Genetically engineered CD276-anchoring biomimetic nanovesicles target senescent escaped tumor cells to overcome chemoresistant and immunosuppressive breast cancer.

Chemotherapy-induced cellular senescence leads to an increased proportion of cancer stem cells (CSCs) in breast cancer (BC), contributing to recurrence and metastasis, while effective means to clear them are currently lacking. Herein, we aim to develop new approaches for selectively killing senescent-escape CSCs. High CD276 (95.60%) expression in multidrug-resistant BC cells, facilitates immune evasion by low-immunogenic senescent escape CSCs. CALD1, upregulated in ADR-resistant BC, promoting senescent-escape of CSCs with an anti-apoptosis state and upregulating CD276, PD-L1 to promote chemoresistance and immune escape. We have developed a controlled-released thermosensitive hydrogel containing pH- responsive anti-CD276 scFV engineered biomimetic nanovesicles to overcome BC in primary, recurrent, metastatic and abscopal humanized mice models. Nanovesicles coated anti-CD276 scFV selectively fuses with cell membrane of senescent-escape CSCs, then sequentially delivers siCALD1 and ADR due to pH-responsive MnP shell. siCALD1 together with ADR effectively induce apoptosis of CSCs, decrease expression of CD276 and PD-L1, and upregulate MHC I combined with Mn2+ to overcome chemoresistance and promote CD8+T cells infiltration. This combined therapeutic approach reveals insights into immune surveillance evasion by senescent-escape CSCs, offering a promising strategy to immunotherapy effectiveness in cancer therapy.

Fluorescence and photoacoustic (FL/PA) dual-modal probe: Responsive to reactive oxygen species (ROS) for atherosclerotic plaque imaging.

Accurate and early detection of atherosclerosis (AS) is imperative for their effective treatment. However, fluorescence probes for efficient diagnosis of AS often encounter insufficient deep tissue penetration, which hinders the reliable assessment of plaque vulnerability. In this work, a reactive oxygen species (ROS) activated near-infrared (NIR) fluorescence and photoacoustic (FL/PA) dual model probe TPA-QO-B is developed by conjugating two chromophores (TPA-QI and O-OH) and ROS-specific group phenylboronic acid ester. The incorporation of ROS-specific group not only induces blue shift in absorbance, but also inhibits the ICT process of TPA-QO-OH, resulting an ignorable initial FL/PA signal. ROS triggers the convertion of TPA-QO-B to TPA-QO-OH, resulting in the concurrent amplification of FL/PA signal. The exceptional selectivity of TPA-QO-B towards ROS makes it effectively distinguish AS mice from the healthy. The NIR emission can achieve a tissue penetration imaging depth of 0.3 cm. Moreover, its PA775 signal possesses the capability to penetrate tissues up to a thickness of 0.8 cm, ensuring deep in vivo imaging of AS model mice in early stage. The ROS-triggered FL/PA dual signal amplification strategy improves the accuracy and addresses the deep tissue penetration problem simultaneously, providing a promising tool for in vivo tracking biomarkers in life science and preclinical applications.

Coffee intake leads to preeclampsia-like syndromes in susceptible pregnant rats.

Coffee is one of the most popular beverages worldwide, and there is an increasing concern of the health risk of coffee consumption in pregnancy. Preeclampsia (PE) is a serious pregnancy disease that causes elevated blood pressure and proteinuria in pregnant women and growth restriction of fetuses due to poorly developed placental vasculature. The aim of our study is to investigate the possible effect of coffee intake during pregnancy in rats with potential underlying vasculature conditions. The endothelial nitric oxide synthase inhibitor N(gamma)-nitro-L-arginine methyl ester (L-NAME) at a high dose (125 mg/kg/d) was used to induce PE in pregnant rats, which were used as the positive control group. In addition, low-dose L-NAME (10 mg/kg/d) was used to simulate the compromised placental vasculature function in pregnant rats. Coffee was given together with low-dose L-NAME to the pregnant rats from gestational day 10.5-18.5. Our results show that the pregnant rats treated with low-dose L-NAME + coffee, but not low-dose L-NAME alone, developed PE symptoms such as prominent fetal growth restriction, hypertension, and proteinuria. Therefore, our findings suggest that coffee intake during pregnancy may cause an increased risk of PE in susceptible women.

Engineered Biomimetic Nanovesicles Synergistically Remodel Folate-Nucleotide and γ-Aminobutyric Acid Metabolism to Overcome Sunitinib-Resistant Renal Cell Carcinoma.

Reprogramming of cellular metabolism in tumors promoted the epithelial-mesenchymal transition (EMT) process and established immune-suppressive tumor microenvironments (iTME), leading to drug resistance and tumor progression. Therefore, remodeling the cellular metabolism of tumor cells was a promising strategy to overcome drug-resistant tumors. Herein, CD276 and MTHFD2 were identified as a specific marker and a therapeutic target, respectively, for targeting sunitinib-resistant clear cell renal cell carcinoma (ccRCC) and its cancer stem cell (CSC) population. The blockade of MTHFD2 was confirmed to overcome drug resistance via remodeling of folate-nucleotide metabolism. Moreover, the manganese dioxide nanoparticle was proven here by a high-throughput metabolome to be capable of remodeling γ-aminobutyric acid (GABA) metabolism in tumor cells to reconstruct the iTME. Based on these findings, engineered CD276-CD133 dual-targeting biomimetic nanovesicle EMφ-siMTHFD2-MnO2@Suni was designed to overcome drug resistance and terminate tumor progression of ccRCC. Using ccRCC-bearing immune-humanized NPG model mice, EMφ-siMTHFD2-MnO2@Suni was observed to remodel folate-nucleotide and GABA metabolism to deactivate the EMT process and reconstruct the iTME thereby overcoming the drug resistance. In the incomplete-tumor-resection recurrence model and metastasis model, EMφ-siMTHFD2-MnO2@Suni reduced recurrence and metastasis in vivo. This work thus provided an innovative approach that held great potential in the treatment of drug-resistant ccRCC by remodeling cellular metabolism.

The association of psoriasis with composite dietary antioxidant index and its components: a cross-sectional study from the National Health and Nutrition Examination Survey.

BACKGROUND: Psoriasis is a chronic inflammatory skin disorder associated with various comorbidities. The role of nutrition and dietary antioxidants in psoriasis management has gained attention. The Composite Dietary Antioxidant Index (CDAI) quantifies overall dietary antioxidant intake, but its association with psoriasis remains unclear. This study aimed to investigate the association between the CDAI and psoriasis, as well as the relationship between individual components of CDAI and psoriasis risk. METHODS: Data from the US National Health and Nutrition Examination Survey (NHANES) were analyzed. Baseline characteristics, CDAI scores, and psoriasis status were assessed. Multivariable logistic regression and restricted cubic splines were employed to analyze the association. RESULTS: The study included 23,311 participants, with 621 diagnosed with psoriasis. Higher CDAI scores were associated with a lower odds ratio (OR) of psoriasis occurrence (OR = 0.72, 95% CI 0.56-0.92, P = 0.009 in Model 3). Vitamin E intake exhibited an inverse correlation with psoriasis risk (OR = 0.76, 95% CI 0.60-0.96, P = 0.039 in Model 3). Other CDAI components did not show significant associations with psoriasis. CONCLUSION: This study demonstrates a significant inverse association between CDAI and psoriasis, indicating that higher dietary antioxidant intake is associated with a reduced risk of psoriasis. Specifically, higher vitamin E intake was associated with a lower likelihood of psoriasis. These findings underscore the potential role of dietary antioxidants in psoriasis management. Further research is warranted to elucidate the underlying mechanisms and explore targeted dietary interventions.

Unveiling the role of uranium in enhancing the transformation of antibiotic resistance genes.

Transformation represents one of the most important pathways for the horizontal transfer of antibiotic resistance genes (ARGs), which enables competent bacteria to acquire extracellular ARGs from the surrounding environment. Both heavy metals and irradiation have been demonstrated to influence the bacterial transformation process. However, the impact of ubiquitously occurring radioactive heavy metals on the transformation of ARGs remains largely unknown. Here, we showed that a representative radioactive nuclide, uranium (U), at environmental concentrations (0.005-5 mg/L), improved the transformation frequency of resistant plasmid pUC19 into Escherichia coli by 0.10-0.85-fold in a concentration-dependent manner. The enhanced ARGs transformation ability under U stress was demonstrated to be associated with reactive oxygen species (ROS) overproduction, membrane damage, and up-regulation of genes related to DNA uptake and recombination. Membrane permeability and ROS production were the predominant direct and indirect factors affecting transformation ability, respectively. Our findings provide valuable insight into the underlying mechanisms of the impacts of U on the ARGs transformation process and highlight concerns about the exacerbated spread of ARGs in radioactive heavy metal-contaminated ecosystems, especially in areas with nuclear activity or accidents.

The jacktree genome and population genomics provides insights for the mechanisms of the germination obstacle and the conservation of endangered ornamental plants.

Sinojackia Hu represents the first woody genus described by Chinese botanists, with all species classified as endangered ornamental plants endemic to China. Their characteristic spindle-shaped fruits confer high ornamental value to the plants, making them favored in gardens and parks. Nevertheless, the fruits likely pose a germination obstacle, contributing to the endangered status of this lineage. Here we report the chromosome-scale genome of S. xylocarpa, and explore the mechanisms underlying its endangered status, as well as its population dynamics throughout evolution. Population genomic analysis has indicated that S. xylocarpa experienced a bottleneck effect following the recent glacial period, leading to a continuous population reduction. Examination of the pericarp composition across six stages of fruit development revealed a consistent increase in the accumulation of lignin and fiber content, responsible for the sturdiness of mature fruits' pericarps. At molecular level, enhanced gene expression in the biosynthesis of lignin, cellulose and hemicellulose was detected in pericarps. Therefore, we conclude that the highly lignified and fibrotic pericarps of S. xylocarpa, which inhibit its seed germination, should be its threatening mechanism, thus proposing corresponding strategies for improved conservation and restoration. This study serves as a seminal contribution to conservation biology, offering valuable insights for the study of other endangered ornamental plants.

Directed crystalline symmetry transformation of blue-phase liquid crystals by reverse electrostriction.

Soft-matter-based photonic crystals like blue-phase liquid crystals (BPLC) have potential applications in wide-ranging photonic and bio-chemical systems. To date, however, there are limitations in the fabrication of large monocrystalline BPLCs. Traditional crystal-growth process involves the transition from a high-temperature disordered phase to an ordered (blue) phase and is generally slow (takes hours) with limited achievable lattice structures, and efforts to improve molecular alignment through post-crystallization field application typically prove ineffective. Here we report a systematic study on the molecular self-assembly dynamics of BPLC starting from a highly ordered phase in which all molecules are unidirectionally aligned by a strong electric field. We have discovered that, near the high-temperature end of the blue phase, if the applied field strength is then switched to an intermediate level or simply turned off, large-area monocrystalline BPLCs of various symmetries (tetragonal, orthorhombic, cubic) can be formed in minutes. Subsequent temperature tuning of the single crystal at a fixed applied field allows access to different lattice parameters and the formation of never-before-seen monoclinic structures. The formed crystals remain stable upon field removal. The diversity of stable monocrystalline BPLCs with widely tunable crystalline symmetries, band structures, and optical dispersions will significantly improve and expand their application potentials.

[Transverse characteristics of normodivergent patients in different sagittal skeletal patterns].

PURPOSE: This study aimed to measure and analyze the transverse indicators of normodivergent patients with different sagittal skeletal malocclusions, to explore the transverse characteristics of different sagittal skeletal malocclusions. METHODS: Lateral cephalograms and CBCT of 90 normodivergent patients with skeletal Class Ⅰ, Ⅱ and Ⅲ in their permanent dentition were collected. Dolphin software was applied to measure the widths of the basal bone, alveolar bone, dental arch and buccolingual inclination angle of the corresponding teeth in the maxillary and mandibular canine, premolar and molar areas. SPSS 22.0 software package was applied for statistical analysis of the data. RESULTS: The widths of the mandibular basal bone in canine, premolar and molar areas of skeletal Class Ⅲ were (27.15±2.74), (39.30±2.82) and (59.97±2.93) mm, respectively. The widths of the mandibular alveolar bone of skeletal Class Ⅲ were (25.38±1.78), (34.51±2.28) and (47.72±2.73) mm, respectively. The dental arch widths of the maxillary premolar and mandibular canine areas of skeletal Class Ⅲ were (48.70±2.35) and (30.69±2.31)mm, respectively. The above data of skeletal Class Ⅲ were significantly larger than those of skeletal Class Ⅰ and Ⅱ(P＜0.01). The dental arch widths of the maxillary canine, maxillary molar and mandibular molar areas of skeletal Class Ⅲ were (38.88±1.90), (59.51±3.40) and (56.01±2.86)mm, respectively, which were significantly larger than those of skeletal Class Ⅱ(P＜0.05). The maxillomandibular width difference of basal bone in the canine, premolar and molar areas of skeletal Class Ⅲ were (4.69±2.84), (2.31±2.39) and (3.27±2.05) mm, respectively, which were significantly less than that of skeletal Class Ⅰ and Ⅱ(P＜0.01). Compared with skeletal Class Ⅰ, the maxillary canines and first molars of skeletal Class Ⅱ had larger lingual inclination level, while the maxillary first premolars and first molars of skeletal Class Ⅲ had larger buccal inclination level, the mandibular canines and the mandibular first premolars of skeletal Class Ⅲ had larger lingual inclination level(P＜0.01). CONCLUSIONS: For normodivergent patients, the width of the mandibular base bone, alveolar bone, and maxillary and mandibular dental arch in skeletal Class Ⅲ is the widest, which is more likely to have width discrepancy in basal bone. In skeletal Class Ⅲ, the maxillary teeth are buccally inclined, and the mandibular teeth are ingually inclined. In skeletal Class Ⅱ, the maxillary teeth are lingually inclined, and the mandibular teeth are compensatory upright.

An Insulin-Modified pH-Responsive Nanopipette Based on Ion Current Rectification.

The properties of nanopipettes largely rely on the materials introduced onto their inner walls, which allow for a vast extension of their sensing capabilities. The challenge of simultaneously enhancing the sensitivity and selectivity of nanopipettes for pH sensing remains, hindering their practical applications. Herein, we report insulin-modified nanopipettes with excellent pH response performances, which were prepared by introducing insulin onto their inner walls via a two-step reaction involving silanization and amidation. The pH response intensity based on ion current rectification was significantly enhanced by approximately 4.29 times when utilizing insulin-modified nanopipettes compared with bare ones, demonstrating a linear response within the pH range of 2.50 to 7.80. In addition, insulin-modified nanopipettes featured good reversibility and selectivity. The modification processes were monitored using the I-V curves, and the relevant mechanisms were discussed. The effects of solution pH and insulin concentration on the modification results were investigated to achieve optimal insulin introduction. This study showed that the pH response behavior of nanopipettes can be greatly improved by introducing versatile molecules onto the inner walls, thereby contributing to the development and utilization of pH-responsive nanopipettes.

Neurosyphilis Presenting as Psychiatric Symptoms at Younger Age: A Case Report.

Neurosyphilis is a central nervous system infection caused by Treponema pallidum that imitates various neurological and mental disorders. Therefore, patients with this disease are prone to misdiagnoses. Here, we report a case of neurosyphilis with a psychotic disorder as the main manifestation. A young girl exhibited mental and behavioural abnormalities after a heartbreak, which manifested as alternating low mood, emotional irritability, and a lack of interest in social relations, followed by memory loss. The cerebrospinal fluid protein - Treponema pallidum particle agglutination test was positive, the toluidine red unheated serum test titre was 1:4, the white blood cell count was 5 × 10^6/L, the cerebrospinal fluid protein level was 0.97 g/L, and the brain CT was abnormal. After admission, the possibility of neurosyphilis was considered and the patient received intravenous penicillin G treatment. The patient's clinical symptom ms improved. This case emphasises that doctors should maintain clinical suspicion of Treponema pallidum infection in adolescent patients with mental abnormalities.

Alantolactone enhances the sensitivity of melanoma to MAPK pathway inhibitors by targeting inhibition of STAT3 activation and down-regulating stem cell markers.

Mitogen-activated protein kinase inhibitors (MAPKi) were the first line drugs for advanced melanoma patients with BRAF mutation. Targeted therapies have significant therapeutic effects; however, drug resistance hinders their long-term efficacy. Therefore, the development of new therapeutic strategies against MAPKi resistance is critical. Our previous results showed that MAPKi promote feedback activation of STAT3 signaling in BRAF-mutated cancer cells. Studies have shown that alantolactone inhibited the activation of STAT3 in a variety of tumor cells. Our results confirmed that alantolactone suppressed cell proliferation and promoted apoptosis by inhibiting STAT3 feedback activation induced by MAPKi and downregulating the expression of downstream Oct4 and Sox2. The inhibitory effect of alantolactone combined with a MAPKi on melanoma cells was significantly stronger than that on normal cells. In vivo and in vitro experiments showed that combination treatment was effective against drug-resistant melanomas. Our research indicates a potential novel combination therapy (alantolactone and MAPKi) for patients with BRAF-mutated melanoma.

Genome-Wide Identification of the TGA Gene Family and Expression Analysis under Drought Stress in Brassica napus L.

TGA transcription factors belong to Group D of the bZIP transcription factors family and play vital roles in the stress response of plants. Brassica napus is an oil crop with rich economic value. However, a systematic analysis of TGA gene family members in B. napus has not yet been reported. In this study, we identified 39 full-length TGA genes in B. napus, renamed TGA1~TGA39. Thirty-nine BnTGA genes were distributed on 18 chromosomes, mainly located in the nucleus, and differences were observed in their 3D structures. Phylogenetic analysis showed that 39 BnTGA genes could be divided into five groups. The BnTGA genes in the same group had similar structure and motif compositions, and all the BnTGA genes had the same conserved bZIP and DOG1 domains. Phylogenetic and synteny analysis showed that the BnTGA genes had a close genetic relationship with the TGA genes of the Brassica juncea, and BnTGA11 and BnTGA29 may play an important role in evolution. In addition, qRT-PCR revealed that three genes (BnTGA14/17/23) showed significant changes in eight experimental materials after drought treatment. Meanwhile, it can be inferred from the results of drought treatment on different varieties of rapeseed that the stress tolerance of parental rapeseed can be transmitted to the offspring through hybridization. In short, these findings have promoted the understanding of the B. napus TGA gene family and will contribute to future research aimed at B. napus resistant breeding.

Factors influencing fatigue, mental workload and burnout among Chinese health care workers during public emergencies: an online cross-sectional study.

OBJECTIVES: The purpose of this study was to investigate fatigue, mental workload, and burnout among health care workers (HCWs) and explore the possible underlying factors. MATERIALS AND METHODS: An online cross-sectional survey design was used to collect data from HCWs in Chongqing, China. The online survey included the Fatigue Severity Scale, NASA Task Load Index, and Chinese version of the Maslach Burnout Inventory-General Survey to assess fatigue, mental workload, and burnout, respectively, and was conducted from February 1 to March 1, 2023. RESULTS: In this study, the incidence of fatigue and burnout among HCWs was 76.40% and 89.14%, respectively, and the incidence of moderate to intolerable mental workloads was 90.26%. Work-family conflict, current symptoms, number of days of COVID-19 positivity, mental workload, burnout and reduced personal accomplishment were significantly associated with fatigue. Mental workload was affected by fatigue and reduced personal accomplishment. Furthermore, burnout was influenced by marital status and fatigue. Moreover, there was a correlation among mental workload, fatigue, and burnout. CONCLUSIONS: Fatigue, mental workload and burnout had a high incidence and were influenced by multiple factors during COVID-19 public emergencies in China.

Controlled synthesized of ternary Cu-Co-Ni-S sulfides nanoporous network structure on carbon fiber paper: a superior catalytic electrode for highly-sensitive glucose sensing.

BACKGROUND: Efficient monitoring of glucose concentration in the human body necessitates the utilization of electrochemically active sensing materials in nonenzymatic glucose sensors. However, prevailing limitations such as intricate fabrication processes, lower sensitivity, and instability impede their practical application. Herein, ternary Cu-Co-Ni-S sulfides nanoporous network structure was synthesized on carbon fiber paper (CP) by an ultrafast, facile, and controllable technique through on-step cyclic voltammetry, serving as a superior self-supporting catalytic electrode for the high-performance glucose sensor. RESULTS: The direct growth of free-standing Cu-Co-Ni-S on the interconnected three-dimensional (3D) network of CP boosted the active site of the composites, improved ion diffusion kinetics, and significantly promoted the electron transfer rate. The multiple oxidation states and synergistic effects among Co, Ni, Cu, and S further promoted glucose electrooxidation. The well-architected Cu-Co-Ni-S/CP presented exceptional electrocatalytic properties for glucose with satisfied linearity of a broad range from 0.3 to 16,000 µM and high sensitivity of 6829 µA mM- 1 cm- 2. Furthermore, the novel sensor demonstrated excellent selectivity and storage stability, which could successfully evaluate the glucose levels in human serum. Notably, the novel Cu-Co-Ni-S/CP showed favorable biocompatibility, proving its potential for in vivo glucose monitoring. CONCLUSION: The proposed 3D hierarchical morphology self-supported electrode sensor, which demonstrates appealing analysis behavior for glucose electrooxidation, holds great promise for the next generation of high-performance glucose sensors.

Rapid, portable, and sensitive detection of CaMV35S by RPA-CRISPR/Cas12a-G4 colorimetric assays with high accuracy deep learning object recognition and classification.

Fast, sensitive, and portable detection of genetic modification contributes to agricultural security and food safety. Here, we developed RPA-CRISPR/Cas12a-G-quadruplex colorimetric assays that can combine with intelligent recognition by deep learning algorithms to achieve sensitive, rapid, and portable detection of the CaMV35S promoter. When the crRNA-Cas12a complex recognizes the RPA amplification product, Cas12 cleaves the G-quadruplex, causing the G4-Hemin complex to lose its peroxide mimetic enzyme function and be unable to catalyze the conversion of ABTS2- to ABTS, allowing CaMV35S concentration to be determined based on ABTS absorbance. By utilizing the RPA-CRISPR/Cas12a-G4 assay, we achieved a CaMV35S limit of detection down to 10 aM and a 0.01 % genetic modification sample in 45 min. Deep learning algorithms are designed for highly accurate classification of color results. Yolov5 objective finding and Resnet classification algorithms have been trained to identify trace (0.01 %) CaMV35S more accurately than naked eye colorimetry. We also coupled deep learning algorithms with a smartphone app to achieve portable and rapid photo identification. Overall, our findings enable low cost ($0.43), high accuracy, and intelligent detection of the CaMV35S promoter.

Mitochondria targeted drug delivery system overcoming drug resistance in intrahepatic cholangiocarcinoma by reprogramming lipid metabolism.

The challenge of drug resistance in intrahepatic cholangiocarcinoma (ICC) is intricately linked with lipid metabolism reprogramming. The hepatic lipase (HL) and the membrane receptor CD36 are overexpressed in BGJ398-resistant ICC cells, while they are essential for lipid uptake, further enhancing lipid utilization in ICC. Herein, a metal-organic framework-based drug delivery system (OB@D-pMOF/CaP-AC, DDS), has been developed. The specifically designed DDS exhibits a successive targeting property, enabling it to precisely target ICC cells and their mitochondria. By specifically targeting the mitochondria, DDS produces reactive oxygen species (ROS) through its sonodynamic therapy effect, achieving a more potent reduction in ATP levels compared to non-targeted approaches, through the impairment of mitochondrial function. Additionally, the DDS strategically minimizes lipid uptake through the incorporation of the anti-HL drug, Orlistat, and anti-CD36 monoclonal antibody, reducing lipid-derived energy production. This dual-action strategy on both mitochondria and lipids can hinder energy utilization to restore drug sensitivity to BGJ398 in ICC. Moreover, an orthotopic mice model of drug-resistant ICC was developed, which serves as an exacting platform for evaluating the multifunction of designed DDS. Upon in vivo experiments with this model, the DDS demonstrated exceptional capabilities in suppressing tumor growth, reprogramming lipid metabolism and improving immune response, thereby overcoming drug resistance. These findings underscore the mitochondria-targeted DDS as a promising and innovative solution in ICC drug resistance.

Thermosensitive gel-nano system against esophageal cancer via restoring p53 activity and boosting T-cell immunity.

In esophageal cancer (EC), clinical specimen testing has uncovered a significant increase in BTB and CNC homolog 1 (BACH1) expression and a shift towards an immunosuppressive environment, alongside a notable decrease in p53 protein expression. Therefore, therapeutic strategies focusing on BACH1 inhibition and p53 upregulation appear promising. Traditional oral treatments for EC lack precision and efficacy. Here, we propose a novel approach employing tumor-targeted nanoparticles (NPs) for drug delivery. However, the formation of a drug reservoir at the esophageal site, crucial for the sustained release of therapeutics, presents significant challenges in nano-delivery systems for EC treatment. To address this, we developed a thermosensitive hydrogel composed of F127 and tannic acid, serving as a vehicle for NP loading. These NPs, synthesized through the emulsion/volatization methods of mPEG-PLGA-PLL-cRGD, facilitate in situ drug delivery. Upon contacting esophageal tissue, the hydrogel transitions to a gel, adhering to the lining and enabling sustained release of encapsulated therapeutics. The formulation encompasses NPs laden with small interfering RNA targeting BACH1 (siBACH1) and the p53 activator PRIMA-1, creating a cohesive gel-nano system. Preliminary biological assessments demonstrate that this injectable, thermosensitive gel-nano system adheres effectively to esophageal tissue and targets EC cells. For better modeling clinical outcomes, a patient-derived organoid xenograft (PDOX) model was innovated, involving transplantation of EC-derived organoids into humanized mice, reconstructed with peripheral blood mononuclear cells (PBMCs). Post-treatment analysis showed substantial EC growth inhibition (89.51% tumor inhibition rate), significant BACH1 level reduction, restored anti-tumor immune responses, and pronounced tumor apoptosis. In summary, our study introduces a thermosensitive gel-nano system for EC treatment via restoring p53 activity and boosting T-cell immunity, with potential for clinical application.

Is better readiness the key to deeper learning in distance education? A cross-sectional online study.

Background: The COVID-19 pandemic has required teachers and students to suddenly transition from face-to-face formats to distance education (DE). The uniqueness of nursing discipline is that it requires both theoretical and skills-based learning. Therefore, it is necessary to explore the influencing factors and effectiveness of DE in nursing education. This exploration can guide teaching practice and provide a basis for the future application of DE in nursing education. Aims: To describe the current distance education readiness and depth of learning among undergraduate nursing students and explore possible influencing factors. To determine the relationship between students' distance education readiness and the depth of learning. Design: This is a descriptive and cross-sectional online study. Settings: School of Nursing in a traditional Chinese medicine university, Beijing, China. Participants: A total of 222 undergraduate nursing students from a traditional Chinese medicine university were recruited. Methods: A questionnaire, which is composed of information form, the Online Learning Readiness Scale, and the Scale of Students Making Deep Learning, was used for data collection. Frequency, percentage, arithmetic mean, standard deviation, t-test, one-way ANOVA, and Pearson correlations were used in the analysis of the data. Result: Undergraduate nursing students have lower averages in distance education readiness and higher averages in the depth of learning. Significant differences in distance education readiness and depth of learning between different grade groups. A positive correlation was found between distance education readiness and depth of learning (r = 0.894, p < 0.001). Conclusion: Distance education is a feasible approach to learning today. Undergraduate nursing students have exhibited poor readiness for distance education but demonstrated deeper learning conditions. Upper grades may lead to better learning outcomes. Better distance education readiness can lead to deeper learning. These conclusions prompt teachers and students to be prepared before participating in distance education to obtain better academic performance.

IFNα-induced BST2+ tumor-associated macrophages facilitate immunosuppression and tumor growth in pancreatic cancer by ERK-CXCL7 signaling.

Pancreatic ductal adenocarcinoma (PDAC) features an immunosuppressive tumor microenvironment (TME) that resists immunotherapy. Tumor-associated macrophages, abundant in the TME, modulate T cell responses. Bone marrow stromal antigen 2-positive (BST2+) macrophages increase in KrasG12D/+; Trp53R172H/+; Pdx1-Cre mouse models during PDAC progression. However, their role in PDAC remains elusive. Our findings reveal a negative correlation between BST2+ macrophage levels and PDAC patient prognosis. Moreover, an increased ratio of exhausted CD8+ T cells is observed in tumors with up-regulated BST2+ macrophages. Mechanistically, BST2+ macrophages secrete CXCL7 through the ERK pathway and bind with CXCR2 to activate the AKT/mTOR pathway, promoting CD8+ T cell exhaustion. The combined blockade of CXCL7 and programmed death-ligand 1 successfully decelerates tumor growth. Additionally, cGAS-STING pathway activation in macrophages induces interferon (IFN)α synthesis leading to BST2 overexpression in the PDAC TME. This study provides insights into IFNα-induced BST2+ macrophages driving an immune-suppressive TME through ERK-CXCL7 signaling to regulate CD8+ T cell exhaustion in PDAC.