Grooved Microneedle Patch Augments Adoptive T Cell Therapy Against Solid Tumors via Diverting Regulatory T Cells.

The efficacy of adoptive T cell therapy (ACT) for the treatment of solid tumors remains challenging. In addition to the poor infiltration of effector T (Teff) cells limited by the physical barrier surrounding the solid tumor, another major obstacle is the extensive infiltration of regulatory T (Treg) cells, a major immunosuppressive immune cell subset, in the tumor microenvironment. Here, we developed a grooved microneedle patch for augmenting ACT, aiming to simultaneously overcome physical and immunosuppressive barriers. The microneedles are engineered through an ice-templated method to generate the grooved structure for sufficient T-cell loading. In addition, with the surface modification of chemokine CCL22, the MNs could not only directly deliver tumor-specific T cells into solid tumors through physical penetration, but also specifically divert Treg cells from the tumor microenvironment to the surface of the microneedles via a cytokine concentration gradient, leading to an increase in the ratio of Teff cells/Treg cells in a mouse melanoma model. Consequently, this local delivery strategy of both T cell receptor T cells or chimeric antigen receptor T cells via the CCL22-modified grooved microneedles as a local niche could significantly enhance the antitumor efficacy and reduce on-target off-tumor toxicity of ACT. This article is protected by copyright. All rights reserved.

A knowledge-enhanced interpretable network for early recurrence prediction of hepatocellular carcinoma via multi-phase CT imaging.

BACKGROUND: Predicting early recurrence (ER) of hepatocellular carcinoma (HCC) accurately can guide treatment decisions and further enhance survival. Computed tomography (CT) imaging, analyzed by deep learning (DL) models combining domain knowledge, has been employed for the prediction. However, these DL models utilized late fusion, restricting the interaction between domain knowledge and images during feature extraction, thereby limiting the prediction performance and compromising decision-making interpretability. METHODS: We propose a novel Vision Transformer (ViT)-based DL network, referred to as Dual-Style ViT (DSViT), to augment the interaction between domain knowledge and images and the effective fusion among multi-phase CT images for improving both predictive performance and interpretability. We apply the DSViT to develop pre-/post-operative models for predicting ER. Within DSViT, to balance the utilization between domain knowledge and images within DSViT, we propose an adaptive self-attention mechanism. Moreover, we present an attention-guided supervised learning module for balancing the contributions of multi-phase CT images to prediction and a domain knowledge self-supervision module for enhancing the fusion between domain knowledge and images, thereby further improving predictive performance. Finally, we provide the interpretability of the DSViT decision-making. RESULTS: Experiments on our multi-phase data demonstrate that DSViTs surpass the existing models across multiple performance metrics and provide the decision-making interpretability. Additional validation on a publicly available dataset underscores the generalizability of DSViT. CONCLUSIONS: The proposed DSViT can significantly improve the performance and interpretability of ER prediction, thereby fortifying the trustworthiness of artificial intelligence tool for HCC ER prediction in clinical settings.

A longitudinal study of the brain structure network changes in HIV patients with ANI: combined VBM with SCN.

Background: Despite the widespread adoption of combination antiretroviral therapy (cART) in managing HIV, the virus's impact on the brain structure of patients remains significant. This study aims to longitudinally explore the persistent effects of HIV on brain structure, focusing on changes in gray matter volume (GMV) and structural covariance network (SCN) among patients at the Asymptomatic Neurocognitive Impairment (ANI) stage. Methods: This research involved 45 HIV patients diagnosed with ANI and 45 demographically matched healthy controls (HCs). The participants were observed over a 1.5-year period. Differences in GMV between groups were analyzed using voxel-based morphometry (VBM), while the graph theory model facilitated the establishment of topological metrics for assessing network indices. These differences were evaluated using two-sample t-tests and paired-sample t-tests, applying the network-based statistics method. Additionally, the study examined correlations between GMV and cognitive performance, as well as clinical variables. Results: Compared with HCs, HIV patients demonstrated reduced GMV in the right middle temporal gyrus and left middle frontal gyrus (FWE, p < 0.05), along with decreased betweenness centrality (BC) in the left anterior cingulate and paracingulate cortex. Conversely, an increase in the clustering coefficient (Cp) was observed (FDR, p < 0.05). During the follow-up period, a decline in GMV in the right fusiform gyrus (FWE, p < 0.05) and a reduction in node efficiency (Ne) in the triangular part of the inferior frontal gyrus were noted compared with baseline measurements (FDR, p < 0.05). The SCN of HIV patients exhibited small-world properties across most sparsity levels (Sigma >1), and area under the curve (AUC) analysis revealed no significant statistical differences between groups. Conclusion: The findings suggest that despite the administration of combination antiretroviral therapy (cART), HIV continues to exert slow and sustained damage on brain structures. However, when compared to HCs, the small-world properties of the patients' SCNs did not significantly differ, and the clustering coefficient, indicative of the overall information-processing capacity of the brain network, was slightly elevated in HIV patients. This elevation may relate to compensatory effects of brain area functions, the impact of cART, functional reorganization, or inflammatory responses.

A randomized, double-blind, placebo-controlled phase I clinical trial of rotavirus inactivated vaccine (Vero cell) in a healthy adult population aged 18-49 years to assess safety and preliminary observation of immunogenicity.

We conducted a phase I, randomized, double-blind, placebo-controlled trial including healthy adults in Sui County, Henan Province, China. Ninety-six adults were randomly assigned to one of three groups (high-dose, medium-dose, and low-dose) at a 3:1 ratio to receive one vaccine dose or placebo. Adverse events up to 28 days after each dose and serious adverse events up to 6 months after all doses were reported. Geometric mean titers and seroconversion rates were measured for anti-rotavirus neutralizing antibodies using microneutralization tests. The rates of total adverse events in the placebo group, low-dose group, medium-dose group, and high-dose group were 29.17 % (12.62 %-51.09 %), 12.50 % (2.66 %-32.36 %), 50.00 % (29.12 %-70.88 %), and 41.67 % (22.11 %-63.36 %), respectively, with no significant difference in the experimental groups compared with the placebo group. The results of the neutralizing antibody assay showed that in the adult group, the neutralizing antibody geometric mean titer at 28 days after full immunization in the low-dose group was 583.01 (95 % confidence interval [CI]: 447.12-760.20), that in the medium-dose group was 899.34 (95 % CI: 601.73-1344.14), and that in the high-dose group was 1055.24 (95 % CI: 876.28-1270.75). The GMT of serum-specific IgG at 28 days after full immunization in the low-dose group was 3444.26 (95 % CI: 2292.35-5175.02), that in the medium-dose group was 6888.55 (95 % CI: 4426.67-10719.6), and that in the high-dose group was 7511.99 (95 % CI: 3988.27-14149.0). The GMT of serum-specific IgA at 28 days after full immunization in the low-dose group was 2332.14 (95 % CI: 1538.82-3534.45), that in the medium-dose group was 4800.98 (95 % CI: 2986.64-7717.50), and that in the high-dose group was 3204.30 (95 % CI: 2175.66-4719.27). In terms of safety, adverse events were mainly Grades 1 and 2, indicating that the safety of the vaccine is within the acceptable range in the healthy adult population. Considering the GMT and positive transfer rate of neutralizing antibodies for the main immunogenicity endpoints in the experimental groups, it was initially observed that the high-dose group had higher levels of neutralizing antibodies than the medium- and low-dose groups in adults aged 18-49 years. This novel inactivated rotavirus vaccine was generally well-tolerated in adults, and the vaccine was immunogenic in adults (ClinicalTrials.gov number, NCT04626856).

Endosymbionts of citrus leafminer Phyllocnistis citrella Stainton among different citrus orchards in China.

Endosymbionts regulate the behavior of pest species, which could provide insights into their control. The citrus leafminer (Phyllocnistis citrella Stainton) is a widely distributed pest associated with diseases of citrus, especially of young trees. Here, we determined the endosymbiont composition of P. citrella in citrus orchards across China. The resulting dataset comprised average 50,430 high-quality reads for bacterial 16S rRNA V3-V4 regions of endosymbionts from 36 P. citrella larvae sampled from 12 citrus orchards across China. The sequencing depth and sampling size of this dataset were sufficient to reveal most of the endosymbionts of P. citrella. In total, 2,875 bacterial amplicon sequence variants were obtained; taxonomic analysis revealed a total of 372 bacterial genera, most of which were Proteobacteria phylum with Undibacterium being the most abundant genus. This dataset provides the first evidence of P. citrella endosymbionts that could support the development of pest management approaches in citrus orchards.

Phase 2 Study of Preoperative Tislelizumab in Combination with Low-dose Nab-Paclitaxel in Patients with Muscle-invasive Bladder Cancer.

BACKGROUND AND OBJECTIVE: Combinations of immune checkpoint inhibitors and nab-paclitaxel have achieved significant therapeutic effects in the treatment of advanced urothelial carcinoma. Our aim was to assess the efficacy and safety of tislelizumab combined with low-dose nab-paclitaxel in patients with muscle-invasive bladder cancer (MIBC). METHODS: TRUCE-01 was a single-arm phase 2 study that included 62 patients with T2-4a N0/X M0 MIBC tumors with predominant urothelial carcinoma histology. Eligible patients received three 21-d cycles of intravenous 200 mg tislelizumab on day 1 plus intravenous 200 mg nab-paclitaxel on day 2, followed by surgical assessment. The primary study endpoint was a clinical complete response (cCR). Treatment-related adverse event (TRAE) profiles were recorded according to Common Terminology Criteria for Adverse Events version 5.0. KEY FINDINGS AND LIMITATIONS: The safety analysis included all 62 patients and the efficacy analysis included 48 patients. The primary efficacy endpoint (cCR) was met by 25 patients (52%) patients. Among the 62 patients in the safety analysis, six (9.7%) had grade ≥3 TRAEs. CONCLUSIONS: Tislelizumab combined with low-dose nab-paclitaxel showed promising antitumor effectiveness and was generally well tolerated, which makes it an excellent preoperative therapy option for MIBC. PATIENT SUMMARY: We found that a combination of the drugs tislelizumab and low-dose nab-paclitaxel had satisfactory efficacy and safety for preoperative treatment of muscle-invasive bladder cancer.

Spatial heterogeneity plays a vital role in shaping the structure and function of estuarine carbon-fixing bacterial communities.

Carbon-fixing bacterial communities are essential drivers of carbon fixation in estuarine ecosystems that critically affect the global carbon cycle. This study compared the abundances of the Calvin cycle functional genes cbbL and cbbM and Reductive tricarboxylic acid cycle gene aclB, as well as compared carbon-fixing bacterial community features in the two estuaries, predicted potential ecological functions of carbon-fixation bacteria, and analyzed their symbiosis strategies in two estuaries having different geographical distributions. Gammaproteobacteria was the dominant carbon-fixing bacterial community in the two estuaries. However, a higher number of Alphaproteobacteria were noted in the Liaohe Estuary, and a higher number of Betaproteobacteria were found in the Yalujiang Estuary. The carbon-fixing functional gene levels exhibited the order of aclB > cbbL > cbbM, and significant effects of Cu, Pb, and petroleum were observed (p < 0.05). Nitrogen-associated nutrient levels are major environmental factors that affect carbon-fixing bacterial community distribution patterns. Spatial factors significantly affected cbbL carbon-fixing functional bacterial community structure more than environmental factors. With the increase in offshore distance, the microbial-led processes of methylotrophy and nitrogen fixation gradually weakened, but a gradual strengthening of methanotrophy and nitrification was observed. Symbiotic network analysis of the microorganisms mediating these ecological processes revealed that the carbon-fixing bacterial community in these two estuaries had a non-random symbiotic pattern, and microbial communities from the same module were strongly linked among the carbon, nitrogen, and sulfur cycle. These findings could advance the understanding of carbon fixation in estuarine ecosystems.

Masting promotes transformation from predation to mutualism in an oak-weevil-rodent system.

The significance of ecological non-monotonicity (a function whose first derivative changes signs) in shaping the structure and functions of the ecosystem has recently been recognized, but such studies involving high-order interactions are rare. Here, we have proposed a three-trophic conceptual diagram on interactions among trees, rodents, and insects in mast and non-mast years and tested the hypothesis that oak (Quercus wutaishanica) masting could result in increased mutualism and less predation in an oak-weevil-rodent system in a warm temperate forest of China. Our 14-year dataset revealed that mast years coincided with a relatively low rodent abundance but a high weevil abundance. Masting not only benefited seedling recruitment of oaks through increased dispersal by rodents but also a decrease in predation by rodents and weevils, as well as an increase in the overwintering survival of rodents. Masting appeared to have increased weevil survival by reducing predation of infested acorns by rodents. These results suggest that masting benefits all participants in the plant-insect-rodent system by increasing mutualism and reducing predation behavior (i.e., a non-monotonic function). Our study highlights the significance of masting in maintaining the diversity and function of the forest ecosystem by facilitating the transformation from predation to mutualism among trophic species.

The relationship between cardiac oxidative stress, inflammatory cytokine response, cardiac pump function, and prognosis post-myocardial infarction.

This study delves into the potential connections between cardiac oxidative stress, inflammatory cytokine response, cardiac pump function, and prognosis in individuals following myocardial infarction. A total of 276 patients were categorized into two groups: the control group (n = 130) and the observation group (n = 146), based on the drug intervention strategies. The control group received standard drug treatment, while the observation group received early drug intervention targeting antioxidant and anti-inflammatory treatment in addition to standard treatment. Serum levels of inflammatory factors, including tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and interleukin-9 (IL-6), were assessed using enzyme-linked immuno sorbent assay (ELISA) kits. The Forkhead Box Protein A2 (FOX2) reagent was used to determine the overall oxidation level. Left Ventricular End-Diastolic Diameter (LVEDD), Left Ventricular Ejection Fraction (LVEF), and End-Systolic Diameter (ESD) were measured using Doppler ultrasound. The observation group exhibited significantly reduced serum levels of TNF-α, IL-1ß, and IL-6 compared to the control group (P < 0.05). Moreover, the observation group exerted lower total oxidation levels, OSI, EDD, and ESD compared to the control group (P < 0.05), while the LVEF and TAS levels in the observation group were higher than those in the control group (P < 0.05). Remarkably, the observation group experienced a significant reduction in the incidences of reinfarction, heart failure, arrhythmia, and abnormal valve function compared to the control group (P < 0.05). Decreased cardiac pump function and a more unfavorable prognosis were associated with elevated levels of cardiac oxidative stress and inflammatory factors (P < 0.05). Timely intervention with appropriate medications have a crucial effect in decreasing inflammatory marker levels, mitigating oxidative pressure, and enhancing cardiac pumping capacity and overall prognosis.

Potato miR394 targets StA/N-INVE and StLCR to negatively regulate late blight resistance.

MicroRNAs (miRNAs) are small noncoding RNAs in eukaryotes. Plant endogenous miRNAs play pivotal roles in regulating plant development and defense responses. MicroRNA394 (miR394) has been reported to regulate plant development, abiotic stresses and defense responses. Previous reports showed that miR394 responded to P. infestans inoculation in potato, indicating that miR394 may be involved in defense responses. In this study, we further investigated its role in potato defense against P. infestans. Stable expression of miR394 in tobacco and potato enhances the susceptibility to P. infestans, which is accompanied with the reduced accumulation of ROS and down-regulation of the PTI (pattern-triggered immunity) marker genes. Besides well-known target StLCR, miR394 also targets StA/N-INVE, which encodes a chloroplast Alkaline/Neutral Invertases (A/N-INVE). Both StLCR and StA/N-INVE positively regulate late blight resistance, while miR394 degrades them. Interestingly, StA/N-INVE is located in the chloroplast, indicating that miR394 may manipulate chloroplast immunity. Degradation of StA/N-INVE may affect the chloroplast function and hence lead to the compromised ROS (reactive oxygen species) burst and reduced retrograde signaling from the chloroplast to the nucleus and cytoplasm. In summary, this study provides new information that miR394 targets and degrades StA/N-INVE and StLCR, which are positive regulators, to enhance potato susceptibility to P. infestans.

ML241 Antagonizes ERK 1/2 Activation and Inhibits Rotavirus Proliferation.

Rotavirus (RV) is the main pathogen that causes severe diarrhea in infants and children under 5 years of age. No specific antiviral therapies or licensed anti-rotavirus drugs are available. It is crucial to develop effective and low-toxicity anti-rotavirus small-molecule drugs that act on novel host targets. In this study, a new anti-rotavirus compound was selected by ELISA, and cell activity was detected from 453 small-molecule compounds. The anti-RV effects and underlying mechanisms of the screened compounds were explored. In vitro experimental results showed that the small-molecule compound ML241 has a good effect on inhibiting rotavirus proliferation and has low cytotoxicity during the virus adsorption, cell entry, and replication stages. In addition to its in vitro effects, ML241 also exerted anti-RV effects in a suckling mouse model. Transcriptome sequencing was performed after adding ML241 to cells infected with RV. The results showed that ML241 inhibited the phosphorylation of ERK1/2 in the MAPK signaling pathway, thereby inhibiting IκBα, activating the NF-κB signaling pathway, and playing an anti-RV role. These results provide an experimental basis for specific anti-RV small-molecule compounds or compound combinations, which is beneficial for the development of anti-RV drugs.

Effect of cellulase on dough structure and quality characteristics of tough biscuits enriched with potato whole flour.

Potato whole flour is a promising way to improve the nutrition of tough biscuits, while its gluten-free characteristic was difficult to form acceptable texture properties. In this study, cellulase was used to degrade the cellulose in dough enriched with potato whole flour, so as to mitigate the interference of cellulose with the gluten network, resulting in forming the potato whole flour biscuit with great characteristics. Results indicated that cellulase within 0.2% led to the gradually reduced G' and G'' values of dough from 5.50×104 to 4.00×104 and 2.66×104 to 1.35×104, respectively. Cellulase at 0.2% resulted in the significantly increased tensile properties of the dough compared to the control. The incorporation of cellulase within 0.2% also led to the tightly ordered and intact network structure base on the results of SEM, disulfide bonds determination and FTIR. Those results indicated that cellulase was beneficial to improve the baking quality of dough, which was conductive to form tough biscuit with great characteristics. The hardness, crunchiness, crispness and specific volume analysis results confirmed that 0.2% cellulase resulted in the significantly decreased hardness by 45.25% and the significantly increased specific volume, crunchiness and crispness by 24.74%, 121.20% and 156.47%, respectively. Overall, cellulase ultimately improved the quality of the biscuits by improving the properties and structure of the dough. It was of great significance for the utilization of potato whole flour resources and the industrial production of its tough biscuits. PRACTICAL APPLICATION: The results showed that inclusion of cellulase led to the reduced hardness and increased crunchiness, crispness, and specific volume of potato whole flour tough biscuits. Cellulase could be used as a potential improver of tough biscuits. This study will provide guidance for practical uses of cellulase in improving potato whole flour dough and tough biscuit quality.

The Characterization of the Key Aroma Compounds in Non-Smoked Bacon by Instrumental and Sensory Methods.

The aroma profiles in non-smoked bacon were investigated via GC-O-MS, GC × GC-TOFMS, and GC-IMS. GC-O-MS is advantageous for detecting aldehydes. GC × GC-TOFMS is more sensitive to hydrocarbons and alcohols, while GC-IMS detects a balanced range of categories. Only 9 of the 239 detected volatiles were identifiable by all three methods. Therefore, the combination of all three methods proved to be the most effective way to comprehensively analyze the aroma profiles of bacon. Recombination and omission tests were performed using aroma compounds with a flavor dilution (FD) factor greater than 27; five volatiles were identified as key aroma compounds in non-smoked bacon, including hexanal, (E,E)-2,4-decadienal, 1-octen-3-ol, dihydro-5-pentyl-2(3H)-furanone, and 3-methyl-butanoic acid. Among these, hexanal and 1-octen-3-ol exhibited relatively high FD factors and odor activity values (OAVs), so they were confirmed as the primary contributors. Meanwhile, seven volatiles contributed to the unique aroma of non-smoked bacon in different regions. The difference in the aroma of bacon in different regions is mainly due to the content of various volatiles rather than the type. A comprehensive analysis of the aroma in non-smoked bacon can reveal theoretical information for improving the process and quality control of the product.

Quantitative proteomic analysis to identify potential biomarkers linked to quality traits of beef tripe from different sources.

In this work, the 4D data-independent acquisition (DIA) quantitative strategy was used for differential proteomic analysis of four beef tripe samples from different sources to explore the associations between differentially expressed proteins (DEPs) and meat quality traits. A total of 68 shared DEPs were identified in all comparison groups, which were mainly involved in phosphorylation signaling pathway, peroxisome proliferator-activated receptor (PPAR) signaling pathway, and glucuronic acid pathway. In the correlation analysis between DEPs and quality traits of beef tripe, it was found that 21 proteins were significantly associated with the quality traits in beef tripe, which could be considered as the potential biomarkers of beef tripe quality. This study has successfully uncovered the protein composition of beef tripe for the very first time, which helps to understand the key proteins and biological processes associated with the quality traits of beef tripe from different sources and improve the quality control of beef tripe.

Contrasting benthic bacterial and fungal communities in two temperate coastal areas affected by different levels of anthropogenic pressure.

Benthic microbial communities play a crucial role in maintaining the stability and function of estuarine ecosystems. However, their organization and response to multiple stresses in severely disturbed coastal areas remains to be elucidated. In this study, we revealed the presence of contrasting benthic bacterial and fungal communities in the Liaohe (LH) and Yalujiang (YLJ) estuaries, which are located at similar latitudes and are characterized by similar climates but are subjected to different levels of anthropogenic pressure. The results showed that Firmicutes and Chloroflexi were more abundant in LH, which reflected the influence of anthropogenic pressure in this area. Functional analyses indicated that the functional genes involved in the generation of precursor metabolites and energy pathways were more enriched in the LH community, while genes regulating degradation/utilization/assimilation processes were more enriched in the YLJ community. Distance-dependent similarity analysis showed that the bacterial community in LH was more affected by environmental changes, while that in YLJ was more influenced by geographic dispersion. In contrast, no significant distance-dependent similarity was found for the fungal communities in the two areas. In addition, the network analysis showed that the bacterial-fungal network in YLJ was more complex and stable than that in the LH. Our results highlight the important roles of environmental heterogeneity in controlling microbial community composition, biogeographic patterns, and co-occurrence networks. These findings fill knowledge gaps in the understanding of the different response patterns of benthic communities under varying anthropogenic pressures.

Cryo-shocked tumor cells deliver CRISPR-Cas9 for lung cancer regression by synthetic lethality.

Although CRISPR-mediated genome editing holds promise for cancer therapy, inadequate tumor targeting and potential off-target side effects hamper its outcomes. In this study, we present a strategy using cryo-shocked lung tumor cells as a CRISPR-Cas9 delivery system for cyclin-dependent kinase 4 (CDK4) gene editing, which initiates synthetic lethal in KRAS-mutant non-small cell lung cancer (NSCLC). By rapidly liquid nitrogen shocking, we effectively eliminate the pathogenicity of tumor cells while preserving their structure and surface receptor activity. This delivery system enables the loaded CRISPR-Cas9 to efficiently target to lung through the capture in pulmonary capillaries and interactions with endothelial cells. In a NSCLC-bearing mouse model, the drug accumulation is increased nearly fourfold in lung, and intratumoral CDK4 expression is substantially down-regulated compared to CRISPR-Cas9 lipofectamine nanoparticles administration. Furthermore, CRISPR-Cas9 editing-mediated CDK4 ablation triggers synthetic lethal in KRAS-mutant NSCLC and prolongs the survival of mice.

Effect of heme proteins on the lipid molecule profile and aroma formation during hot air drying of non-smoked bacon.

Heme proteins and their derivatives play important roles in inducing lipid oxidation to produce volatile compounds during bacon drying. This study investigated the effects of heme proteins and their derivatives (hemoglobin, myoglobin, nitrosylmyoglobin, hemin, Fe2+, and Fe3+) on lipid and volatiles profiles in the washed pig muscle (WPM) model. The results of the study indicated that the inducers primarily caused the oxidation of glycerophospholipids. Furthermore, hemoglobin and myoglobin had the most significant impact, and their potential substrates may include PE (O-18:2/20:4), PE (O-18:1/20:4), PC (16:0/18:1), and PE (O-18:2/18:2). Nitrosomyoglobin has limited ability to promote lipid oxidation and may protect ether phospholipids from oxidation. The analysis of the volatiles in the model revealed that heme proteins and their derivatives have the ability to induce the production of key aroma compounds. The descending order of effectiveness in inducing the production of aroma compounds is as follows: hemoglobin, myoglobin, hemin, and nitrosylmyoglobin. The effectiveness of Fe2+ and Fe3+ is similar to that of nitrosylmyoglobin.

Fluorinated Lipid Nanoparticles for Enhancing mRNA Delivery Efficiency.

Lipid nanoparticles (LNPs), a nonviral nucleic acid delivery system, have shown vast potential for vaccine development and disease treatment. LNPs assist mRNA to cross physiological barriers such as cell membranes and endosomes/lysosomes, promoting the intracellular presentation of mRNA. However, the endosome escape efficiency and biosafety of currently commercialized LNPs are still unsatisfactory, resulting in underutilization of mRNA. Herein, we report that fluorinated modification of the 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-poly(ethylene glycol)-2000 (PEG-DSPE), termed as FPD, in the LNPs can improve the delivery efficiency of mRNA. FPD accounts for only 1.5% of lipids in LNPs but could mediate a 5-fold and nearly 2-fold enhancement of mRNA expression efficiency in B16F10 tumor cells and primary dendritic cells, respectively. Mechanism studies reveal that FPD promotes the cellular internalization of LNPs as well as endosome escape. In vivo studies substantiate that FPD can augment overall mRNA expression at least 3-fold, either by intravenous or intraperitoneal injection, compared to LNPs prepared with nonfluorinated PEG-lipids at a relatively low mRNA dose. Besides, with the introduction of FPD, mRNA expression in the spleen augmented compared to that of the DMG-PEG commercial formulations. Benefiting from a prudent dosage of fluorine, the fluorinated LNPs display favorable biosafety profiles at cellular and zoological levels.

Spatiotemporal dynamics of bacterioplankton communities in the estuaries of two differently contaminated coastal areas: Composition, driving factors and ecological process.

Seasonal variations of environmental parameters usually lead to considerable changes in microbial communities. Nevertheless, the specific response patterns of these communities in coastal areas subjected to different levels of contamination remain unclear. Our results revealed notable fluctuations in the bacterioplankton community both seasonally and spatially, with seasonal variations being particularly significant. The diversity and composition of bacterioplankton communities in the estuaries varied significantly across seasons and between seas. Some bacterial phyla that were highly abundant in the dry season (e.g., Patescibacteria and Epsilonbacteraeota) were almost absent in the wet season. Furthermore, the network analysis revealed that the bacterioplankton networks were more complex during the wet season than in the dry season. In the wet season, the estuarine bacterioplankton network in the Yellow Sea region was more complex and stable, while the opposite was true in the dry season. According to the neutral community model, stochastic processes played a more significant role in the formation of bacterioplankton communities during the wet season than during the dry season. Estuarine bacterioplankton communities in the Yellow Sea region were more affected by stochastic processes compared to those in the Bohai Sea. In summary, in the estuaries of two differently contaminated coastal areas, the seasonal increase in nutrient levels enhanced the deterministic processes and network complexity of the bacterioplankton communities.