Network analysis of suicide ideation and depression-anxiety symptoms among Chinese adolescents.

Background: The co-occurrence of depression and anxiety among adolescents is typically associated with suicide ideation. Aims: The study aimed to investigate the symptom-level relationship between suicide ideation and the comorbidity of depression and anxiety. Methods: 1501 adolescents aged 12-19 years were assessed using the Patient Health Questionnaire (PHQ-9) and the Generalized Anxiety Disorder Scale, and 716 adolescents who scored ≥5 on both scales were selected as participants. Network analysis was used to identify the network structure of depressive symptoms and anxiety symptoms. Participants were categorised into either the suicide ideation or non-suicide ideation groups based on their scoring on the suicide-related item in PHQ-9. A comparison was made between the depression-anxiety symptom networks of the two groups. Results: 'Restlessness', 'sad mood' and 'trouble relaxing' were the most prominent central symptoms in the depression-anxiety symptom network, and 'restlessness', 'nervousness' and 'reduced movement' were the bridge symptoms in this network. 'Sad mood' was found to be directly related to 'suicide ideation' with the highest variance. The network structure was significantly different in properties between the suicide ideation group and the non-suicide ideation group, with 'restlessness' and 'sad mood' exhibiting significantly higher influence in the network of the suicide ideation group than that in the non-suicide ideation group. Conclusion: Restlessness and sad mood could be targeted for the intervention of depression-anxiety symptoms among adolescents with suicide ideation.

Comprehensive genomic and clinical analyses identify APOBEC mutational signatures as a brain metastasis risk factor in lung adenocarcinoma patients.

BACKGROUND: Lung adenocarcinoma is the most common source of brain metastasis (BM), resulting in significant morbidity and mortality. We aimed to identify patients with high BM risk who possibly benefit from brain-penetrant drugs, prophylactic cranial irradiation, or close brain magnetic resonance imaging surveillance. METHODS: Metastatic lung adenocarcinoma patients with extracranial tumor samples profiled by a next-generation sequencing panel targeting 425 tumor-related genes were retrospectively enrolled between February 2008 and July 2021. We compared BM and non-BM patients' genomic and clinical features and studied their associations with BM risk. Two external cohorts were used for result validation and molecular mechanisms investigation, respectively. RESULTS: We included 174 eligible patients, including 90 having developed BM by the end of follow-up. Age≤60, EGFR activating mutations, and high-level apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) mutational signatures were associated with elevated BM risk. Similar findings in BM-free survival were obtained by fitting Fine-Gray subdistribution hazard models addressing competing risks. Increased BM risk related to APOBEC mutational signatures was validated in an external cohort (N = 440). RNA sequencing data analyses performed in another external cohort (N = 230) revealed that expressions of metastasis-related pathways such as transforming growth factor (TGF)ß and epithelial-mesenchymal transition (EMT) were upregulated in the patients with high-level APOBEC mutational signatures. CONCLUSION: APOBEC mutational signatures related to upregulated TGFß and EMT, could serve as an independent risk factor for BM and BM-free survival in metastatic lung adenocarcinoma patients. Further investigations are warranted to tailor personalized treatments to improve the susceptible patient's outcomes.

mRNA-Laden Lipid-Nanoparticle-Enabled in Situ CAR-Macrophage Engineering for the Eradication of Multidrug-Resistant Bacteria in a Sepsis Mouse Model.

Sepsis, which is the most severe clinical manifestation of acute infection and has a mortality rate higher than that of cancer, represents a significant global public health burden. Persistent methicillin-resistant Staphylococcus aureus (MRSA) infection and further host immune paralysis are the leading causes of sepsis-associated death, but limited clinical interventions that target sepsis have failed to effectively restore immune homeostasis to enable complete eradication of MRSA. To restimulate anti-MRSA innate immunity, we developed CRV peptide-modified lipid nanoparticles (CRV/LNP-RNAs) for transient in situ programming of macrophages (MΦs). The CRV/LNP-RNAs enabled the delivery of MRSA-targeted chimeric antigen receptor (CAR) mRNA (SasA-CAR mRNA) and CASP11 (a key MRSA intracellular evasion target) siRNA to MΦs in situ, yielding CAR-MΦs with boosted bactericidal potency. Specifically, our results demonstrated that the engineered MΦs could efficiently phagocytose and digest MRSA intracellularly, preventing immune evasion by the "superbug" MRSA. Our findings highlight the potential of nanoparticle-enabled in vivo generation of CAR-MΦs as a therapeutic platform for multidrug-resistant (MDR) bacterial infections and should be confirmed in clinical trials.

On-site filtration of large sample volumes improves the detection of opportunistic pathogens in drinking water distribution systems.

In this study, we compared conventional vacuum filtration of small volumes through disc membranes (effective sample volumes for potable water: 0.3-1.0 L) with filtration of high volumes using ultrafiltration (UF) modules (effective sample volumes for potable water: 10.6-84.5 L) for collecting bacterial biomass from raw, finished, and tap water at seven drinking water systems. Total bacteria, Legionella spp., Legionella pneumophila, Mycobacterium spp., and Mycobacterium avium complex in these samples were enumerated using both conventional quantitative PCR (qPCR) and viability qPCR (using propidium monoazide). In addition, PCR-amplified gene fragments were sequenced for microbial community analysis. The frequency of detection (FOD) of Legionella spp. in finished and tap water samples was much greater using UF modules (83% and 77%, respectively) than disc filters (24% and 33%, respectively). The FODs for Mycobacterium spp. in raw, finished, and tap water samples were also consistently greater using UF modules than disc filters. Furthermore, the number of observed operational taxonomic units and diversity index values for finished and tap water samples were often substantially greater when using UF modules as compared to disc filters. Conventional and viability qPCR yielded similar results, suggesting that membrane-compromised cells represented a minor fraction of total bacterial biomass. In conclusion, our research demonstrates that large-volume filtration using UF modules improved the detection of opportunistic pathogens at the low concentrations typically found in public drinking water systems and that the majority of bacteria in these systems appear to be viable in spite of disinfection with free chlorine and/or chloramine.IMPORTANCEOpportunistic pathogens, such as Legionella pneumophila, are a growing public health concern. In this study, we compared sample collection and enumeration methods on raw, finished, and tap water at seven water systems throughout the State of Minnesota, USA. The results showed that on-site filtration of large water volumes (i.e., 500-1,000 L) using ultrafiltration membrane modules improved the frequency of detection of relatively rare organisms, including opportunistic pathogens, compared to the common approach of filtering about 1 L using disc membranes. Furthermore, results from viability quantitative PCR (qPCR) with propidium monoazide were similar to conventional qPCR, suggesting that membrane-compromised cells represent an insignificant fraction of microorganisms. Results from these ultrafiltration membrane modules should lead to a better understanding of the microbial ecology of drinking water distribution systems and their potential to inoculate premise plumbing systems with opportunistic pathogens where conditions are more favorable for their growth.

Intracavitary Spraying of Nanoregulator-Encased Hydrogel Modulates Cholesterol Metabolism of Glioma-Supportive Macrophage for Postoperative Glioblastoma Immunotherapy.

Glioblastoma multiforme (GBM) is notoriously resistant to immunotherapy due to its intricate immunosuppressive tumor microenvironment (TME). Dysregulated cholesterol metabolism is implicated in the TME and promotes tumor progression. Here, it is found that cholesterol levels in GBM tissues are abnormally high, and glioma-supportive macrophages (GSMs), an essential "cholesterol factory", demonstrate aberrantly hyperactive cholesterol metabolism and efflux, providing cholesterol to fuel GBM growth and induce CD8+ T cells exhaustion. Bioinformatics analysis confirms that high 7-dehydrocholesterol reductase (DHCR7) level in GBM tissues associates with increased cholesterol biosynthesis, suppressed tumoricidal immune response, and poor patient survival, and DHCR7 expression level is significantly elevated in GSMs. Therefore, an intracavitary sprayable nanoregulator (NR)-encased hydrogel system to modulate cholesterol metabolism of GSMs is reported. The degradable NR-mediated ablation of DHCR7 in GSMs effectively suppresses cholesterol supply and activates T-cell immunity. Moreover, the combination of Toll-like receptor 7/8 (TLR7/8) agonists significantly promotes GSM polarization to antitumor phenotypes and ameliorates the TME. Treatment with the hybrid system exhibits superior antitumor effects in the orthotopic GBM model and postsurgical recurrence model. Altogether, the findings unravel the role of GSMs DHCR7/cholesterol signaling in the regulation of TME, presenting a potential treatment strategy that warrants further clinical trials.

Unrevealing the therapeutic benefits of radiotherapy and consolidation immunotherapy using ctDNA-defined tumor clonality in unresectable locally advanced non-small cell lung cancer.

Progression occurs in approximately two-thirds of patients with locally advanced non-small cell lung cancer (LA-NSCLC) receiving chemoradiation and consolidation immunotherapy. Molecular indicators for outcome prediction are under development. A novel metric, the ratio of mean to max variant allele frequency (mmVAF), was derived from 431 pre-treatment tissue biopsies from The Cancer Genome Atlas and evaluated in serial circulating tumor DNA (ctDNA) from 70 LA-NSCLC patients receiving definitive radiotherapy/chemoradiotherapy (RT/CRT) with/without immunotherapy. High mmVAFs in pre-treatment tissue biopsies, indicating clonal predominant tumors (P < 0.01), were associated with inferior overall survival [OS, hazard ratio (HR): 1.48, 95 % confidence interval (CI): 1.11-1.98]. Similar associations of mmVAF with clonality (P < 0.01) and OS (HR: 2.24, 95 % CI: 0.71-7.08) were observed in pre-treatment ctDNA. At 1-month post-RT, ctDNA mmVAF-high patients receiving consolidation immunotherapy exhibited improved progression-free survival (PFS) compared to those who did not (HR: 0.14, 95 % CI: 0.03-0.67). From the baseline to week 4 of RT and/or 1-month post-RT, survival benefits from consolidation immunotherapy were exclusively observed in ctDNA mmVAF-increased patients (PFS, HR: 0.39, 95 % CI: 0.14-1.15), especially in terms of distant metastasis (HR: 0.11, 95 % CI: 0.01-0.95). In summary, our longitudinal data demonstrated the applicability of ctDNA-defined clonality for prognostic stratification and immunotherapy benefit prediction in LA-NSCLC.

A research on the strengthening effect of sludge charcoal on activated sludge process in sewage treatment.

With the rapid development of urbanization, the number of urban sewage treatment plants is increasing, wastewater treatment volume is gradually becoming large, and correspondingly, the sludge production capacity has a rapid growth. As a new method of sludge disposal, sludge carbonization is characterized by low energy consumption, simple products, and wide resource utilization prospects, which is of great help to solve problems of current sludge disposal in China. The residual sludge from sewage plant was used as raw material in this study in order to investigate the physical and chemical properties of sludge charcoal after high temperature carbonization and explore the enhancement in the removal of pollutants including CODcr, NH3-N, TN, and TP during sewage treatment with the used sludge charcoal. The results show that the optimal dosing amount of sludge charcoal was 2 g.L-1 when it was added into SBR equipment at one time, while the optimal dosing amount is 0.06 g.L-1 when it was added into SBR equipment with each influent process. The enhanced removal effect of pollutants in sewage treatment process mainly depended on the physical adsorption and intensified bio-degradation of sludge charcoal, and activated sludge and sludge charcoal were synergistic in water treatment. The removal effect of pollutants is strengthened in the physical adsorption-bio-degradation-sludge charcoal reproduction-re-adsorption system. These suggested that sludge charcoal could be promising for the enhancement of pollutant removal in sewage through activated sludge process.

Bridge symptoms between parenting styles and proximal psychological risk factors associated with adolescent suicidal thoughts: a network analysis.

BACKGROUND: Parenting styles and the associated proximal psychological factors are suggested to increase suicidal risks in adolescents. However, how the two factors interact and confer risks on the emergence of adolescent suicidal thoughts remains unclear. Herein, we used a network approach to investigate their interrelationship and explore whether the network properties predict adolescent suicidal thoughts. METHODS: Self-report questionnaires were completed by 1171 students aged 12-16. Network analyses were performed by Gaussian graphical models estimating the adolescent psychosocial network structure of parenting styles and psychological variables including depression, anxiety, affective lability, rumination, and resilience. Furthermore, we re-examined the network by adding a variable measuring active suicidal thoughts. Moreover, we conducted linear regressions to examine the predictive utility of bridge symptoms for adolescent suicidal thoughts. RESULTS: Resilience, Afraid, Rumination, Concentration, and affective lability (Anger) had the highest bridge strengths in the adolescent psychosocial network. Among the identified bridge symptoms, Resilience was negatively correlated with active suicidal thoughts (regularized edge weights = -0.181, bootstrapped 95% CIs: [-0.043, -0.155]), whereas affective lability (from Anxiety to Depression, Anger), Rumination, and Afraid were positively correlated with active suicidal thoughts, with edge weights (bootstrapped 95% CIs) ranging from 0.057 (0.001, 0.112) to 0.081(0.026, 0.136). Regression analysis showed that bridge strength was significantly correlated with active suicidal thoughts (R2 = 0.432, P = 0.001). CONCLUSION: Negative parenting styles may drive and maintain suicidal thoughts by modifying the key proximal psychological variables. Our findings highlight the important role of bridge symptoms, which may serve as vital targets for triggering adolescent suicide.

Simultaneous enhancement of coercivity and saturation magnetization in high-performance anisotropic NdFeB thick films with a Dy diffusion layer.

Generally, the addition of the Dy element leads to a decrease of the saturation magnetization and the remanent magnetization in NdFeB films due to its antiferromagnetic coupling with Fe. However, in this study, upon increasing the ratio of Dy in the Nd-Dy diffusion layers of NdFeB thick films, the saturation magnetization has an anomalously slight enhancement, while the coercivity and remanent magnetization have a large enhancement. The increase of coercivity is attributed to the decoupling between Nd2Fe14B grains and the enhanced pinning effect. Microstructural analysis revealed a layered structure composed of spherical Nd2Fe14B grains at the location of the Dy diffusion layer, which is attributed to the Dy diffusion layer reacting with the region of Nd element aggregation during the annealing process, facilitating transformation into Nd2Fe14B grains. The increase of the proportion of Nd2Fe14B grains results in a slight enhancement of saturation magnetization. By this method, we obtained a high-performance anisotropic NdFeB thick film of 28.7 µm with a coercivity of 2.46 T and a surface field of 163 Oe. This work establishes a microscale growth model for NdFeB thick films and helps to prepare high-performance NdFeB thick films applicable directly to microelectromechanical systems.

A Phase II Study of Osimertinib in Patients with Advanced-Stage Non-Small Cell Lung Cancer following Prior Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR TKI) Therapy with EGFR and T790M Mutations Detected in Plasma Circulating Tumour DNA (PLASMA Study).

Epidermal growth factor receptor (EGFR) T790M mutations drive resistance in 50% of patients with advanced non-small cell lung cancer (NSCLC) who progress on first/second generation (1G/2G) EGFR tyrosine kinase inhibitors (TKIs) and are sensitive to Osimertinib. Tissue sampling is the gold-standard modality of T790M testing, but it is invasive. We evaluated the efficacy of Osimertinib in patients with EGFR mutant NSCLC and T790M in circulating tumour DNA (ctDNA). PLASMA is a prospective, open-label, multicentre single-arm Phase II study. Patients with advanced NSCLC harbouring sensitizing EGFR and T790M mutations in plasma at progression from ≥one 1G/2G TKI were treated with 80 mg of Osimertinib daily until progression. The primary endpoint was the objective response rate (ORR); the secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and toxicities. Plasma next-generation sequencing was performed to determine Osimertinib resistance mechanisms and assess serial ctDNA. A total of 110 patients from eight centres in five countries were enrolled from 2017 to 2019. The median follow-up duration was 2.64 (IQR 2.44-3.12) years. The ORR was 50.9% (95% CI 41.2-60.6) and the DCR was 84.5% (95% CI 76.4-90.7). Median PFS was 7.4 (95% CI 6.0-9.3) months; median OS was 1.63 (95% CI 1.35-2.16) years. Of all of the patients, 76% had treatment-related adverse events (TRAEs), most commonly paronychia (22.7%); 11% experienced ≥ Grade 3 TRAEs. The ctDNA baseline load and dynamics were prognostic. Osimertinib is active in NSCLC harbouring sensitizing EGFR and T790M mutations in ctDNA testing post 1G/2G TKIs.

Lineage tracing for multiple lung cancer by spatiotemporal heterogeneity using a multi-omics analysis method integrating genomic, transcriptomic, and immune-related features.

Introduction: The distinction between multiple primary lung cancer (MPLC) and intrapulmonary metastasis (IPM) holds clinical significance in staging, therapeutic intervention, and prognosis assessment for multiple lung cancer. Lineage tracing by clinicopathologic features alone remains a clinical challenge; thus, we aimed to develop a multi-omics analysis method delineating spatiotemporal heterogeneity based on tumor genomic profiling. Methods: Between 2012 and 2022, 11 specimens were collected from two patients diagnosed with multiple lung cancer (LU1 and LU2) with synchronous/metachronous tumors. A novel multi-omics analysis method based on whole-exome sequencing, transcriptome sequencing (RNA-Seq), and tumor neoantigen prediction was developed to define the lineage. Traditional clinicopathologic reviews and an imaging-based algorithm were performed to verify the results. Results: Seven tissue biopsies were collected from LU1. The multi-omics analysis method demonstrated that three synchronous tumors observed in 2018 (LU1B/C/D) had strong molecular heterogeneity, various RNA expression and immune microenvironment characteristics, and unique neoantigens. These results suggested that LU1B, LU1C, and LU1D were MPLC, consistent with traditional lineage tracing approaches. The high mutational landscape similarity score (75.1%), similar RNA expression features, and considerable shared neoantigens (n = 241) revealed the IPM relationship between LU1F and LU1G which were two samples detected simultaneously in 2021. Although the multi-omics analysis method aligned with the imaging-based algorithm, pathology and clinicopathologic approaches suggested MPLC owing to different histological types of LU1F/G. Moreover, controversial lineage or misclassification of LU2's synchronous/metachronous samples (LU2B/D and LU2C/E) traced by traditional approaches might be corrected by the multi-omics analysis method. Spatiotemporal heterogeneity profiled by the multi-omics analysis method suggested that LU2D possibly had the same lineage as LU2B (similarity score, 12.9%; shared neoantigens, n = 71); gefitinib treatment and EGFR, TP53, and RB1 mutations suggested the possibility that LU2E might result from histology transformation of LU2C despite the lack of LU2C biopsy and its histology. By contrast, histological interpretation was indeterminate for LU2D, and LU2E was defined as a primary or progression lesion of LU2C by histological, clinicopathologic, or imaging-based approaches. Conclusion: This novel multi-omics analysis method improves the accuracy of lineage tracing by tracking the spatiotemporal heterogeneity of serial samples. Further validation is required for its clinical application in accurate diagnosis, disease management, and improving prognosis.

DFT studies of solvent effect in hydrogen abstraction reactions from different allyl-type monomers with benzoyl radical.

Inert allyl-type monomers have been widely documented due to reduce degradation chain transfer. Recently, we and others discovered that the [3 + 2] cyclization reaction process by a photo-driven radical reaction, which can accelerate the polymerization. It was discovered that allyl ether monomers had much higher reactivity than other allyl monomers in the suspension photopolymerization initiated by Type I photoinitiator. Since the hydrogen abstraction reaction (HAR) is the initial step of cyclization, and in order to clarify the influence of solvents effect, three allyl-type monomers were employed, containing "O", "N" and "S" atom as hydrogen donors. The benzoyl radical obtained from cleavage of photoinitiator was chosen as hydrogen acceptors. We explored the hydrogen abstraction reaction in different solvents (methanol, water and DMSO) by quantum chemistry for geometry and energy. An investigation was undertaken regarding the structural orbital by electrostatic potential (ESP) and topological analysis (ELF and LOL). The findings were also combined with the distortion model and transition state theory. We obtained the molecular interactions used independent gradient method in the Hirshfeld molecular density partition (IGMH). The Eckart's correction allowed to examine the driving factors of the hydrogen abstraction reaction tunnels and these reactions constant rates are determined in the range of 500-2500 K depending on the modified Arrhenius form in different solvents effect. Our results can provide an answer for the different reactivities.

Analysis of Prospective Genetic Indicators for Prenatal Exposure to Arsenic in Newborn Cord Blood of Using Machine Learning.

Using a machine learning methods, we aim to find biological effect biomarkers of prenatal arsenic exposure in newborn cord blood. From the Gene Expression Omnibus (GEO) database, two datasets (GSE48354 and GSE7967) pertaining to cord blood sequencing while exposed to arsenic were retrieved and merged for additional study. Using the "limma" package in the R, differentially expressed genes (DEGs) were eliminated. Machine learning techniques of the LASSO regression algorithm and SVM-RFE algorithm were used to find potential biological effect biomarkers for cord blood sequencing in pregnant women exposed to arsenic. To evaluate the efficacy of biomarkers, a receiver operating characteristic (ROC) curve was used. Furthermore, we investigated the proportion of invading immune cells in each sample using CIBERSORT, and we investigated the relationship between biomarkers and immune cells using the Spearman approach. Using LASSO regression and the SVM-RFE technique, 28 DEGs were discovered, and the main biomarkers of cord blood exposed to arsenic were discovered to be DENND2D, OLIG1, RGS18, CXCL16, DDIT4, FOS, G0S2, GPR183, JMJD6, and SOCS3. According to an immune infiltration analysis and correlation analysis, key biomarkers were substantially associated with the invading immune cells. Ten genes are important biomarkers of cord blood exposed to arsenic connected with infiltrating immune cells, and infiltrating immune cells may play important roles in cord blood exposed to arsenic, according to the study's findings.

Robust Mutual Synchronization in Long Spin Hall Nano-oscillator Chains.

Mutual synchronization of N serially connected spintronic nano-oscillators boosts their coherence by N and peak power by N2. Increasing the number of synchronized nano-oscillators in chains holds significance for improved signal quality and emerging applications such as oscillator based unconventional computing. We successfully fabricate spin Hall nano-oscillator chains with up to 50 serially connected nanoconstrictions using W/NiFe, W/CoFeB/MgO, and NiFe/Pt stacks. Our experiments demonstrate robust and complete mutual synchronization of 21 nanoconstrictions at an operating frequency of 10 GHz, achieving line widths <134 kHz and quality factors >79,000. As the number of mutually synchronized oscillators increases, we observe a quadratic increase in peak power, resulting in 400-fold higher peak power in long chains compared to individual nanoconstrictions. While chains longer than 21 nanoconstrictions also achieve complete mutual synchronization, it is less robust, and their signal quality does not improve significantly, as they tend to break into partially synchronized states.

Giant Orbital-to-Spin Conversion for Efficient Current-Induced Magnetization Switching of Ferrimagnetic Insulator.

It has long been believed that the attachment of two heavy metals such as Ta and Pt with opposite spin Hall angles results in a weakened net torque generation efficiency in magnetization switching devices. Here, we report a giant orbital-to-spin conversion in Ta/Pt/Tm3Fe5O12 (TmIG) heterostructures. We show that the torque generation efficiency is enhanced by an order of magnitude in the Ta/Pt/TmIG trilayer compared to that in the Pt/TmIG bilayer. This enhancement is further evidenced by the fact that the critical current density for the magnetization switching of the Ta/Pt/TmIG is an order of magnitude smaller than that of the Pt/TmIG. It is found that the orbital current generated from Ta through the orbital Hall effect (OHE) is converted to the spin current in the interior of Pt. Our discovery offers an extraordinary approach to enhance the torque generation for magnetization switching of insulators and provides an important piece of information for orbitronics.

Empirical evidence for the neurocognitive effect of nitrous oxide as an adjunctive therapy in patients with treatment resistant depression: A randomized controlled study.

Nitrous oxide (N2O) has demonstrated an antidepressant effect for treatment-resistant depression (TRD), but no studies investigated the effects of N2O on different cognition domains. This study aimed to test whether N2O would display pro-cognitive effects. We conducted a double-blinded, placebo-controlled, randomized controlled trial, 44 patients with TRD were randomized to N2O group (one-hour inhalation of 50% N2O/50% oxygen) or placebo group (50% air/50% oxygen). Thirty-four patients completed cognitive tests at the pre-treatment phase, 1-week, and 2 weeks post-treatment including subjective cognitive function, processing speed, attention, and executive function. Although the antidepressant effect of N2O was not significant at 1 week, patients still showed better performance of executive function at 1 week after receiving N2O compared with the placebo. Moreover, this significant improvement still existed at 1 week after controlling for the change in depressive symptoms over-time. Additionally, no significant difference was observed in subjective cognitive function, processing speed, and attention between these two groups across the 2-week follow-up period. As the first study investigating the treatment effects of N2O on improving cognitive function in TRD patients, the current study indicated that N2O has a potential pro-cognitive effect on executive function and this effect might be independent from improvements in depressive symptoms.

Identification of two novel T cell epitopes on the E2 protein of classical swine fever virus C-strain.

C-strain, also known as the HCLV strain, is a well-known live attenuated vaccine against classical swine fever (CSF), a devastating disease caused by classical swine fever virus (CSFV). Vaccination with C-strain induces a rapid onset of protection, which is associated with virus-specific gamma interferon (IFN-γ)-secreting CD8+ T cell responses. The E2 protein of CSFV is a major protective antigen. However, the T cell epitopes on the E2 protein remain largely unknown. In this study, eight overlapping nonapeptides of the E2 protein were predicted and synthesized to screen for potential T cell epitopes on the CSFV C-strain E2 protein. Molecular docking was performed on the candidate epitopes with the swine leukocyte antigen-1*0401. The analysis obtained two highly conserved T cell epitopes, 90STEEMGDDF98 and 331ATDRHSDYF339, which were further identified by enzyme-linked immunospot assay. Interestingly, the mutants deleting or substituting the epitopes are nonviable. Further analysis demonstrated that 90STEEMGDDF98 is crucial for the E2 homodimerization, while CSFV infection is significantly inhibited by the 331ATDRHSDYF339 peptide treatment. The two novel T cell epitopes can be used to design new vaccines that are able to provide rapid-onset protection.

Genomic profiling, prognosis, and potential interventional targets in young and old patients with cholangiocarcinoma.

Molecular mechanisms behind potentially inferior prognosis of old cholangiocarcinoma (CCA) patients are unclear. Prevalence of interventional targets and the difference between young and old CCA patients are valuable for promising precision medicine. A total of 188 CCA patients with baseline tumor tissue samples were subgrouped into the young (≤45 years) and old (>45 years) sub-cohorts. Somatic and germline mutation profiles, differentially enriched genetic alterations, and actionable genetic alterations were compared. An external dataset was used for the validation of molecular features and the comparison of overall survival (OS). Compared to young patients, KRAS alterations were more common in old patients (P = .04), while FGFR2 fusions were less frequent (P = .05). TERT promoter mutations were exclusively detected in old patients. The external dataset (N = 392) revealed no significant difference in OS between young and old patients; however, old patient-enriched KRAS (hazard ratio [HR]: 1.96, 95% confidence interval [CI]: 1.37-2.80) and TERT alterations (HR: 2.03, 95% CI: 1.22-3.38) were associated with inferior OS. Approximately 38.3% of patients were identified of actionable oncogenic mutations indicative of a potential response to targeted therapy or immunotherapy. Actionable FGFR2 fusions (P = .01) and BRAFV600E (P = .04) mutations were more frequent in young females than old patients. The enrichment of KRAS/TERT alterations in CCA patients over 45 years resulted in inferior OS. Approximately one-third of CCA patients were eligible for targeted therapy or immunotherapy given the actionable mutations carried, especially young females.

Reversing immune evasion using a DNA nano-orchestrator for pancreatic cancer immunotherapy.

Immune evasion caused by the paucity of MHCI is a prominent characteristic of pancreatic adenocarcinoma (PAAD), which is thought to underlie dysfunctional even absent adaptive T cell immunity and is responsible for ineffective immunotherapy. Here, we report a ROS-responsive DNA nano-orchestrator to cascade reverse MHC I-associated immune evasion and boost anti-tumor T cell stimulation, stimulating the activation of tumoricidal immunity against PAAD. Chloroquine phosphate (CQP) as an autophagy inhibitor was first encapsulated with ferritin, and via DNA modular self-assembly technology, the generated ferritin nanocores (FNC) were then caged into ROS-responsive CpG-DNA nanoframe. After systemic injection, the FNC-laden DNA nanoframe (FNC@NF) was passively enriched in tumor tissues in which the DNA nanoframe was cleaved upon the ROS stimulation. Oligodeoxynucleotide (ODN) with CpG motifs was detached and functioned as a TLR9 agonist. The liberated FNC was then endocytosed in an actively targeted manner by binding to transferrin receptor 1. In the lysosome, CQP was burst released from FNC due to acid-triggering. Through CQP-mediated autophagy abrogation, MHC-I molecules were preserved. We demonstrated that cascade inhibiting autophagy and boosting TLR9 stimulation via our proposed DNA-based hybrid nanosystem restored MHC I on the tumor cell surface and reshaped the antigen presentation of DCs, and ultimately reversed immune evasion and synergistically reinforced the activation of cytotoxic T cells against PAAD cells. In sum, our work provides an alternative strategy for cascade reversing immune evasion and boosting anti-tumor T cell stimulation and holds great potential for pancreatic cancer immunotherapy. STATEMENT OF SIGNIFICANCE: A DNA nano-orchestrator was created by sequentially assembling chloroquine phosphate-laden ferritin nanocores with ROS-responsive CpG-DNA nanoframe. Through cascade inhibiting autophagy and boosting TLR9 stimulation, the nano-orchestrator efficiently reversed MHC I-associated immune evasion and augmented anti-tumor T cell stimulation, which ultimately activated tumoricidal immunity against pancreatic adenocarcinoma.

Surficial nano-deposition locoregionally yielding bactericidal super CAR-macrophages expedites periprosthetic osseointegration.

Tracking and eradicating Staphylococcus aureus in the periprosthetic microenvironment are critical for preventing periprosthetic joint infection (PJI), yet effective strategies remain elusive. Here, we report an implant nanoparticle coating that locoregionally yields bactericidal super chimeric antigen receptor macrophages (CAR-MΦs) to prevent PJI. We demonstrate that the plasmid-laden nanoparticle from the coating can introduce S. aureus-targeted CAR genes and caspase-11 short hairpin RNA (CASP11 shRNA) into macrophage nuclei to generate super CAR-MΦs in mouse models. CASP11 shRNA allowed mitochondria to be recruited around phagosomes containing phagocytosed bacteria to deliver mitochondria-generated bactericidal reactive oxygen species. These super CAR-MΦs targeted and eradicated S. aureus and conferred robust bactericidal immunologic activity at the bone-implant interface. Furthermore, the coating biodegradability precisely matched the bone regeneration process, achieving satisfactory osteogenesis. Overall, our work establishes a locoregional treatment strategy for priming macrophage-specific bactericidal immunity with broad application in patients suffering from multidrug-resistant bacterial infection.