PHGDH/SYK: a hub integrating anti-fungal immunity and serine metabolism.

Immune cells modify their metabolic pathways in response to fungal infections. Nevertheless, the biochemical underpinnings need to be better understood. This study reports that fungal infection drives a switch from glycolysis to the serine synthesis pathway (SSP) and one-carbon metabolism by inducing the interaction of spleen tyrosine kinase (SYK) and phosphoglycerate dehydrogenase (PHGDH). As a result, PHGDH promotes SYK phosphorylation, leading to the recruitment of SYK to C-type lectin receptors (CLRs). The CLR/SYK complex initiates signaling cascades that lead to transcription factor activation and pro-inflammatory cytokine production. SYK activates SSP and one-carbon metabolism by inducing PHGDH activity. Then, one-carbon metabolism supports S-adenosylmethionine and histone H3 lysine 36 trimethylation to drive the production of pro-inflammatory cytokines and chemokines. These findings reveal the crosstalk between amino acid metabolism, epigenetic modification, and CLR signaling during fungal infection.

Effects of silicate stabilizers on cadmium reduction and the quality of rice grains in acidic paddy soil.

Silicate has been proven to be highly-effective at immobilizing soil heavy metals, but the effects of silicate stabilizers on rice grain cadmium (Cd) reduction and rice quality under field conditions are not clear. In this study, a field experiment was conducted over three consecutive years was conducted to examine the Cd reduction in rice grains and to reveal the potential effects of silicate stabilizers on rice grain nutrients, by setting different amounts of bentonite (B), silica‒calcium fertilizer (SC) and zeolite powder (ZP). The results revealed that the application of the B, SC and ZP significantly decreased the soil CaCl2‒Cd concentration (> 39%) and significantly reduced the grain Cd concentration in both early rice (> 70%) and late rice (> 18%) under field conditions; the silicate stabilizers reduced the soil available iron (Fe) but did not limit rice grain Fe nutrition. Additionally, the three silicates promoted rice yield and improved the rice grain Ca and Mg contents; and the application of B increased the amylose concentration of the late rice grains. In conclusion, high amounts of silicate stabilizers did not adversely influence the soil conventional nutrient indices, rice minerals or rice taste, but changes in rice selenium content need attention. Overall, in comparison with lime, silicate stabilizers can improve not only the safety of rice but also the nutritional and taste qualities of rice and are more eco-friendly for long-term use in soil.

Prognostic model for hepatocellular carcinoma based on necroptosis-related genes and analysis of drug treatment responses.

Objective: Recent studies reveal that necroptosis is pivotal in tumorigenesis, cancer metastasis, cancer immunity, and cancer subtypes. Apoptosis or necroptosis of hepatocytes in the liver microenvironment can determine the subtype of liver cancer. However, necroptosis-related genomes have rarely been analyzed in hepatocellular carcinoma (HCC). Therefore, this study aims to construct an HCC risk scoring model based on necroptosis-related genes and to validate its predictive performance in overall survival prediction and immunotherapy efficacy evaluation in HCC, as well as to analyze drug treatment responses. Methods: This study analyzed clinical information and RNA-seq expression data of liver cancer patients from TCGA public data, identified necroptosis-related genes, and conducted GO and KEGG enrichment analyses. Using Cox regression analysis and LASSO analysis to identify independent prognostic factors, a predictive model was established and validated in clinical subgroups, and correlation analysis with immune cells and ssGSEA differential analysis were conducted. Finally, potential drugs for HCC were screened to explore the drug sensitivity of different subtypes. Results: We identified 19 differentially expressed necroptosis-related genes and constructed a predictive model with 3 independent prognostic factors through stepwise Cox regression. Validation results from clinical subgroups showed that the constructed model performed well in risk prediction, and ssGSEA differential analysis results were significant. We analyzed 55 immunotherapy drugs, and clustered them by distinct IC50 values to guide drug selection for HCC patients. Notable, Bleomycin, Obatoclax. Mesylate, PF.562271, PF.02341066, QS11, X17. AAG, and Bl. D1870 exhibited significantly different sensitivities in different subtypes, providing references for clinical practice in HCC patients.

A distinct neuronal ensemble of prelimbic cortex mediates spontaneous pain in rats with peripheral inflammation.

The absence of a comprehensive understanding of the neural basis of spontaneous pain limits the development of therapeutic strategies targeting this primary complaint of patients with chronic pain. Here we report a distinct neuronal ensemble within the prelimbic cortex which processes signals related to spontaneous pain in rats with chronic inflammatory pain. This neuronal ensemble specifically encodes spontaneous pain-related behaviors, independently of other locomotive and evoked behaviors. Activation of this neuronal ensemble elicits marked spontaneous pain-like behaviors and enhances nociceptive responses, whereas prolonged silencing of its activities alleviates spontaneous pain and promotes overall recovery from inflammatory pain. Notably, afferents from the primary somatosensory cortex and infralimbic cortex bidirectionally modulate the activities of the spontaneous pain-responsive prelimbic cortex neuronal ensemble and pain behaviors. These findings reveal the cortical basis of spontaneous pain at the neuronal level, highlighting a distinct neuronal ensemble within the prelimbic cortex and its associated pain-regulatory brain networks.

LncRNA-HMG incites colorectal cancer cells to chemoresistance via repressing p53-mediated ferroptosis.

Upon chemotherapy, excessive reactive oxygen species (ROS) often lead to the production of massive lipid peroxides in cancer cells and induce cell death, namely ferroptosis. The elimination of ROS is pivotal for tumor cells to escape from ferroptosis and acquire drug resistance. Nevertheless, the precise functions of long non-coding RNAs (lncRNAs) in ROS metabolism and tumor drug-resistance remain elusive. In this study, we identify LncRNA-HMG as a chemoresistance-related lncRNA in colorectal cancer (CRC) by high-throughput screening. Abnormally high expression of LncRNA-HMG predicts poorer prognosis in CRC patients. Concurrently, we found that LncRNA-HMG protects CRC cells from ferroptosis upon chemotherapy, thus enhancing drug resistance of CRC cells. LncRNA-HMG binds to p53 and facilitates MDM2-mediated degradation of p53. Decreased p53 induces upregulation of SLC7A11 and VKORC1L1, which contribute to increase the supply of reducing agents and eliminate excessive ROS. Consequently, CRC cells escape from ferroptosis and acquire chemoresistance. Importantly, inhibition of LncRNA-HMG by anti-sense oligo (ASO) dramatically sensitizes CRC cells to chemotherapy in patient-derived xenograft (PDX) model. LncRNA-HMG is also a transcriptional target of ß-catenin/TCF and activated Wnt signals trigger the marked upregulation of LncRNA-HMG. Collectively, these findings demonstrate that LncRNA-HMG promotes CRC chemoresistance and might be a prognostic or therapeutic target for CRC.

Effective soil remediation with fungal Co-inoculation and king grass for robust cadmium and chromium phytoextraction.

Bioremediation, an economical and environmentally friendly approach, provides a sustainable solution for mitigating heavy metal contamination in soils. This study identifies four fungal strains-Trichoderma harzianum DAA8, Trichoderma reesei DAA9, Rhizomucor variabilis DFB3, and Trichoderma asperellum LDA4-that exhibit tolerance to cadmium (Cd) and chromium (Cr). These strains were isolated from soils impacted by heavy metal contamination in mining regions. Rigorous examinations of these strains led us to determine their Minimum Inhibitory Concentrations (MICs) and optimal absorption-reduction conditions. Our microscopic data and GC-MS analysis indicate that these strains can accumulate Cd and Cr by generating compounds, such as ketones and imines, in heavy metal environments. We evaluated the remediation efficacy of both single and co-cultures of Rhizomucor variabilis DFB3 and Trichoderma asperellum LDA4 in conjunction with king grass, a plant known for its heavy metal accumulation capabilities. Our findings indicated an impressive 41.9% increase in plant biomass and 47.2% and 64.4% increase in Cd and Cr accumulation respectively. The removal rates of Cd and Cr were 16.5% and 19.0%, respectively, following the co-inoculation of Rhizomucor variabilis DFB3 and Trichoderma asperellum LDA4. These rates represent increases of 37.1% and 33.7% compared to the removal rates achieved with king grass alone. This study not only advances strategies to manage Cd-Cr contamination but also sets a pathway for efficient heavy metal soil remediation using a microbial-plant combined technique.

Peptide-Functionalized Gold Nanoparticles for Boron Neutron Capture Therapy with the potential to use in Glioblastoma Treatment.

Glioblastoma is a highly aggressive glioma with limited treatment options. Boron neutron capture therapy (BNCT) offers a promising approach for refractory cancers, utilizing boron-10 (10B) and thermal neutrons to generate cytotoxic particles. Effective BNCT depends on selective targeting and retention of 10B in tumors. Current BNCT drugs face issues with rapid clearance and poor tumor accumulation. To address this, we developed gold nanoparticles (AuNPs) functionalized with cyclic arginine-glycine-aspartic acid (cRGD) peptides as a nanocarrier for Sodium Mercaptododecaborate (BSH), resulting in AuNPs-BSH&PEG-cRGD. In vitro, AuNPs-BSH&PEG-cRGD increased 10B content in GL261 glioma cells by approximately 2.5-fold compared to unmodified AuNPs-BSH&PEG, indicating enhanced targeting due to cRGD's affinity for integrin receptor αvß3. In a subcutaneous glioma mouse model, 6 hours post-intratumoral administration, the 10B concentration in tumors was 17.98 µg/g for AuNPs-BSH&PEG-cRGD, significantly higher than 0.45 µg/g for BSH. The tumor-to-blood (T/B) and tumor-to-normal tissue (T/N) ratios were also higher for AuNPs-BSH&PEG-cRGD, suggesting improved targeting and retention. This indicates that AuNPs-BSH&PEG-cRGD may enhance BNCT efficacy and minimize normal tissue toxicity. In summary, this study provides a novel strategy for BSH delivery and may broaden the design vision of BNCT nano-boron capture agents.

Role of MYO1F in neutrophil and macrophage recruitment and pro-inflammatory cytokine production in Aspergillus fumigatus keratitis.

PURPOSE: Myosin 1f (Myo1f), an unconventional long-tailed class Ⅰ myosin, plays significant roles in immune cell motility and innate antifungal immunity. This study was aimed to assess the expression and role of Myo1f in Aspergillus fumigatus (AF) keratitis. METHODS: Myo1f expression in the corneas of mice afflicted with AF keratitis and in AF keratitis-related cells was assessed using protein mass spectrometry, quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, and immunofluorescence. Myo1f expression following pre-treatment with inhibitors of dendritic cell-associated C-type lectin-1 (Dectin-1), Toll-like receptor 4 (TLR-4), and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) was also examined. In AF keratitis mouse models, Myo1f small interfering RNA (siRNA) was administered via subconjunctival injection to observe disease progression, inflammatory cell recruitment, and protein production using slit lamp examination, immunofluorescence, hematoxylin-eosin (HE) staining, and western blotting. RESULTS: Myo1f expression was upregulated in both AF keratitis mouse models and AF keratitis-related cells. Dectin-1, TLR-4, and LOX-1 were found to be essential for the production of Myo1f in response to the infection with AF. In mice with AF keratitis, knockdown of Myo1f reduced disease severity, decreased the recruitment of neutrophils alongside macrophages to inflammatory areas, suppressed the myeloid differentiation factor 88 (MyD88)/ nuclear factor-kappaB (NF-κB) signaling pathway, and decreased the production of interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, along with IL-6. Additionally, Myo1f was associated with apoptosis and pyroptosis in mice with AF keratitis. CONCLUSIONS: These findings demonstrated that Myo1f contributed to the recruitment of neutrophils and macrophages, the production of pro-inflammatory cytokines, and was associated with apoptosis and pyroptosis during AF keratitis.

Global research trends and hotspots of oxidative stress in diabetic retinopathy (2000-2024).

Introduction: Oxidative stress has been identified as a major contributor to the pathogenesis of DR, and many diagnostic and therapeutic strategies have been developed to target oxidative stress. Our aim was to understand the contribution of the country of origin of the publication, the institution, the authors, and the collaborative relationship between them. Methods: We performed a bibliometric analysis to summarize and explore the research hotspots and trends of oxidative stress in the DR. Results: We observe an upward trend in the number of posts on related topics from year to year. Expanding on this, Queens University Belfast is the most influential research institution. Current research hotspots and trends focus on the mechanism of autophagy and NLRP3 inflammasome's role in oxidative stress in DR. Discussion: We conducted a multi-dimensional analysis of the research status of oxidative stress in diabetic retinopathy through bibliometric analysis, and proposed possible future research trends and hotspots.

HTFSMMA: Higher-Order Topological Guided Small Molecule-MicroRNA Associations Prediction.

Small molecules (SMs) play a pivotal role in regulating microRNAs (miRNAs). Existing prediction methods for associations between SM-miRNA have overlooked crucial aspects: the incorporation of local topological features between nodes, which represent either SMs or miRNAs, and the effective fusion of node features with topological features. This study introduces a novel approach, termed high-order topological features for SM-miRNA association prediction (HTFSMMA), which specifically addresses these limitations. Initially, an association graph is formed by integrating SM-miRNA association data, SM similarity, and miRNA similarity. Subsequently, we focus on the local information of links and propose target neighborhood graph convolutional network for extracting local topological features. Then, HTFSMMA employs graph attention networks to amalgamate these local features, thereby establishing a platform for the acquisition of high-order features through random walks. Finally, the extracted features are integrated into the multilayer perceptron to derive the association prediction scores. To demonstrate the performance of HTFSMMA, we conducted comprehensive evaluations including five-fold cross-validation, leave-one-out cross-validation (LOOCV), SM-fixed local LOOCV, and miRNA-fixed local LOOCV. The area under receiver operating characteristic curve values were 0.9958 ± 0.0024 (0.8722 ± 0.0021), 0.9986 (0.9504), 0.9974 (0.9111), and 0.9977 (0.9074), respectively. Our findings demonstrate the superior performance of HTFSMMA over existing approaches. In addition, three case studies and the DeLong test have confirmed the effectiveness of the proposed method. These results collectively underscore the significance of HTFSMMA in facilitating the inference of associations between SMs and miRNAs.

Efficacy of Combination of Antiviral Therapy With Neutralizing Monoclonal Antibodies for Recurrent Persistent SARS-CoV-2 Pneumonia in Patients With Lymphoma.

Despite the potential of neutralizing antibodies in the management of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), clinical research on its efficacy in Chinese patients remains limited. This study is aimed at investigating the therapeutic effect of combination of antiviral therapy with neutralizing monoclonal antibodies for recurrent persistent SARS-CoV-2 pneumonia in patients with lymphoma complicated by B cell depletion. A prospective study was conducted on Chinese patients who were treated with antiviral nirmatrelvir/ritonavir therapy and the neutralizing antibody tixagevimab-cilgavimab (tix-cil). The primary outcome was the rate of recurrent SARS-CoV-2 infection. Five patients with lymphoma experienced recurrent SARS-CoV-2 pneumonia and received tix-cil treatment. All patients had a history of CD20 monoclonal antibody use within the year preceding SARS-CoV-2 infection, and two patients also had a history of Bruton's tyrosine kinase (BTK) inhibitor use. These patients had notably low lymphocyte counts and exhibited near depletion of B cells. All five patients tested negative for serum SARS-CoV-2 IgG and IgM antibodies. None of the patients developed reinfection with SARS-CoV-2 pneumonia after antiviral and tix-cil treatment during the 6-month follow-up period. In conclusion, the administration of antiviral and SARS-CoV-2-neutralizing antibodies showed encouraging therapeutic efficacy against SARS-CoV-2 pneumonia in patients with lymphoma complicated by B cell depletion, along with the potential preventive effect of neutralizing antibodies for up to 6 months.

Multi-objective optimization and life cycle assessment of mass-integrated combined heat and power system.

As the effects of climate change become more widely recognized, technical innovation and green energy will promote the growth of combined heat and power systems. This study proposes a novel mass-integrated combined heat and power system and conducts energy analysis, exergy analysis, and techno-economic analysis for the system. The optimization strategy integrated polynomial regression and non-dominated sorting genetic algorithm III is established, with system thermal efficiency, exergy efficiency, and return on investment (ROI) as objective functions. The system's environmental consequences are then assessed throughout its life cycle using life cycle assessment (LCA) under ideal operating circumstances. The findings reveal that the waste heat recovery heat exchanger has the highest exergy destruction in the system, with a value of 674.61 kW. Furthermore, the intermediate heat exchanger 1 and intermediate heat exchanger 2 (IHX2) with lesser exergy efficiency have an exergy destruction of less than 32.00 kW. The IHX2 is the most expensive equipment in the system, costing $90,931.19, but it also provides the most potential for system improvement. The multi-objective optimization findings suggest that the thermal efficiency, exergy efficiency, and ROI for the system are 0.17, 0.97, and 0.30, respectively. The LCA demonstrates that the system has a negligible influence on global warming and ozone generation with corresponding LCA findings of less than 4.20. The construction and operation phases of the investigation system have the most significant environmental consequences. The correlation between the raw materials necessary for the construction of the equipment in the system and the reaction temperatures, conditions, and waste composition during the preparation of the working fluids is large, so it is necessary to take corresponding environmental protection measures during production and processing to reduce the system's environmental emissions from the source and promote ecologically sustainable development.

Role of LECT2 in exacerbating atopic dermatitis: insight from in vivo and in vitro models via NF-κB signaling pathway.

Leukocyte cell-derived chemotaxin 2 (LECT2) is linked to various immune diseases. Previously, we reported that serum LECT2 levels correlate with disease severity in atopic dermatitis (AD) patients. To investigate the role of LECT2 in AD and elucidate its potential mechanisms, we used LECT2 to treat an AD mouse model induced by 1-Chloro-2,4-dinitrobenzene (DNCB) in LECT2 knockout (KO) and wild-type (WT) mice, and an AD cell model using TNF-α/IFN-γ-induced HaCaT cells. Inflammatory factors and barrier proteins were analyzed by histology, immunohistochemistry, RT-qPCR, ELISA, and Western Blot. Activation of the NF-κB signaling pathway was evaluated by Western Blot and immunofluorescence. In the AD mouse model, LECT2 treatment increased epidermal and dermal thickness, mast cell infiltration, and downregulated barrier proteins. Inflammatory factors were increased in skin lesions and serum. In the AD cell model, LECT2 decreased barrier protein levels and increased inflammatory factor levels, enhancing NF-κB P65 nuclear translocation. These results indicate that LECT2 exacerbates AD-like responses by dysregulating the NF-κB signaling pathway, highlighting its potential as a therapeutic target for AD management.

Enhancing mango yield and soil health with organic and slow-release fertilizers: A multifaceted evaluation.

Excessive utilization of chemical fertilizers in mango orchards not only hampers the attainment of sustainable harvests but also poses significant ecological detriments. This investigation proposes a promising solution by advocating the judicious replacement of chemical fertilizers with organic fertilizer (OF) and slow-release fertilizer (SRF), with potential to bolster soil health and augment crop productivity. In light of the promise held by these alternatives, it is imperative to establish detailed fertilization protocols for enhanced sustainable practices in mango farming. This two-year field study employed a comprehensive suite of seven fertilization strategies, unveiling that a 25 % chemical fertilizers substitution with OF and SRF improved mango yields by 12.5 % and 11.3 %, respectively, over standard practices. Additionally, these approaches substantially augmented the nutritional quality of mangoes, evident from Vitamin C enhancements of 53.9 % to 56.9 %, and improvements in sugar-to-acid ratio (19.2 %-30.3 %) and solid-to-acid ratio (12.1 %-25.3 %). Notably, the application of OF and SRF led to increased leaf nitrogen and phosphorus concentrations, while simultaneously reducing soil phosphorus and potassium levels. Furthermore, these fertilizers fostered the growth of beneficial soil microorganisms, namely Actinobacteria and Proteobacteria, and strengthened the synergy within the soil bacterial community, hence optimizing bacterial competition and nutrient cycling. The study proposes that the adoption of OF or SRF can effectively regulate soil nutrient balance, promote resilient and functional soil bacterial ecosystems, and ultimately improve mango yield and fruit quality. It recommends a fertilization scheme incorporating 25 % organic or slow-release nitrogen to align with ecological sustainability goals, promoting a more vigorous and resilient soil and crop system.

Differential uptake and translocation of perfluoroalkyl substances by vegetable roots and leaves: Insight into critical influencing factors.

Crop contamination of perfluoroalkyl substances (PFASs) may threaten human health, with root and leaves representing the primary uptake pathways of PFASs in crops. Therefore, it is imperative to elucidate the uptake characteristics of PFASs by crop roots and leaves as well as the critical influencing factors. In this study, the uptake and translocation of PFASs by roots and leaves of pak choi and radish were systematically explored based on perfluorobutanoic acid (PFBA), perfluorohexanoic acid (PFHxA), perfluorooctanoic acid (PFOA), and perfluorooctane sulfonate (PFOS). Additionally, the roles of root Casparian strips, leaf stomata, and PFAS structures in the aforementioned processes were elucidated. Compared with pak choi, PFASs are more easily transferred to leaves after root uptake in radish, resulting from the lack of root Casparian strips. In pak choi root, the bioaccumulation of C4-C8 perfluoroalkyl carboxylic acids (PFCAs) showed a U-shaped trend with the increase of their carbon chain lengths, and the translocation potentials of individual PFASs from root to leaves negatively correlated with their chain lengths. The leaf uptake of PFOA in pak choi and radish mainly depended on cuticle sorption, with the evidence of a slight decrease in the concentrations of PFOA in exposed leaves after stomatal closure induced by abscisic acid. The leaf bioaccumulation of C4-C8 PFCAs in pak choi exhibited an inverted U-shaped trend as their carbon chain lengths increased. PFASs in exposed leaves can be translocated to the root and then re-transferred to unexposed leaves in vegetables. The longer-chain PFASs showed higher translocation potentials from exposed leaves to root. PFOS demonstrated a higher bioaccumulation than PFOA in crop roots and leaves, mainly due to the greater hydrophobicity of PFOS. Planting root vegetables lacking Casparian strips is inadvisable in PFAS-contaminated environments, in view of their higher PFAS bioaccumulation and considerable human intake.

Bronchoscopic holmium laser ablation continuous cryoablation for the treatment of airway stenosis caused by tissue hyperplasia after tracheal intubation: clinical case observation.

This study aimed to design a standardised bronchoscopic holmium laser ablation continuous cryoablation for the treatment of airway stenosis caused by tissue hyperplasia after tracheal intubation and to retrospectively analyse its safety and feasibility. We collected the data of patients who had undergone bronchoscopic holmium laser ablation continuous cryoablation due to airway stenosis caused by tracheal mucosal tissue hyperplasia after tracheal intubation. The patients' baseline characteristics, ablation effects, surgical complications and other data were analysed. In total, 16 patients were enrolled in this study. On average, airway stenosis occurred 96.00 (interquartile range, 69.75-152.50) days after tracheal intubation and bronchoscopic holmium laser ablation continuous cryoablation took an average of 90.38 minutes (standard deviation: 16.78). After the first continuous cryoablation, 75.0% (12/16) of the patients had complete ablation of hyperplastic tissue, and 25.0% (4/16) had most of the hyperplastic tissue (>50%) removed. Altogether, 18.75% (3/16) and 6.25% (1/16) of the patients had complete ablation of hyperplastic tissue after the second and third cryoablation, respectively. Moreover, one patient (6.25%) had minimal wound bleeding postoperatively, and no other surgical complications occurred. No airway stenosis was found in all enrolled patients during follow-up 1 and 6 months after the last cryoablation. According to the above results of our small sample study indicated that bronchoscopic holmium laser ablation continuous cryoablation seems safe and effective for treating airway stenosis caused by tissue hyperplasia after tracheal intubation.

Self-Healing Hydrogel Resulting from the Noncovalent Interaction between Ropivacaine and Low-Molecular-Weight Gelator Sodium Deoxycholate Achieves Stable and Endurable Local Analgesia in Vivo.

Regional analgesia based on the local anesthetic ropivacaine plays a crucial role in postoperative pain management and recovery; however, the short duration of analgesia limits its clinical potential. Various drug delivery systems such as microparticles and lipid carriers have been used to prolong the analgesic effect, yet most of them are prone to abrupt release from the site of administration or have poor analgesic effects of less than 48 h, which fail to meet the needs of postoperative analgesia. In this study, a low-molecular-weight gelator sodium deoxycholate-based hydrogel loaded with ropivacaine (DC-ROP gel) was designed for long-acting analgesia. The noncovalent interaction between ropivacaine and sodium deoxycholate helps to improve the stability and sustained release performance of the gel. This internal drug-binding hydrogel also avoids experiencing the burst release effect commonly seen in polymer hydrogels previously reported for the slow release of local anesthetics. DC-ROP gel exhibited the dual advantages of self-healing after compression and long-term controlled release. In mice with inflammatory pain, DC-ROP gel achieved peripheral nerve block for more than 1 week after a single injection. Histological and blood biochemical analyses confirmed that the DC-ROP gel did not produce systemic toxicity, and cytotoxicity experiments demonstrated that the DC-ROP gel resulted in low irritation. These results suggest that DC-ROP gel provides a promising strategy for local anesthetics in long-term postoperative pain management, broadening the potential of bile salt-based low-molecular-weight hydrogels for drug delivery.

ETS1-mediated Regulation of SOAT1 Enhances the Malignant Phenotype of Oral Squamous Cell Carcinoma and Induces Tumor-associated Macrophages M2-like Polarization.

Oral squamous cell carcinoma (OSCC) is an aggressive cancer that poses a substantial threat to human life and quality of life globally. Lipid metabolism reprogramming significantly influences tumor development, affecting not only tumor cells but also tumor-associated macrophages (TAMs) infiltration. SOAT1, a critical enzyme in lipid metabolism, holds high prognostic value in various cancers. This study revealed that SOAT1 is highly expressed in OSCC tissues and positively correlated with M2 TAMs infiltration. Increased SOAT1 expression enhanced the capabilities of cell proliferation, tumor sphere formation, migration, and invasion in OSCC cells, upregulated the SREBP1-regulated adipogenic pathway, activated the PI3K/AKT/mTOR pathway and promoted M2-like polarization of TAMs, thereby contributing to OSCC growth both in vitro and in vivo. Additionally, we explored the upstream transcription factors that regulate SOAT1 and discovered that ETS1 positively regulates SOAT1 expression levels. Knockdown of ETS1 effectively inhibited the malignant phenotype of OSCC cells, whereas restoring SOAT1 expression significantly mitigated this suppression. Based on these findings, we suggest that SOAT1 is regulated by ETS1 and plays a pivotal role in the development of OSCC by facilitating lipid metabolism and M2-like polarization of TAMs. We propose that SOAT1 is a promising target for OSCC therapy with tremendous potential.

Dominant activities of fear engram cells in the dorsal dentate gyrus underlie fear generalization in mice.

Over-generalized fear is a maladaptive response to harmless stimuli or situations characteristic of posttraumatic stress disorder (PTSD) and other anxiety disorders. The dorsal dentate gyrus (dDG) contains engram cells that play a crucial role in accurate memory retrieval. However, the coordination mechanism of neuronal subpopulations within the dDG network during fear generalization is not well understood. Here, with the Tet-off system combined with immunostaining and two-photon calcium imaging, we report that dDG fear engram cells labeled in the conditioned context constitutes a significantly higher proportion of dDG neurons activated in a similar context where mice show generalized fear. The activation of these dDG fear engram cells encoding the conditioned context is both sufficient and necessary for inducing fear generalization in the similar context. Activities of mossy cells in the ventral dentate gyrus (vMCs) are significantly suppressed in mice showing fear generalization in a similar context, and activating the vMCs-dDG pathway suppresses generalized but not conditioned fear. Finally, modifying fear memory engrams in the dDG with "safety" signals effectively rescues fear generalization. These findings reveal that the competitive advantage of dDG engram cells underlies fear generalization, which can be rescued by activating the vMCs-dDG pathway or modifying fear memory engrams, and provide novel insights into the dDG network as the neuronal basis of fear generalization.

Analysis of risk factors for weaning failure from mechanical ventilation in critically ill older patients with coronavirus disease 2019.

Objective: This study aimed to investigate the factors influencing weaning failure from invasive mechanical ventilation (IMV) in critically ill older patients with coronavirus disease 2019 (COVID-19). Methods: We enrolled critically ill older patients with COVID-19 who were admitted to the medical intensive care unit (ICU) and received IMV between December 2022 and June 2023. Results: We included 68 critically ill older patients with COVID-19 (52 male [76.5 %] and 16 female individuals [23.5 %]). The patients' median age (interquartile range) was 75.5 (70.3-82.8) years. The median length of ICU stay was 11.5 (7.0-17.8) days; 34 cases (50.0 %) were successfully weaned from IMV. The successfully weaned group had a higher proportion of underlying chronic obstructive pulmonary disease [6 (17.6 %) vs. 0, P = 0.033] and fewer cases of diabetes [7 (20.6 %) vs. 16 (47.1 %), P = 0.021] compared with the weaning failure group. Serum lactate levels [1.5 (1.2-2.3) vs. 2.6 (1.9-3.1) mmol/L, P < 0.001], blood urea nitrogen [8.2 (6.3-14.4) vs. 11.4 (8.0-21.3) mmol/L, P = 0.033], Acute Physiology and Chronic Health Evaluation (APACHE) II score [19.0 (12.0-23.3) vs. 22.5 (16.0-29.3), P = 0.014], and hospitalization days before endotracheal intubation [1.0 (0.0-5.0) vs. 3.0 (0.0-11.0), P = 0.023] were significantly decreased in the successfully weaned group, whereas PaO2/FiO2 [148.3 (94.6-200.3) vs. 101.1 (67.0-165.1), P = 0.038] and blood lymphocyte levels [0.6 (0.4-1.0) vs. 0.5 (0.2-0.6) 109/L, P = 0.048] were significantly increased, compared with the weaning failure group. Multivariate logistic regression analysis showed that diabetes (OR= 3.413, 95 %CI 1.029-11.326), P = 0.045), APACHE II Score (OR = 1.089, 95 % CI 1.008-1.175), P = 0.030), and hospitalization days before endotracheal intubation (OR = 1.137, 95 % CI 1.023-1.264), P = 0.017) were independent risk factors for weaning failure. Conclusion: In critically ill older patients with COVID-19 with diabetes, higher APACHE II Score, and longer hospitalization days before endotracheal intubation, weaning from IMV was more challenging. The study could help develop strategies for improving COVID-19 treatment.