The sociality of sleep in animal groups.

Group-living animals sleep together, yet most research treats sleep as an individual process. Here, we argue that social interactions during the sleep period contribute in important, but largely overlooked, ways to animal groups' social dynamics, while patterns of social interaction and the structure of social connections within animal groups play important, but poorly understood, roles in shaping sleep behavior. Leveraging field-appropriate methods, such as direct and video-based observation, and increasingly common on-animal motion sensors (e.g., accelerometers), behavioral indicators can be tracked to measure sleep in multiple individuals in a group of animals simultaneously. Sleep proximity networks and sleep timing networks can then be used to investigate the collective dynamics of sleep in wild group-living animals.

Prognostic and immune infiltration implications of SIGLEC9 in SKCM.

The occurrence and progression of skin cutaneous melanoma (SKCM) is strongly associated with immune cells infiltrating the tumor microenvironment (TME). This study examined the expression, prognosis, and immune relevance of SIGLEC9 in SKCM using multiple online databases. Analysis of the GEPIA2 and Ualcan databases revealed that SIGLEC9 is highly expressed in SKCM, and patients with high SIGLEC9 expression had improved overall survival (OS). Furthermore, the mutation rate of SIGLEC9 in SKCM patients was found to be 5.41%, the highest observed. The expression of SIGLEC9 was positively correlated with macrophages, neutrophils and B cells, CD8 + T cells, CD4 + T cells, and dendritic cells, according to TIMER. Based on TCGA-SKCM data, we verified that high SIGLEC9 expression is closely associated with a good prognosis for SKCM patients, including overall survival, progression-free interval, and disease-specific survival. This positive prognosis could be due to the infiltration of immune cells into the TME. Additionally, our analysis of single-cell transcriptome data revealed that SIGLEC9 not only played a role in the normal skin immune microenvironment, but is also highly expressed in immune cell subpopulations of SKCM patients, regulating the immune response to tumors. Our findings suggest that the close association between SIGLEC9 and SKCM prognosis is primarily mediated by its effect on the tumor immune microenvironment.

Antimicrobial polymer-based zeolite imidazolate framework composite membranes for uranium extraction from wastewater and seawater.

Extraction uranium (VI) (U(VI)) from wastewater and seawater is highly important for environmental protection and life safety, but it remains a great challenge. In this work, the growth of the zeolitic imidazolate framework-8 (ZIF-8) nanoparticles on the tannic acid (TA)-3-aminopropyltriethoxysilane (APTES) modified PVDF (TAP) membrane was designed to obtain an excellent U(VI) adsorbent. The zeolite imidazolate framework composite membrane (TAPP-ZIF-60) was prepared through polyethyleneimine (PEI) bridging strategy and temperature regulation strategy in solvothermal method. The coordination bond between PEI and ZIF-8 and the covalent bond between PEI and TAP are essential in forming stable composite membrane. TAPP-ZIF with different properties was synthesized through a temperature regulation process and the TAPP-ZIF prepared at 60 °C has the uniform morphology and good performance. The adsorption capacity of TAPP-ZIF-60 is 153.68 mg/g (C0 = 95.01 mg/L and pH = 8.0) and water permeability is 5459 L m-2 h-1 bar-1. After ten adsorption-desorption cycles, it is proved that TAPP-ZIF-60 has good repeatability and stability. In addition, the TAPP-ZIF-60 composites membrane has a good inhibitory effect on Staphylococcus aureus and Escherichia coli. X-ray photoelectron spectroscopy (XPS) and density functional theory (DFT) analysis reveal that the coordination between TAPP-ZIF-60 and uranyl ions is the primary factor contributing to the high adsorption capacity.

A robust amphiphilic ionic covalent organic framework intercalated into functionalized graphene oxide hybrid membranes for ultrafast extraction uranium from wastewater.

The efficient capture of uranium from wastewater is crucial for environmental remediation and the sustainable development of nuclear energy, yet it poses considerable challenges. In this study, amphiphilic ionic covalent organic framework intercalated into graphene oxide (GO) nanosheets functionalized with polyethyleneimine (PEI) were used to construct hybrid membranes with ultrafast uranium adsorption. These hybrid membranes achieved equilibrium in just 10 min and the adsorption capacity was as high as 358.8 mg g-1 at pH = 6. X-ray photoelectron spectroscopy (XPS) and density functional theory (DFT) analyses revealed that the strong interaction between sulfonic acid groups and uranyl ions was the primary reason for the high adsorption capacity and selectivity. The extended transition state and natural orbitals for chemical valence (ETS-NOCV) analysis revealed that the interaction between the 7 s and 5f orbitals of uranyl and the 2p orbitals of S and O in the sulfonate was the primary reason for the strong interaction between the sulfonate and the uranyl ion. This research presents an effective method for the rapid extraction of uranium from wastewater.

Artificial neural network prediction of postoperative complications in papillary thyroid microcarcinoma based on preoperative ultrasonographic features.

OBJECTIVE: To predict post-thyroidectomy complications in papillary thyroid microcarcinoma (PTMC) patients using a deep learning model based on preoperative ultrasonographic features. This study addresses the global rise in PTMC incidence and the challenges in treatment decision-making with high-resolution ultrasonography. METHOD: This study enrolled 1638 patients with clinically staged cN0 PTMC who received surgical treatment from 1997 to 2019 at Beijing Friendship Hospital. Deep learning model was developed using fully connected neural network. Feature selection included 1000 iterations of Bootstrap sampling and Recursive Feature Elimination (RFE) to identify the top 10 features. Data preprocessing involved normalization and imputation for missing values. SMOTE addressed class imbalance. The model was trained and tested on random data split, with performance metrics including Accuracy (ACC), Area Under the Curve (AUC), Sensitivity (SEN), and Specificity (SPE), visualized through a ROC curve and confusion matrix. RESULTS: The fully connected deep neural network model demonstrated high accuracy (ACC 0.81), Area Under the Curve (AUC 0.74), sensitivity (SEN 0.65), and specificity (SPE 0.83) and visualized by ROC curve and confusion matrix. These results highlight the model's reliability and potential as an effective tool in predicting postoperative complications and assisting in clinical decision-making for PTMC patients. CONCLUSION: This study highlights the potential of deep learning in enhancing medical predictions and personalized healthcare. Despite promising results, limitations include a single-center data source and unconsidered factors like lifestyle and genetics. Future research should expand data sources, include more influencing factors, and refine algorithms to improve accuracy and applicability in thyroid cancer treatment.

Effectiveness and safety of sequential transarterial chemoembolization and microwave ablation for subphrenic hepatocellular carcinoma: A comprehensive evaluation.

BACKGROUND: Subphrenic carcinoma has been identified as a significant risk factor for the thermal ablation of intrahepatic tumors, resulting in a high rate of residual tumor recurrence. Some studies have proposed that combination treatment with transarterial chemoembolization (TACE) followed by radiofrequency ablation is both feasible and safe for tumors in the subphrenic region. However, research specifically examining the therapeutic outcomes of combination therapy using TACE and microwave ablation (TACE-MWA) in subphrenic tumors is lacking. AIM: To evaluate the efficacy and safety of TACE-MWA in patients with subphrenic hepatocellular carcinoma (HCC). METHODS: Between December 2017 and December 2021, 49 patients diagnosed with HCC ≤ 6 cm, who received TACE-MWA, were included in this retrospective cohort study. These patients were classified into subphrenic and non-subphrenic groups based on the distance between the diaphragm and the tumor margin. The rates of local tumor progression (LTP), progression-free survival (PFS), and overall survival (OS) were compared between the two groups. Complications were evaluated by using a grading system developed by the Society of Interventional Radiology. RESULTS: After a median follow-up time of 38 mo, there were no significant differences in LTP between the subphrenic and non-subphrenic groups (27.3% and 22.2% at 5 years, respectively; P = 0.66), PFS (55.5% at 5 years in both groups; P = 0.91), and OS (85.0% and 90.9% in the subphrenic and non-subphrenic groups at 5 years; P = 0.57). However, a significantly higher rate of LTP was observed in subphrenic HCC > 3 cm compared to those ≤ 3 cm (P = 0.085). The dosage of iodized oil [hazard ratio (HR): 1.52; 95% confidence interval (CI): 1.11-2.08; P = 0.009] and multiple tumors (HR: 13.22; 95%CI: 1.62-107.51; P = 0.016) were independent prognostic factors for LTP. There were no significant differences in complication rates between the two groups (P = 0.549). CONCLUSION: Combined TACE and MWA was practical and safe for managing subphrenic HCC. The efficacy and safety levels did not vary significantly when tumors outside the subphrenic region were treated.

Single-Cell RNA Sequencing Deconstructs the Distribution of Immune Cells Within Abdominal Aortic Aneurysms in Mice.

BACKGROUND: Inflammation is a key component in the development of abdominal aortic aneurysm (AAA), yet insights into the roles of immune cells and their interactions in this process are limited. METHODS: Using single-cell RNA transcriptomic analysis, we deconstructed the CD45+ cell population in elastase-induced murine AAA at the single-cell level. We isolated each group of immune cells from murine AAA tissue at different time points and divided them into several subtypes, listed the remarkable differentially expressed genes, explored the developmental trajectories of immune cells, and demonstrated the interactions among them. RESULTS: Our findings reveal significant differences in several immune cell subsets, including macrophages, dendritic cells, and T cells, within the AAA microenvironment compared with the normal aorta. Especially, conventional dendritic cell type 1 exclusively existed in the AAA tissue rather than the normal aortas. Via CellChat analysis, we identified several intercellular communication pathways like visfatin, which targets monocyte differentiation and neutrophil extracellular trap-mediated interaction between neutrophils and dendritic cells, which might contribute to AAA development. Some of these pathways were validated in human AAA. CONCLUSIONS: Despite the absence of external pathogenic stimuli, AAA tissues develop a complex inflammatory microenvironment involving numerous immune cells. In-depth studies of the inflammatory network shall provide new strategies for patients with AAA.

A highly effective ferritin-based divalent nanoparticle vaccine shields Syrian hamsters against lethal Nipah virus.

The Nipah virus (NiV), a highly deadly bat-borne paramyxovirus, poses a substantial threat due to recurrent outbreaks in specific regions, causing severe respiratory and neurological diseases with high morbidity. Two distinct strains, NiV-Malaysia (NiV-M) and NiV-Bangladesh (NiV-B), contribute to outbreaks in different geographical areas. Currently, there are no commercially licensed vaccines or drugs available for prevention or treatment. In response to this urgent need for protection against NiV and related henipaviruses infections, we developed a novel homotypic virus-like nanoparticle (VLP) vaccine co-displaying NiV attachment glycoproteins (G) from both strains, utilizing the self-assembling properties of ferritin protein. In comparison to the NiV G subunit vaccine, our nanoparticle vaccine elicited significantly higher levels of neutralizing antibodies and provided complete protection against a lethal challenge with NiV infection in Syrian hamsters. Remarkably, the nanoparticle vaccine stimulated the production of antibodies that exhibited superior cross-reactivity to homologous or heterologous henipavirus. These findings underscore the potential utility of ferritin-based nanoparticle vaccines in providing both broad-spectrum and long-term protection against NiV and emerging zoonotic henipaviruses challenges.

Photodynamically Tumor Vessel Destruction Amplified Tumor Targeting of Nanoparticles for Efficient Chemotherapy.

Efficient tumor-targeted drug delivery is still a challenging and currently unbreakable bottleneck in chemotherapy for tumors. Nanomedicines based on passive or active targeting strategy have not yet achieved convincing chemotherapeutic benefits in the clinic due to the tumor heterogeneity. Inspired by the efficient inflammatory-cell recruitment to acute clots, we constructed a two-component nanosystem, which is composed of an RGD-modified pyropheophorbide-a (Ppa) micelle (PPRM) that mediates the tumor vascular-targeted photodynamic reaction to activate local coagulation and subsequently transmits the coagulation signals to the circulating clot-targeted CREKA peptide-modified camptothecin (CPT)-loaded nanodiscs (CCNDs) for amplifying tumor targeting. PPRM could effectively bind with the tumor vasculature and induce sufficient local thrombus by a photodynamic reaction. Local photodynamic reaction-induced tumor target amplification greatly increased the tumor accumulation of CCND by 4.2 times, thus significantly enhancing the chemotherapeutic efficacy in the 4T1 breast tumor model. In other words, this study provides a powerful platform to amplify tumor-specific drug delivery by taking advantage of the efficient crosstalk between the PPRM-activated coagulation cascade and clot-targeted CCND.

LARS1 is a Prognostic Biomarker and Exhibits a Correlation with Immune Infiltrates in Hepatocellular Carcinoma.

Purpose: To study the relationship between LARS1 expression and immune infiltration and prognosis in hepatocellular carcinoma (HCC). Patients and Methods: The clinical characteristics together with LARS1 expression levels were obtained from the TCGA database. Immunohistochemistry confirmed LARS1 expression levels in paraneoplastic and tumor tissues. To investigate LARS1-related downstream molecules, a network of protein-protein interactions (PPIs) and the Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) were built. Furthermore, gene set enrichment analysis (GSEA) was used to analyze the pathways associated with LARS1 expression, whereas Single-sample GSEA (ssGSEA) was applied to perform an association study between immune infiltration and LARS1 gene expression. The TISCH Database and the TISIDB database were used to compare the difference of LARS1 expression in hepatocellular carcinoma and immunomodulators. Results: In comparison to that in normal tissues, the LARS1 expression level was elevated in tumor tissues. LARS1 expression exhibited substantial correlation with AFP, Histologic grade, pathologic stage, Residual tumor, and Vascular invasion in HCC. Higher LARS1 expression in HCC was linked to lower progression-free survival (PFS), disease-specific survival (DSS), and overall survival (OS). According to the GO/KEGG study, the important biological process (neutral lipid metabolic process), cellular component (triglyceride-rich plasma lipoprotein), molecular functions (lipase inhibitor activity), and KEGG pathway (cholesterol metabolism) could be a probable function mechanism in promoting HCC. Various pathways as per GSEA revealed that they were enriched in samples with elevated LARS1 expression. The expression level of LARS1 in malignant tumor cells after immunotherapy was significantly higher than that before immunotherapy. LARS1 was also remarkably linked to the infiltration level and the immunomodulators. Conclusion: LARS1 can be used as a biomarker of HCC, which is associated to immune infiltration of HCC.

Updated mechanisms of MASLD pathogenesis.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has garnered considerable attention globally. Changing lifestyles, over-nutrition, and physical inactivity have promoted its development. MASLD is typically accompanied by obesity and is strongly linked to metabolic syndromes. Given that MASLD prevalence is on the rise, there is an urgent need to elucidate its pathogenesis. Hepatic lipid accumulation generally triggers lipotoxicity and induces MASLD or progress to metabolic dysfunction-associated steatohepatitis (MASH) by mediating endoplasmic reticulum stress, oxidative stress, organelle dysfunction, and ferroptosis. Recently, significant attention has been directed towards exploring the role of gut microbial dysbiosis in the development of MASLD, offering a novel therapeutic target for MASLD. Considering that there are no recognized pharmacological therapies due to the diversity of mechanisms involved in MASLD and the difficulty associated with undertaking clinical trials, potential targets in MASLD remain elusive. Thus, this article aimed to summarize and evaluate the prominent roles of lipotoxicity, ferroptosis, and gut microbes in the development of MASLD and the mechanisms underlying their effects. Furthermore, existing advances and challenges in the treatment of MASLD were outlined.

[LASSO regression based risk prediction model for postoperative control in chronic sinusitis with nasal polyps].

Objective:To establish a risk prediction model for postoperative control of chronic sinusitis with nasal polyps. Methods:Retrospective analysis was done on the clinical of patients who underwent endoscopic sinus surgery in the Department of Otolaryngology of the First Affiliated Hospital of Soochow University during August 2020 to June 2021. Patients were classified into uncontrolled group（40 cases） and controlled group（104 cases）, based on the European Position Paper on rhinosinusitis and nasal polyps（EPOS 2020）, and the clinical and pathological characteristics of the two groups were compared. The least absolute shrinkage and selection operator（LASSO） regression was used to screen the factors that might affect the prognosis of chronic sinusitis with nasal polyps and multivariate logistic regression was performed. The Receiver operating characteristic curve（ROC） was ploted, the area under curve（AUC） was calculated, and the ability of the prediction model was evaluated using the consistency index（C-index）. Results:A total of 144 patients with CRS with nasal polyps 1 year after operation were enrolled in this study, including 40 patients in the uncontrolled group and 104 patients in the control group（complete control or partial control）. 12 risk factors（allergic rhinitis, allergic dermatitis, olfactory dysfunction, E/M ratio, serum alkaline phosphatase, number of pathological eosinophils, number of pathological lymphocytes, number of plasma cells in pathological tissues, percentage of eosinophils in pathological tissues, stromal edema, basement membrane thickening, and hyperplasia of goblet cells） were found to be associated with postoperative recurrence of chronic sinusitis with nasal polyps. The seven variables（allergic rhinitis, olfactory dysfunction, E/M ratio, pathological eosinophilic percentage, stromal edema, basement membrane thickening, and hyperplasia of goblet cell） were extracted after reduced by LASSO regression. Multivariate logistic regression analysis showed that the 7 variables were risk factors for postoperative recurrence of chronic sinusitis with nasal polyps（P<0.05）. Nomogram prediction model for postoperative recurrence of chronic sinusitis with nasal polyps were established based on the 7 variables above. The verification results of the model showed that the C-index and AUC of the model were 0.937 and 0.937（95%CI 0.901-0.973）, suggesting that the nomogram model had a relatively accurate prediction ability. Conclusion:Combined with the basic clinical data of patients, the prediction model established in this study can facilitate the risk prediction of postoperative control of chronic sinusitis with nasal polyps, and thus help to formulate better therapeutic plans for patients.

Carboxymethyl cellulose and metal-organic frameworks immobilized into polyacrylamide hydrogel for ultrahigh efficient and selective adsorption U(VI) from seawater.

Metal-organic frameworks (MOF)-polymer hybrid hydrogel solves the processable forming of MOF powder and energy consumption of uranium extraction. However, the hybrid hydrogel by conventional synthesis methods inevitably lead to MOF agglomeration, poor filler-polymer interfacial compatibility and slowly adsorption. Herein, we designed that ZIF-67 was implanted into the carboxymethyl cellulose/polyacrylamide (CMC/PAM) by network-repairing strategy. The carboxyl and amino groups on the surface of CMC/PAM drive the uniform growth of ZIF-67 inside the CMC/PAM, which form an array of oriented and penetrating microchannels through coordination bonds. Our strategy eliminate the ZIF-67 agglomeration, increase the interfacial compatibility between MOF and polymer. The method also improve the free and fast diffusion of uranium in CMC/PAM/ZIF-67 hydrogel. According to the experimental, these enhancements synergistically enabled the CMC/PAM/ZIF-67 have a maximum adsorption capacity of 952 mg g-1. The adsorption process of CMC/PAM/ZIF-67 fits well with pseudo-second-order model and Langmuir isotherm. Meanwhile, the CMC/PAM/ZIF-67 maintain a high removal rate (87.3 %) and chemical stability even during ten adsorption-desorption cycles. It is worth noting that the adsorption amount of CMC/PAM/ZIF-67 in real seawater is 9.95 mg g-1 after 20 days, which is an ideal candidate adsorbent for uranium extraction from seawater.

Manipulating Redox Homeostasis of Cancer Stem Cells Overcome Chemotherapeutic Resistance through Photoactivatable Biomimetic Nanodiscs.

Tumor heterogeneity remains a significant obstacle in cancer therapy due to diverse cells with varying treatment responses. Cancer stem-like cells (CSCs) contribute significantly to intratumor heterogeneity, characterized by high tumorigenicity and chemoresistance. CSCs reside in the depth of the tumor, possessing low reactive oxygen species (ROS) levels and robust antioxidant defense systems to maintain self-renewal and stemness. A nanotherapeutic strategy is developed using tumor-penetrating peptide iRGD-modified high-density lipoprotein (HDL)-mimetic nanodiscs (IPCND) that ingeniously loaded with pyropheophorbide-a (Ppa), bis (2-hydroxyethyl) disulfide (S-S), and camptothecin (CPT) by synthesizing two amphiphilic drug-conjugated sphingomyelin derivatives. Photoactivatable Ppa can generate massive ROS which as intracellular signaling molecules effectively shut down self-renewal and trigger differentiation of the CSCs, while S-S is utilized to deplete GSH and sustainably imbalance redox homeostasis by reducing ROS clearance. Simultaneously, the depletion of GSH is accompanied by the release of CPT, which leads to subsequent cell death. This dual strategy successfully disturbed the redox equilibrium of CSCs, prompting their differentiation and boosting the ability of CPT to kill CSCs upon laser irradiation. Additionally, it demonstrated a synergistic anti-cancer effect by concurrently eliminating therapeutically resistant CSCs and bulk tumor cells, effectively suppressing tumor growth in CSC-enriched heterogeneous colon tumor mouse models.

High-Throughput Screening of pH-Dependent ß-sheet Self-Assembling Peptide.

pH-dependent peptide biomaterials hold tremendous potential for cell delivery and tissue engineering. However, identification of responsive self-assembling sequences with specified secondary structure remains a challenge. In this work, An experimental procedure based on the one-bead one-compound (OBOC) combinatorial library is developed to rapidly screen self-assembling ß-sheet peptides at neutral aqueous solution (pH 7.5) and disassemble at weak acidic condition (pH 6.5). Using the hydrophobic fluorescent molecule thioflavin T (ThT) as a probe, resin beads displaying self-assembling peptides show fluorescence under pH 7.5 due to the insertion of ThT into the hydrophobic domain, and are further cultured in pH 6.5 solution. The beads with extinguished fluorescence are selected. Three heptapeptides are identified that can self-assemble into nanofibers or nanoparticles at pH 7.5 and disassemble at pH 6.5. P1 (LVEFRHY) shows a rapid acid response and morphology transformation with pH modulation. Changes in the charges of histidine and hydrophobic phenyl motif of phenylalanine may play important roles in the formation of pH-responsive ß-sheet nanofiber. This high-throughput screening method provides an efficient way to identify pH-dependent ß-sheet self-assembling peptide and gain insights into structural design of such nanomaterials.

Novel antiviral discoveries for Japanese encephalitis virus infections through reporter virus-based high-throughput screening.

Japanese encephalitis (JE) caused by JE virus (JEV), remains a global public health concern. Currently, there is no specific antiviral drug approved for the treatment of JE. While vaccines are available for prevention, they may not cover all at-risk populations. This underscores the urgent need for prophylaxis and potent anti-JEV drugs. In this context, a high-content JEV reporter system expressing Nanoluciferase (Nluc) was developed and utilized for a high-throughput screening (HTS) of a commercial antiviral library to identify potential JEV drug candidates. Remarkably, this screening process led to the discovery of five drugs with outstanding antiviral activity. Further mechanism of action analysis revealed that cepharanthine, an old clinically approved drug, directly inhibited virus replication by blocking GTP binding to the JEV RNA-dependent RNA polymerase. Additionally, treatment with cepharanthine in mice models alleviated JEV infection. These findings warrant further investigation into the potential anti-JEV activity of cepharanthine as a new therapeutic approach for the treatment of JEV infection. The HTS method employed here proves to be an accurate and convenient approach that facilitates the rapid development of antiviral drugs.

Up-front autologous stem cell transplant in peripheral T-cell lymphoma patients achieving complete response after first-line treatment: A multicentre real-world analysis.

We conducted a retrospective, multicentre study to compare consolidation therapy with or without first-line autologous stem cell transplant (ASCT) for peripheral T-cell lymphoma (PTCL) patients in a real-world setting. We enrolled 347 PTCL patients who achieved complete response after first-line treatment. Of these, 257 received consolidation chemotherapy (non-ASCT group) and 90 received ASCT (ASCT group). Clinical outcomes were comparable between ASCT and non-ASCT groups. After propensity score matching, the 2-year cumulative incidence of treatment-related mortality and relapse remained similar between groups (1.9% vs. 2.0%, p = 0.985; 24.7% vs. 47.1%, p = 0.021). However, significant differences emerged in progression-free survival and overall survival probabilities. Within the T-cell lymphoma subgroup, ASCT patients exhibited favourable outcomes compared to non-ASCT patients: 2-year progression-free survival (73.4% vs. 50.8%, p = 0.024) and overall survival (92.1% vs. 73.5%, p = 0.021). Notably, no significant differences were observed for patients with NK/T-cell lymphoma. These real-world data suggest that up-front ASCT is a safe and effective consolidation option for PTCL patients in remission, particularly those with T-cell lymphoma.

Yi-qi-hua-yu-jie-du decoction induces ferroptosis in cisplatin-resistant gastric cancer via the AKT/GSK3ß/NRF2/GPX4 axis.

BACKGROUND: Resistance to chemotherapy in gastric cancer (GC) is a ubiquitous challenge for its treatment. Yi-qi-hua-yu-jie-du decoction (YJD), an empirical formula in Traditional Chinese Medicine (TCM), demonstrated survival-prolonging functions in patients with GC. Previous research has shown that YJD could also inhibit drug resistance in GC. However, the precise mechanisms for how YJD accomplishes this remain incompletely explained. PURPOSE: The research aimed to identify differential metabolic characteristics in cisplatin-resistant GC and investigate whether YJD can target these differences to suppress GC drug resistance. METHODS: Metabolomic analysis was conducted to identify metabolic disparities between cisplatin-resistant and parental GC cells, as well as metabolic modifications resulting from YJD intervention in cisplatin-resistant GC cells. The effect of YJD on ferroptosis stimulation was assessed by measuring the levels of reactive oxygen species (ROS), malondialdehyde (MDA), iron ions, the reduced glutathione (GSH) to oxidised glutathione (GSSG) ratio, and alterations in mitochondrial morphology. Western blotting and quantitative real-time polymerase chain reaction (Q-PCR) were employed to verity the mechanisms of YJD-triggered ferroptosis through GPX4 and NRF2 overexpression models, alongside the AKT activator SC79. In vivo validation was conducted using nude mouse xenograft models. RESULTS: Cisplatin-resistant GC exhibited altered GSH/GPX4 metabolism, and ferroptosis was a significantly enriched cell death pattern with YJD treatment in cisplatin-resistant GC cells. Ferroptosis biomarkers, including ROS, MDA, iron ions, the GSH/GSSG ratio, and mitochondrial morphology, were remarkably changed with the YJD intervention. Mechanistic experiments demonstrated that YJD inhibited the phosphorylation cascade activity of the AKT/GSK3ß pathway, thereby reducing NRF2 expression. The level of GPX4, a crucial enzyme involved in glutathione metabolism, was attenuated, facilitating ferroptosis induction in cisplatin-resistant GC. CONCLUSION: The research reveals, for the first time, changes in GSH/GPX4 metabolism in cisplatin-resistant GC cells based on metabolomic analysis. YJD induced ferroptosis in cisplatin-resistant GC by inhibiting GPX4 through the AKT/GSK3ß/NRF2 pathway, thus attenuating the cisplatin drug resistance in GC. Our findings identify metabolic changes in cisplatin-resistant GC and establish a theoretical framework for YJD on tackling drug resistance in GC through ferroptosis.

Vaccines based on the fusion protein consensus sequence protect Syrian hamsters from Nipah virus infection.

Nipah virus (NiV), a bat-borne paramyxovirus, results in neurological and respiratory diseases with high mortality in humans and animals. Developing vaccines is crucial for fighting these diseases. Previously, only a few studies focused on the fusion (F) protein alone as the immunogen. Numerous NiV strains have been identified, including 2 representative strains from Malaysia (NiV-M) and Bangladesh (NiV-B), which differ significantly from each other. In this study, an F protein sequence with the potential to prevent different NiV strain infections was designed by bioinformatics analysis after an in-depth study of NiV sequences in GenBank. Then, a chimpanzee adenoviral vector vaccine and a DNA vaccine were developed. High levels of immune responses were detected after AdC68-F, pVAX1-F, and a prime-boost strategy (pVAX1-F/AdC68-F) in mice. After high titers of humoral responses were induced, the hamsters were challenged by the lethal NiV-M and NiV-B strains separately. The vaccinated hamsters did not show any clinical signs and survived 21 days after infection with either strain of NiV, and no virus was detected in different tissues. These results indicate that the vaccines provided complete protection against representative strains of NiV infection and have the potential to be developed as a broad-spectrum vaccine for human use.

Both chimpanzee adenovirus-vectored and DNA vaccines induced long-term immunity against Nipah virus infection.

Nipah virus (NiV) is a highly lethal zoonotic paramyxovirus that poses a severe threat to humans due to its high morbidity and the lack of viable countermeasures. Vaccines are the most crucial defense against NiV infections. Here, a recombinant chimpanzee adenovirus-based vaccine (AdC68-G) and a DNA vaccine (DNA-G) were developed by expressing the codon-optimized full-length glycoprotein (G) of NiV. Strong and sustained neutralizing antibody production, accompanied by an effective T-cell response, was induced in BALB/c mice by intranasal or intramuscular administration of one or two doses of AdC68-G, as well as by priming with DNA-G and boosting with intramuscularly administered AdC68-G. Importantly, the neutralizing antibody titers were maintained for up to 68 weeks in the mice that received intramuscularly administered AdC68-G and the prime DNA-G/boost AdC68-G regimen, without a significant decline. Additionally, Syrian golden hamsters immunized with AdC68-G and DNA-G via homologous or heterologous prime/boost immunization were completely protected against a lethal NiV virus challenge, without any apparent weight loss, clinical signs, or pathological tissue damage. There was a significant reduction in but not a complete absence of the viral load and number of infectious particles in the lungs and spleen tissue following NiV challenge. These findings suggest that the AdC68-G and DNA-G vaccines against NiV infection are promising candidates for further development.