, 7, and 8 displayed weak antibacterial activity against Staphylococcus areus subsp. aureus at a concentration of 100 µM.

Effects of benzophenone-3 and its metabolites on the marine diatom Chaetoceros neogracilis: Underlying mechanisms and environmental implications.

The wide application of benzophenones (BPs), such as benzophenone-3 (BP3), as an ingredient in sunscreens, cosmetics, coatings, and plastics, has led to their global contamination in aquatic environments. Using the marine diatom Chaetoceros neogracilis as a model, this study assessed the toxic effects and mechanisms of BP3 and its two major metabolites (BP8 and BP1). The results showed that BP3 exhibited higher toxicity on C. neogracilis than BP8 and BP1, with their 72-h median effective concentrations being 0.4, 0.8 and 4 mg/L, respectively. Photosynthesis efficiencies were significantly reduced after exposure to environmentally relevant concentrations of the three benzophenones, while cell viability, membrane integrity, membrane potential, and metabolic activities could be further impaired at their higher concentrations. Comparative transcriptomic analysis, followed by gene ontology and KEGG pathway enrichment analyses unraveled that all the three tested benzophenones disrupted photosynthesis and nitrogen metabolism of the diatom through alteration of similar pathways. The toxic effect of BP3 was also attributable to its unique inhibitory effects on eukaryotic ribosome biosynthesis and DNA replication. Taken together, our findings underscore that benzophenones may pose a significant threat to photosynthesis, oxygen production, primary productivity, carbon fixation, and the nitrogen cycle of diatom in coastal waters worldwide.

Enhancing Visible-Light Absorption of 2D Carbon Nitride by Constructing 2D/2D van der Waals Heterojunctions of Carbon Nitride/Nitrogen-Superdoped Graphene.

Carbon nitride sheets (CNs) down to the two-dimensional (2D) limit have been widely used in photoelectric conversion due to their inherent band gap and extremely short charge-carrier diffusion distance. However, the utilization of visible light remains low due to the rapid recombination of photogenerated electron-hole pairs and enlarged band gap. Here, atomically thin 2D/2D van der Waals heterojunctions (vdWHs) of N-superdoped graphene (NG) and CNs (CNs/NG) are fabricated via a facile electrostatic self-assembly method. Our results revealed that the vdWHs can increase the visible-light absorption of CNs by extending the absorption edge from 455 to up to 490 nm. The recombination of photogenerated electron-hole pairs is inhibited because superdoped N in CNs/NG facilitates the transmission of photogenerated carriers in the melon chain. This study opens a new avenue for narrowing the band gap and promoting photoexcited carrier separation in carbon-nitride-based materials.

Intensified conditioning regimens with total marrow irradiation/etoposide/cyclophosphamide and busulfan/etoposide/cyclophosphamide overcome the impact of pre-transplant minimal residual disease on outcomes in high-risk acute lymphoblastic leukemia patients in complete remission.

PURPOSE: Among high-risk acute lymphoblastic leukemia (ALL) patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT), those with positive minimal residual disease (MRD) are susceptible to poor outcomes. Therefore, it is necessary to determine the most suitable preparatory regimen for these patients. METHODS: Data were analyzed from 141 patients who received allo-HSCT and were diagnosed with high-risk ALL. These patients underwent intensified conditioning regimens, including either total marrow and lymphoid irradiation (TMLI)-etoposide (VP16)-cyclophosphamide (CY) or busulfan (BU)-VP16-CY between October 2016 and November 2022. A total of 141 individuals were in complete remission (CR) before transplantation and, among all patients, 90 individuals exhibited a negative MRD status and 51 patients had a positive MRD status. RESULTS: In patients who tested negative for MRD, the incidence of relapse within a 2-year timeframe was 25.0% (24.8%-25.5%), compared with 32.2% (31.2%-33.2%) in MRD-positive patients; however, this difference was not statistically significant. There were no significant differences in the 2-year disease-free survival (DFS) and 2-year overall survival (OS) rates between the MRD-negative and MRD-positive groups (DFS: 67.2% (57.9%-78.1%) vs. 55.5% (42.6%-72.3%); OS: 69.0% (61.9%-88.2%) vs. 66.7% (53.9%-82.5%)). Furthermore, no notable variations were observed in the occurrence of transplant-related mortality (TRM) and graft-versus-host disease (GVHD) across the two groups. CONCLUSION: This study reveals the benefits of TMLI-VP16-CY and BU-VP16-CY conditioning regimens in high-risk ALL patients with CR and MRD-positive status. A large-scale prospective clinical trial is warranted in the future.

Randomized Control Trial of a School-Based Curriculum that Teaches About Multiple Forms of Abuse.

Most school-based prevention curricula for young children fail to address multiple types of abuse and limit instruction to a single day, despite evidence that polyvictimization is common and children learn better when allowed to practice material repeatedly. This study utilized a cluster randomized control trial design to evaluate a multi-abuse prevention program, the Monique Burr Foundation for Children (MBF) Child Safety Matters®, based on varying lesson structure. Participants included nine Florida schools consisting of 843 children in grades K-2. Schools were randomized within cluster to implement in two lessons, four lessons, or after study data collection (i.e., control group). Lessons averaged 34 minutes (SD = 8.8 minutes) in length for 2-lesson group and 23.6 minutes (SD = 6.9 minutes) for the 4-lesson condition. Knowledge was assessed before implementation and on average 11 weeks after implementation. There were no statistical differences between clusters. Controlling for pre-test scores, schools in the four-lesson group scored highest on a measure of knowledge of potentially risky and unsafe situations (M = 69.68, SE = .80) on post-test, followed by schools in the two-lesson group (M = 67.31, SE = .77), followed by schools in the control group (M = 62.92, SE = .76). Results support use of more frequent, shorter lessons for prevention programs and the promise of addressing multiple forms of child victimization.

Exploring the efficacious constituents and underlying mechanisms of sini decoction for sepsis treatment through network pharmacology and multi-omics.

BACKGROUND: Traditional Chinese medicine prescription sini decoction (SND) can alleviate inflammation, improve microcirculation, and modulate immune status in sepsis patients. However, its underlying mechanisms remain unclear, and therapeutic effects may vary among individuals. PURPOSE: Through a comprehensive and systematic network pharmacology analysis, the purpose of this study is to investigate the therapeutic mechanisms of SND in treating sepsis. METHODS: An analysis of WGCNA identified CX3CR1 as a key gene influencing sepsis prognosis. A drug-active component-target network for SND was created using the traditional Chinese medicine systems pharmacology (TCMSP) database and Cytoscape software. Shared targets between SND and CX3CR1 high-expression gene modules were found through the GEO database. Gene module functionality was analyzed using GO, KEGG, GSEA, and GSVA. Unsupervised clustering of sepsis patients was performed based on the ferroptosis gene set, and immune cell interactions and mechanisms were explored using CIBERSORT, single-cell sequencing, and intercellular communication analysis. RESULTS: This study demonstrates that high expression of CX3CR1 improves survival rates in sepsis patients and is associated with immune cell signaling pathways. SND contains 116 active components involved in oxidative stress and lipid metabolism pathways. HMOX1, a co-expressed gene in SND and CX3CR1 high-expression gene module, plays a crucial role in sepsis survival. Unsupervised clustering analysis classified sepsis patients into three clusters based on the ferroptosis gene set, revealing differences in immune cell expression and involvement in heme metabolism pathways. Notably, intercellular interactions among immune cells primarily occur through paracrine and autocrine mechanisms in MIF, GALECTIN, and IL16 signaling pathways, modulating the immune-inflammatory microenvironment in sepsis. CONCLUSIONS: This study identifies CX3CR1 as a crucial molecule impacting sepsis prognosis through WGCNA analysis. It reveals that SND's active component, quercetin and kaempferol, target HMOX1 via related pathways to regulate heme metabolism, reduce inflammation, inhibit ferroptosis, and improve immune function, ultimately improving sepsis prognosis. These findings offer a solid pharmacological foundation and potential therapeutic targets for SND in treating sepsis.

Association between gut microbiota and its functional metabolites with prenatal depression in women.

Background: The gut microbiota may affect mood through the microbiota-gut-brain axis. The purpose of this study was to examine the effect of the gut microbiota and its metabolites, such as short-chain fatty acids (SCFAs), on prenatal depression and to determine the role of 5-hydroxytryptamine (5-HT) on prenatal depression in association with the gut microbiota and its metabolites (i.e. SCFAs). Methods: Eighty-six pregnant women in the third trimester were recruited. Prenatal depression was determined by a score of 10 via the Edinburgh Postpartum Depression Scale. Demographic data, stool, and blood samples were collected. The gut microbiota and its metabolites SCFAs were determined by 16S rRNA gene sequencing and liquid chromatography-mass spectrometry analysis. Plasma 5-HT was determined by gas chromatography-mass spectrometry analysis. Results: After controlling relevant covariates, our results found the higher the abundance of Candidatus_Soleaferrea, the lower the risk of prenatal depression; the higher the concentration of propanoic acid, the higher risk of prenatal depression. Our results also found the lower the plasma 5-HT, the higher the risk of prenatal depression, and 5-HT was related to unclassified_c_Clostridia and NK4A214_group. However, results of this study did not support the moderating effect of plasma 5-HT on the association of Candidatus_Soleaferrea or propionic acid with prenatal depression. Conclusions: Results of this study supported that changes in certain gut microbiota, SCFAs, and plasma 5-HT during pregnancy were associated with prenatal depression. This finding provides new ideas for interventions based on diet or probiotics to regulate mood during pregnancy.

Zero-derivation in Korean: the effect of covert structure in real-time processing.

Korean words like balgda 'bright/become bright' and gilda 'long/become long' are categorially ambiguous; they can appear as both adjectives and verbs. Some suggest that these words are listed under separate lexical entries, while others propose that they share one single lexical entry, and that the verb form is morphologically derived from the base adjective through a process called zero derivation. This study presents the results of a real-time experiment that investigates whether these words involve zero derivation and if so, how zero derivation may affect the real-time processing of these words. Our findings suggest that the reader recognizes the base adjective and obtains the derived-verb form by virtue of adding a covert category-changing morpheme in real-time sentence processing. This study provides promising evidence of the zero derivation of Korean categorially ambiguous adjectives and verbs, as well as crosslinguistic evidence of the role of covert structure in lexical access.

Self-stigmatization of high-school students seeking professional psychological help: the chain-mediating effect of perceived social support and optimism.

Background: Research has shown that stigmatization of professional psychological help-seeking is an important factor influencing attitudes toward seeking professional psychological help (ATSPPH). However, how perceived social support (PSS) and optimism have a mediating role is not clear. Objective: Examine the associations between ATSPPH, self-stigmatization of seeking help, PSS, and optimism in a cohort of Chinese high-school students (HSSs). Methods: An offline survey was conducted in three high schools in Chongqing (China) from 20 February to 20 May 2023. Participants were HSSs recruited through their teachers. A total of 2,159 HSSs completed a survey on demographic information as well as the Self-Stigmatization of Seeking Help (SSOSH) score, ATSPPH, Perceived Social Support Scale (PASS), and Life Orientation Test (LOT). Mediation analyses were conducted using the "Process" macro in SPSS 26.0 to estimate the direct and indirect effects of self-stigmatization of seeking psychological help on ATSPPH. Results: Self-stigmatization of seeking psychological help was significantly and negatively related to ATSPPH among HSSs. Self-stigmatization of psychological help-seeking influenced ATSPPH through three pathways: (a) separate mediating effect of PSS (effect = -0.029); (b) separate mediating effect of optimism (effect = -0.069); (c) chain-mediating effect of PSS and optimism (effect = -0.017). These data suggested that self-stigmatization of psychological help-seeking could influence ATSPPH directly and indirectly through PSS and optimism. Conclusion: PSS and optimism mediated the relationship between self-stigmatization of seeking help and ATSPPH. Improving the ability of HSSs to perceive social support and cultivating optimism could help improve the self-stigmatization of help-seeking and promote a positive attitude toward professional help-seeking.

Effects of granular feed on reproductive metabolism of breeding pigeons, intestinal development and microbiota of squab pigeons-A double-edged sword.

Pigeons like to eat raw grains, but meat pigeon enterprises often use compound feeds instead of raw grains to feed breeding pigeons to increase economic efficiency, which may change the pigeon's dietary behavior, and consequently lead to health and welfare problems. The purpose of this study was to investigate the effect of granular feeds on the health of high-yielding breeding pigeons and squabs in lactation. The results showed that, compared with raw grain group, the provision of granular feed resulted in lower total feed intake without affecting the weight of lactating breeding pigeons. Meanwhile, reproductive metabolism was improved and no oxidative stress was observed, which indicated that granular feeds had a positive effect on breeding pigeon's health. However, granular feed adversely affected jejunum development in squabs, compare wtih raw grain group, the growth rate of squab was reduced. Sequencing of the 16 s rRNA gene revealed that granular feed induced intestinal microbiota dysbiosis in the squabs. The use of granular feed reduced the relative abundance of gut microorganisms in functional categories related to lipid and energy metabolism, resulting in a decrease in the relative abundance of beneficial bacteria such as Bifidobacterium, Ligilactobacillus, Atopobium, and an increase in that of inflammation-related Limosilactobacillus, which likely inhibited squab intestinal development and growth. Although the use of granular feed can improve breeder metabolism, it affect the composition of the microbial community and gut development of squabs. Therefore, the use of granular feed in production should be more careful to avoid causing growth obstruction of squab.

Pgam5-mediated PHB2 dephosphorylation contributes to endotoxemia-induced myocardial dysfunction by inhibiting mitophagy and the mitochondrial unfolded protein response.

Numerous mitochondrial abnormalities are reported to result from excessive inflammation during endotoxemia. Prohibitin 2 (PHB2) and phosphoglycerate mutase 5 (Pgam5) have been associated with altered mitochondrial homeostasis in several cardiovascular diseases; however, their role in endotoxemia-related myocardial dysfunction has not been explored. Our experiments were aimed to evaluate the potential contribution of Pgam5 and PHB2 to endotoxemia-induced mitochondrial dysfunction in cardiomyocytes, with a focus on two endogenous protective programs that sustain mitochondrial integrity, namely mitophagy and the mitochondrial unfolded protein response (UPRmt). We found that PHB2 transgenic mice are resistant to endotoxemia-mediated myocardial depression and mitochondrial damage. Our assays indicated that PHB2 overexpression activates mitophagy and the UPRmt, which maintains mitochondrial metabolism, prevents oxidative stress injury, and enhances cardiomyocyte viability. Molecular analyses further showed that Pgam5 binds to and dephosphorylates PHB2, resulting in cytosolic translocation of mitochondrial PHB2. Silencing of Pgam5 or transfection of a phosphorylated PHB2 mutant in mouse HL-1 cardiomyocytes prevented the loss of mitochondrially-localized PHB2 and activated mitophagy and UPRmt in the presence of LPS. Notably, cardiomyocyte-specific deletion of Pgam5 in vivo attenuated LPS-mediated myocardial dysfunction and preserved cardiomyocyte viability. These findings suggest that Pgam5/PHB2 signaling and mitophagy/UPRmt are potential targets for the treatment of endotoxemia-related cardiac dysfunction.

Aberrant reward dynamics in depression with anticipatory anhedonia.

OBJECTIVE: Previous studies have shown that anticipatory anhedonia is linked to abnormal reward processing. The present study aimed to explore the underlying neural mechanism of the influence of anticipatory anhedonia symptoms on reward processing. METHODS: Electrophysiological activities in the anticipatory and consummatory phase were recorded during the Monetary Incentive Delay (MID) task in 24 depressed high anticipatory anhedonia (HAA) patients, 25 depressed low anticipatory anhedonia (LAA) patients, and 29 healthy controls (HC). RESULTS: We suggested a significant condition × group interaction effect on feedback-related negativity (FRN) amplitudes during the consummatory phase, a smaller FRN in reward cue trails compared with neutral cue trail was revealed in the HC and LAA group, but such reward-related effect was not found in the HAA group. In addition, we found significant correlations between FRN, fb-P3 and cue-N1, cue-N2 in the HC group, besides, significant correlations between FRN, fb-P3 and cue-P2 was also revealed in the HC and LAA group. However, no significant correlation was found in HAA patients. CONCLUSIONS: Our results suggest that the link between the anticipatory and consummatory phase was interrupted in depressed HAA patients, which may be driven by the aberrant consummatory reward processing. SIGNIFICANCE: The current study is the first one to demonstrate the influence of anticipatory anhedonia symptom on the association between anticipatory and consummatory phase of reward process.

Visible Light-Guided Gene Delivery with Nonviral Supramolecular Block Copolymer Vectors.

To achieve efficient gene delivery in vitro or in vivo, nonviral vectors should have excellent biostability across cellular and tissue barriers and also smart stimuli responsiveness toward controlled release of therapeutic genes into the cell nucleus. However, it remains a key challenge to effectively combine the biostability of covalent polymers with the stimuli responsiveness of noncovalent polymers into one nonviral vehicle. In this work, we report the construction of a kind of cationic supramolecular block copolymers (SBCs) through noncovalent polymerization of ß-cyclodextrin/azobenzene-terminated pentaethylenehexamine (DMA-Azo-PEHA-ß-CD) in aqueous media using ß-CD-monosubstituted poly(ethylene glycol) (PEG-ß-CD) as a supramolecular initiator. The resultant SBC exhibits superior biostability, biocompatibility, and light/pH dual-responsive characteristics, and it also demonstrates efficient plasmid DNA condensation capacity and the ability to rapidly release plasmid DNA into cells driven by visible light (450 nm). Eventually, this SBC-based delivery system demonstrates visible light-induced enhancement of gene delivery in both COS-7 and HeLa cells. We anticipate that this work provides a facile and robust strategy to enhance gene delivery in vitro or in vivo via visible light-guided manipulation of genes, further achieving safe, highly efficient, targeting gene therapy for cancer.

Drug release and solubility properties of two zeolitic metal-organic frameworks influenced by their hydrophobicity/hydrophilicity.

Metal-organic frameworks (MOFs) have shown significant potential for drug delivery applications. However, there remains a scarcity of comprehensive research addressing the influence of surface properties of MOFs on drug release kinetics and drug solubility. This study focuses on examining the influence of MOFs hydrophilicity and hydrophobicity on the controlled release and solubility of drugs. To achieve this, we prepared drug-loaded nanoparticles through in situ synthesis and created a drug-MOF co-amorphous system using the ball milling technique. Under neutral conditions, the hydrophilic MOF-based drug delivery system demonstrated a comparatively slower drug release profile than its hydrophobic counterpart. This observation suggests that the hydrophilic system holds promise in mitigating drug side effects by enabling improved control over drug release. The implementation of hydrophobic MOFs in co-amorphous systems yields a more pronounced effect on enhancing solubility compared to hydrophilic MOFs. This study offers valuable insights for achieving optimal drug release kinetics and solubility by delicately manipulating surface properties of MOFs.

Recent advances in magnetism of graphene from 0D to 2D.

Graphene appears as a promising candidate in the spintronic application due to its fascinating electrical properties. A large number of theoretical and experimental studies have demonstrated the accessibility and significance of inducing magnetism in graphene-based systems. This review is dedicated to the overview of the latest five-year advances of studies on graphene's magnetism based on a dimensional viewpoint, including nanoflakes (0D), graphene nanoribbons (1D), graphene sheets and twisted bilayer graphene (2D). Various methods, such as edge engineering, defect engineering, sp3 functionalization, heteroatom adsorption and interlayer rotation, are suggested to induce intriguing magnetic behaviors. Finally, we summarized the challenges and opportunities in the field to provide guidance for future research.

The selective and sustainable separation of Cd(II) using C6MImT/[C6MIm]PF6 extractant.

Cadmium has been classified as a kind of human carcinogens, and has a strong mobility in the water environment and this can result in serious harm to human health and environmental safety. Here, a new selective and efficient extraction-recovery strategy for Cd purification is provided by using C6MimT/[C6Mim]PF6 as the green extractant. Due to the high compatibility between C6MimT and [C6Mim]PF6, C6MimT-Cd was efficiently separated from the aqueous phase. When the concentration of Cd(II) was 1000 mg/L, the extraction rate could reached 99.9 %. By comparing [C6MIm]BF4 with [C6MIm]PF6, the hydrophobicity restrained the ion exchange between cation and Cd and significantly reduced the loss of extractant. The extracted Cd(II) was separated in the form of precipitation after stripping. The extraction system of C6MimT/[C6Mim]PF6 was stable after several extraction-stripping cycles. The extraction of Cd(II) by C6MimT/[C6Mim]PF6 system mainly realized by forming a neutral and extractable cadmium complexes between Cd(II) and thione. Based on the natural complexation mechanism between metal and C6MImT, Cd exists as obvious competitive advantage in coordination with C6MimT compare to Pb, Zn, Mg, Cr, Fe. This work overcomes the problems of extractant loss and organic pollution caused by volatile or ion exchange, which can only reduce environmental hazards, but also promote the recovery of cadmium and other valuable resources.