Associations between specific dietary patterns, gut microbiome composition, and incident subthreshold depression in Chinese young adults.

INTRODUCTION: The interplay between influential factors and the incidence of subthreshold depression (SD) in young adults remains poorly understood. OBJECTIVES: This study sought to understand the dietary habits, gut microbiota composition, etc. among individuals with SD in young adults and to investigate their association with SD occurrence. METHODS: Employing a cross-sectional approach, 178 individuals with SD, aged 18-32 years, were matched with 114 healthy counterparts. SD status was evaluated using the Zung Self-rating Depression Scale (SDS), Zung Self-rating Anxiety Scale (SAS), Beck Depression Inventory 2nd version (BDI-II), the 17-item Hamilton Rating Scales of Depression (HAMD-17), and Pittsburgh Sleep Quality Index (PSQI). Metagenomic sequencing was utilized to identify fecal microbial profiles. Dietary patterns were discerned via factor analysis of a 25-item food frequency questionnaire (FFQ). Logistic regression analysis and mediation analysis were performed to explore the potential links between gut microbiota, dietary patterns, and incident SD. RESULTS: Data on dietary habits were available for 292 participants (mean [SD] age, 22.1 [2.9] years; 216 [73.9 %] female). Logistic regression analysis revealed that dietary patterns Ⅰ (odds ratio [OR], 0.34; 95 % CI, 0.15-0.75) and IV (OR, 0.39; 95 % CI, 0.17-0.86 and OR, 0.39; 95 % CI, 0.18-0.84) were associated with reduced risk of SD. Distinct microbial profiles were observed in young adults with SD, marked by increased microbial diversity and taxonomic alterations. Moreover, mediation analysis suggested Veillonella atypica as a potential mediator linking SDS or BDI-II scores with a healthy dietary pattern rich in bean products, coarse grains, nuts, fruits, mushrooms, and potatoes (ß = 0.25, 95 % CI: 0.02-0.78 and ß = 0.18, 95 % CI: 0.01-0.54). CONCLUSIONS: Our findings highlight the complex interplay between dietary patterns, gut microbiota, and the risk of developing SD in young adults, underscoring the potential for dietary interventions and microbiome modulation in mental health promotion.

Factors influencing the level of insight and treatment attitude: a cross-sectional study of 141 elderly patients of major depression in Guangzhou, China.

Objective: To explore the insight, treatment attitude, and related influencing factors of hospitalized elderly patients suffering from major depression. Methods: A total of 141 hospitalized elderly patients with depression were selected as the research objects. Insight was evaluated by the total score of the Insight and Treatment Attitude questionnaire (ITAQ). The data collected included sociodemographic characteristics, psychiatric symptoms, delirium status, social functioning, social support, suicide risk, and cognitive function. Results: The sample included 74.5% of female patients, and the mean age was 67.53 (sd=7.19) years. The influencing factors of inpatients with depression included alcohol consumption, length of hospitalization, admission types, and the main caregivers (P<0.05). The various factors were further analyzed by linear regression, revealing that the insight and treatment attitude of elderly depressed hospitalized patients were mainly related to the Mini-Mental State Examination (MMSE) (ß= 0.225, 95% CI 0.055-0.395, P=0.01), dependent on a caregiver (ß=-5.810, 95% CI -8.086~-3.535, P<0.001), the type of admission (involuntary admission) (ß=-3.365, 95% CI -5.448~-1.283, P=0.002), Functional Activities Questionnaire (FAQ) (ß=-0.156, 95% CI -0.303~-0.010, P=0.037), and length of stay (≤28 days) (ß=2.272, 95% CI 0.055~-4.489, P=0.045). Conclusion: The level of insight was affected by cognitive function, involuntary admission, dependent on a caregiver, social function and length of stay. Future studies should focus on cognitive function recovery, observation of admission mode, and self-care ability in elderly patients with depression.

Effects of Mindfulness-Based Cognitive Therapy on Depression and Anxiety in Late Life: A Meta-Analysis.

Objective: This study aims to assess the efficacy of mindfulness-based cognitive therapy (MBCT) in alleviating depression in older adults. Methods: A comprehensive search was conducted in 4 electronic databases and 1 registered database from inception up to July 2021 to identify relevant trials. The meta-analysis employed Hedge's g, along with its 95% CI, and associated z and P-values for the included studies, utilizing Comprehensive Meta-Analysis software. Results: Qualitative synthesis was performed on 5 eligible studies. Evaluation of methodological quality and bias risk across the papers involved scrutiny of key variables due to the heterogeneous research formats. Our findings indicated a significant moderating effect of MBCT against current depressive symptoms in older adults (g = 0.53, 95% Confidence Intervals (CI) = 0.31-0.75) and a similar effect size for anxiety (g = 0.43, 95% CI = 0.20-0.65). However, caution is warranted due to the limited number of studies and potential publication bias. Further extensive research with longer follow-up measures and larger sample sizes is essential. Conclusion: This study underscores the effectiveness of MBCT as a treatment for anxiety and despair in older individuals. Mindfulness-based cognitive therapy should be recommended for its positive impact on older adults with depression, and the involvement of authorized psychiatric nurses is crucial for conducting successful MBCT interventions. However, caution is warranted due to the limited number of studies and potential publication bias. Further extensive research with longer follow-up measures and larger sample sizes is essential.

Phentolamine Protects against Apoptosis and Inflammation in a Neonatal Pneumonia Cell Model Induced by LPS by Regulating the TrkA/Akt Signaling Pathways.

BACKGROUND: Phentolamine is an α-adrenergic receptor blocker that can be used to treat neonatal pneumonia, but its underlying mechanism is unclear. The purpose of this study is to probe the function of phentolamine on lipopolysaccharide (LPS)-induced inflammation and cell death in an in vitro model of neonatal pneumonia. METHODS: Human MRC-5 cells were incubated with varying doses of phentolamine in vitro to evaluate cell viability. Subsequently, LPS was introduced to further investigate the combined effects of phentolamine and LPS on cell viability and apoptosis in MRC-5 cells. The effect of phentolamine/LPS treatment on the Neurotrophic Tyrosine Kinase Receptor A (TrkA)/Protein Kinase B (Akt) signaling pathway and the phosphorylation of pathway proteins in MRC-5 cells was further analyzed via western blot. Additionally, knockout of TrkA and Akt genes in MRC-5 cells was performed to explore the effects of phentolamine/LPS treatment on cell viability, apoptosis levels, and inflammatory factor levels in MRC-5 cells. RESULTS: Preincubation of MRC-5 cells with a low concentration of phentolamine (≤6 µg/mL) protected against LPS-induced cell inflammatory injury. Phentolamine promoted both TrkA and Akt phosphorylation and Akt activation induced by LPS in MRC-5 cells. The protective effect of phentolamine against LPS-induced apoptosis and inflammation was significantly reduced in response to TrkA or Akt gene knockdown in MRC-5 cells. CONCLUSIONS: Phentolamine may protect LPS-induced apoptosis and inflammation by activating the TrkA and Akt signaling pathways.

Reporting and influencing factors of patient-reported outcomes in acupuncture randomised controlled trials: a cross-sectional study protocol.

INTRODUCTION: Patient-reported outcomes (PROs) are health reports that come directly from the patients themselves and represented the experience and insights of the patient's perspective on the impact of the intervention. PROs were increasingly emphasised in acupuncture randomised controlled trials (RCTs). However, the reporting quality of PROs in acupuncture RCTs has not been investigated to date. Therefore, we constructed this study to reveal the basic characteristics and reporting quality of PROs in acupuncture RCTs, and explore the relationship between concealment, blinding and RROs. We hope our findings can provide guidance for the reporting standards and future development of PROs in acupuncture RCTs in reverse. METHODS AND ANALYSIS: RCTs using acupuncture treatment as the intervention and PROs as primary outcomes or secondary outcomes will be systematically searched through seven databases MEDLINE, EMBASE, CENTRAL, CBM, CNKI, Wanfang and VIP between 1 January 2012 and 15 October 2022. The basic characteristics, concealment, blinding design and the characteristics of PROs in included RCTs will be summarised. The reporting quality of PROs will be assessed based on the CONSORT PRO extension. Logistic analysis will be performed to identify the association between concealment, blinding and RROs. ETHICS AND DISSEMINATION: Ethical approval is not required for this study. This protocol has been registered in Open Science Framework (OSF) Registries. The findings of this study will be submitted to a peer-reviewed academic journal.

Effectiveness of nurse-delivered stepwise swallowing training on dysphagia in patients with Alzheimer's disease: A multi-center randomized controlled trial.

BACKGROUND: Although swallowing exercises are a fundamental treatment for dysphagia, few studies have evaluated the effectiveness of swallowing training in patients with Alzheimer's disease. METHODS: We recruited 93 patients with Alzheimer's disease from three hospitals in Guangdong, China. This was a parallel armed randomized controlled trial that randomly assigned patients to intervention (n = 48) and control (n = 45) groups. The intervention group adopted systematic stepwise swallowing training for four weeks based on routine dysphagia care. The control group implemented routine dysphagia care, including diet and posture management and health education about swallowing dysfunction. The swallowing function was the primary outcome, which was assessed using the Water Swallowing Test and Standard Swallowing Assessment. An abnormal eating behavior questionnaire was used to assess the incidence of aberrant eating behavior in patients with Alzheimer's disease. The Mini-Nutritional Assessment Short Form and Barthel index were adopted to evaluate the nutritional status and ability to carry out daily activities between groups. SPSS software was used to perform the chi-square test, t-test, and generalized estimation equation for data analysis. RESULTS: We analyzed the effects of the stepwise swallowing training program using the generalized estimating equation method. The intervention group exhibited greater improvements in their swallowing function (Water Swallowing Test: ß = -3.133, 95 % CI: -4.113, -2.154, P < 0.001; Standard Swallowing Assessment: ß = -5.813, 95 % CI: -7.782, -3.844, P < 0.001), abnormal eating behaviors (abnormal eating behavior questionnaire: ß = -13.324, 95 % CI: -21.643, -5.005, P = 0.002), daily function (Barthel index: ß = 11.280, 95 % CI: 4.021, 18.540, P = 0.002), and nutritional status (Mini-Nutritional Assessment Short Form: ß = 2.402, 95 % CI: 1.313, 3.490, P < 0.001) over time than the routine-care group in the fourth week. CONCLUSIONS: Stepwise swallowing training is a safe and effective intervention for managing dysphagia and other related symptoms in patients with Alzheimer's disease.

Two-dose "extended priming" immunization amplifies humoral immune responses by synchronizing vaccine delivery with the germinal center response.

"Extended priming" immunization regimens that prolong exposure of the immune system to vaccines during the primary immune response have shown promise in enhancing humoral immune responses to a variety of subunit vaccines in preclinical models. We previously showed that escalating-dosing immunization (EDI), where a vaccine is dosed every other day in an increasing pattern over 2 weeks dramatically amplifies humoral immune responses. But such a dosing regimen is impractical for prophylactic vaccines. We hypothesized that simpler dosing regimens might replicate key elements of the immune response triggered by EDI. Here we explored "reduced ED" immunization regimens, assessing the impact of varying the number of injections, dose levels, and dosing intervals during EDI. Using a stabilized HIV Env trimer as a model antigen combined with a potent saponin adjuvant, we found that a two-shot extended-prime regimen consisting of immunization with 20% of a given vaccine dose followed by a second shot with the remaining 80% of the dose 7 days later resulted in increased total GC B cells, 5-10-fold increased frequencies of antigen-specific GC B cells, and 10-fold increases in serum antibody titers compared to single bolus immunization. Computational modeling of the GC response suggested that this enhanced response is mediated by antigen delivered in the second dose being captured more efficiently as immune complexes in follicles, predictions we verified experimentally. Our computational and experimental results also highlight how properly designed reduced ED protocols enhance activation and antigen loading of dendritic cells and activation of T helper cells to amplify humoral responses. These results suggest that a two-shot priming approach can be used to substantially enhance responses to subunit vaccines.

Histidine Metabolic Pathway Contributes to Clozapine-Induced Sialorrhea Based on Nontargeted Metabolomics.

INTRODUCTION: Clozapine-induced sialorrhea (CIS) is one of the most common side effects of clozapine use, while the mechanism remains unclear. METHODS: A total of 51 schizophrenia patients taking clozapine were selected. Among them, 32 had sialorrhea, and 19 had no sialorrhea. Saliva metabolites were identified using ultra-high-performance liquid chromatography-MS/MS (UHPLC-MS/MS), and the differences in saliva metabolites in each group were analyzed through qualitatively searching HMDB, KEGG, and self-built databases, combined with multivariate statistics. After further evaluation by receiver-operating characteristic curve (ROC) analysis, the screened differential metabolites were enriched and topologically analyzed. RESULTS: The biomarkers potentially related to CIS included 37 differential metabolites involving 17 metabolic pathways, mainly histidine metabolism (p < 0.05, impact = 0.50), pyrimidine metabolism (p < 0.05, impact = 0.08), and ß-alanine metabolism (p < 0.05, impact = 0.06). CONCLUSION: Our study indicates that histidine metabolic pathway may contribute to the mechanism of CIS.

The pharmacological actions of Danzhi-xiaoyao-San on depression involve lysophosphatidic acid and microbiota-gut-brain axis: novel insights from a systems pharmacology analysis of a double-blind, randomized, placebo-controlled clinical trial.

Danzhi-xiaoyao-San (DZXYS), a Traditional Chinese Medicine, plays an essential role in the clinical treatment of depression, but its mechanisms in humans remain unclear. To investigate its pharmacological effects and mechanisms as an add-on therapy for depression, we conducted a double-blind, placebo-controlled trial with depressed patients receiving selective serotonin reuptake inhibitors (SSRIs). Serum and fecal samples were collected for metabolomic and microbiome analysis using UHPLC-QTRAP-MS/MS and 16S rRNA gene sequencing technologies, respectively. Depression symptoms were assessed using the 24-item Hamilton Depression Scale. We employed network pharmacology, metabolomics, and molecular docking to identify potential targets associated with DZXYS. We also examined the correlation between gut microbes and metabolites to understand how DZXYS affects the microbiota-gut-brain axis. The results showed that DZXYS combined with SSRIs was more effective than SSRIs alone in improving depression. We identified 39 differential metabolites associated with DZXYS treatment and found seven upregulated metabolic pathways. The active ingredients quercetin and luteolin were docked to targets (AVPR2, EGFR, F2, and CDK6) associated with the enriched pathways 'pancreatic cancer' and 'phospholipase D signaling pathway', which included the metabolite lysophosphatidic acid [LPA(0:0/16:0)]. Additionally, we identified 32 differential gut microbiota species related to DZXYS treatment, with Bacteroides coprophilus and Ruminococcus gnavus showing negative correlations with specific metabolites such as L-2-aminobutyric acid and LPA(0:0/16:0). Our findings indicate that DZXYS's antidepressant mechanisms involve multiple targets, pathways, and the regulation of LPA and the microbiota-gut-brain axis. These insights from our systems pharmacology analysis contribute to a better understanding of DZXYS's potential pharmacological mechanisms in depression treatment.Communicated by Ramaswamy H. Sarma.

HIGHLIGHTSThis study presents a double-blind, randomized, placebo-controlled clinical trial comparing the clinical effects of Danzhi-xiaoyao-San (DZXYS) plus selective serotonin reuptake inhibitors (SSRIs) and SSRIs alone.This study is the first system pharmacology approach to integrate multi-omics and network pharmacology and examine the clinical pharmacological mechanisms of DZXYS as an add-on therapy for depression.This study highlights that regulation of lysophosphatidic acid (LPA) and the microbiota-gut-brain axis by DZXYS plays an essential role in its antidepressant mechanisms.

Growth promotion of Sargassum fusiforme by epiphytic microbes is dependent on the extent of interspecific interactions of the microbial community.

Profound growth differences such as seedling length and biomass are often observed during the cultivation of Sargassum fusiforme despite the absence of detectable variance in abiotic factors that could have affected this process. This highlights the importance of biotic factors such as epiphytic microbiota in controlling seedling growth. Yet, how, and to what extent microbial activities can affect host growth in the presence of seawater flow and continuous erosion remains debatable. Particularly, the contribution of microbial network interactions to the growth of macroalgae remains poorly understood. This study aimed to compare the physicochemical properties of S. fusiforme seedlings via 16S rRNA gene Illumina sequencing-based profiling of the epiphytic microbial communities of seedlings with different lengths. Significantly different epiphytic bacterial communities were observed among S. fusiforme seedlings of different lengths. The result showed that community from longer seedlings maintained higher bacterial diversity with the taxa Gammaproteobacteria, Burkholderiales, Alteromonadales, Vibrionaceae, Ralstonia, Colwelliaceae, and Thalassotalea being selectively enriched. More importantly, microbial interspecific interactions, which were predominantly positive, were enhanced consistently in communities of the longer seedlings, indicative of reinforced prevalent and mutually cooperative relationships among the microorganisms associated with S. fusiforme seedlings of greater length. Furthermore, longer seedlings also displayed up-regulation of microbial functional potentials involved in N fixation and mineralization, P mineralization and transportation, and ion transportation compared with shorter ones. Lastly, stochastic processes dominated the community assembly of the epiphytic microorganisms. These findings could provide new insights into the relationship between microbial communities and growth in S. fusiforme seedlings and enable us to predict the community diversity and assembly of macroalgae-associated microbial communities. This could have important implications for linking microbial community diversity and network interactions to their host productivity.

Reporting and data-sharing level of acupuncture randomised controlled trials: a cross-sectional study protocol.

INTRODUCTION: Randomised controlled trials (RCTs) play an important role in evidence-based medicine. However, an article with low reporting quality may mislead both experts and the general public into an erroneous decision. Data sharing can contribute to the truthfulness and transparency of trials. Acupuncture RCTs have been increasing rapidly these years, but the reporting quality and data-sharing level of acupuncture RCTs are not clear. Thus, this study will provide the current status of the reporting quality and data-sharing level of acupuncture RCTs. METHODS AND ANALYSIS: A cross-sectional study will be conducted. The seven databases including MEDLINE, EMBASE, CENTRAL, CBM, CNKI, Wanfang Database and VIP will be searched between 1 January 2012 and 15 October 2022 to identify acupuncture RCTs. The basic characteristics of included trials will be summarised. The reporting quality for included RCTs will be assessed by the Consolidated Standards for Reporting Trials 2010 statement and the Standards for Reporting Interventions in Controlled Trials of Acupuncture. The data-sharing level will be assessed by open science practices. ETHICS AND DISSEMINATION: Ethical approval is not required for this study. This protocol has been registered in Open Science Framework Registries. The findings of this study will be submitted to a peer-reviewed academic journal.

Universal redirection of CAR T cells against solid tumours via membrane-inserted ligands for the CAR.

The effectiveness of chimaeric antigen receptor (CAR) T cell therapies for solid tumours is hindered by difficulties in the selection of an effective target antigen, owing to the heterogeneous expression of tumour antigens and to target antigen expression in healthy tissues. Here we show that T cells with a CAR specific for fluorescein isothiocyanate (FITC) can be directed against solid tumours via the intratumoural administration of a FITC-conjugated lipid-poly(ethylene)-glycol amphiphile that inserts itself into cell membranes. In syngeneic and human tumour xenografts in mice, 'amphiphile tagging' of tumour cells drove tumour regression via the proliferation and accumulation of FITC-specific CAR T cells in the tumours. In syngeneic tumours, the therapy induced the infiltration of host T cells, elicited endogenous tumour-specific T cell priming and led to activity against distal untreated tumours and to protection against tumour rechallenge. Membrane-inserting ligands for specific CARs may facilitate the development of adoptive cell therapies that work independently of antigen expression and of tissue of origin.

Multi-copper oxidases SKU5 and SKS1 coordinate cell wall formation using apoplastic redox-based reactions in roots.

The primary cell wall is a fundamental plant constituent that is flexible but sufficiently rigid to support the plant cell shape. Although many studies have demonstrated that reactive oxygen species (ROS) serve as important signaling messengers to modify the cell wall structure and affect cellular growth, the regulatory mechanism underlying the spatial-temporal regulation of ROS activity for cell wall maintenance remains largely unclear. Here, we demonstrate the role of the Arabidopsis (Arabidopsis thaliana) multicopper oxidase-like protein skewed 5 (SKU5) and its homolog SKU5-similar 1 (SKS1) in root cell wall formation through modulating ROS homeostasis. Loss of SKU5 and SKS1 function resulted in aberrant division planes, protruding cell walls, ectopic deposition of iron, and reduced nicotinamide adeninedinucleotide phosphate (NADPH) oxidase-dependent ROS overproduction in the root epidermis-cortex and cortex-endodermis junctions. A decrease in ROS level or inhibition of NADPH oxidase activity rescued the cell wall defects of sku5 sks1 double mutants. SKU5 and SKS1 proteins were activated by iron treatment, and iron over-accumulated in the walls between the root epidermis and cortex cell layers of sku5 sks1. The glycosylphosphatidylinositol-anchored motif was crucial for membrane association and functionality of SKU5 and SKS1. Overall, our results identified SKU5 and SKS1 as regulators of ROS at the cell surface for regulation of cell wall structure and root cell growth.

Microvasculature and microstructure alteration in dry-type high myopia.

BACKGROUND: To investigate the alterations in the retinal vasculature and microstructure in dry-type high myopia. METHODS: One hundred and eighty-nine dry-type high myopia eyes were classified into three groups. Group 1 consisted of 86 eyes with no myopic retinal degenerative lesion (C0). Group 2 consisted of 71 eyes with tessellated fundus (C1). Group 3 consisted of 32 eyes with diffuse chorioretinal atrophy (C2). Retinal vascular density and retinal thickness were measured with optical coherence tomography angiography. The scanning area was a 3 × 3 mm2 ring with the fovea of the macular. All data were analyzed with the SPSS 23.0 by one-way ANOVA test among comparison groups. Pearson's correlation analysis was used to determine the relations among measurements. Univariate linear regression showed a correlation between the vascular densities and retinal thicknesses. RESULTS: The microvessel density significantly decreased and significant thinning of the superior and temporal macular thickness in the C2 group. The vascular densities of macular decreased significantly with the increase of axial length (AL) and refractive diopter in the C2 group. The retinal thicknesses of the macular fovea increased significantly with the increase of vascular densities in the C0 group and C1 group. CONCLUSIONS: The impairment of retinal microstructure is more likely related to reduced oxygen and nutrients due to microvessel density decreases.

Psychological stress and psychological support of Chinese nurses during severe public health events.

The domestic health care system has been facing a difficult task, especially in medical care, and Chinese nurses are under tremendous psychological pressure. Psychological support is a protective factor to relieve stress. This study examined the stress level and characteristics of Chinese nurses with different psychological support-seeking behaviours. Data from online questionnaires for this cross-sectional study were collected between January 2020 and February 2020 and yielded 2248 valid questionnaires for analysis with a response rate of 99.8%. General information of the respondents was also collected. The nurses' stress levels were assessed using the Perceived Stress Scale (PSS-10). T tests, chi-square tests, and linear regression were used to examine the relationships among the factors. The results of this survey showed that between January and February 2020, 26.9% of nurses received psychological counselling, and the proportion was higher among men and nurses with lower education. The PSS-10 was related to gender, age group, provincial severity, and confidence in the control of the epidemic. The results showed that psychological support can effectively improve the confidence of domestic nurses in the face of arduous work and effectively relieve the psychological pressure caused by a heavy workload.

Identification of Highly Cross-Reactive Mimotopes for a Public T Cell Response in Murine Melanoma.

While immune checkpoint blockade results in durable responses for some patients, many others have not experienced such benefits. These treatments rely upon reinvigorating specific T cell-antigen interactions. However, it is often unknown what antigens are being recognized by T cells or how to potently induce antigen-specific responses in a broadly applicable manner. Here, we characterized the CD8+ T cell response to a murine model of melanoma following combination immunotherapy to determine the basis of tumor recognition. Sequencing of tumor-infiltrating T cells revealed a repertoire of highly homologous TCR sequences that were particularly expanded in treated mice and which recognized an antigen from an endogenous retrovirus. While vaccination against this peptide failed to raise a protective T cell response in vivo, engineered antigen mimotopes induced a significant expansion of CD8+ T cells cross-reactive to the original antigen. Vaccination with mimotopes resulted in killing of antigen-loaded cells in vivo yet showed modest survival benefit in a prophylactic vaccine paradigm. Together, this work demonstrates the identification of a dominant tumor-associated antigen and generation of mimotopes which can induce robust functional T cell responses that are cross-reactive to the endogenous antigen across multiple individuals.

STING agonist delivery by tumour-penetrating PEG-lipid nanodiscs primes robust anticancer immunity.

Activation of the innate immune STimulator of INterferon Genes (STING) pathway potentiates antitumour immunity, but systemic delivery of STING agonists to tumours is challenging. We conjugated STING-activating cyclic dinucleotides (CDNs) to PEGylated lipids (CDN-PEG-lipids; PEG, polyethylene glycol) via a cleavable linker and incorporated them into lipid nanodiscs (LNDs), which are discoid nanoparticles formed by self-assembly. Compared to state-of-the-art liposomes, intravenously administered LNDs carrying CDN-PEG-lipid (LND-CDNs) exhibited more efficient penetration of tumours, exposing the majority of tumour cells to STING agonist. A single dose of LND-CDNs induced rejection of established tumours, coincident with immune memory against tumour rechallenge. Although CDNs were not directly tumoricidal, LND-CDN uptake by cancer cells correlated with robust T-cell activation by promoting CDN and tumour antigen co-localization in dendritic cells. LNDs thus appear promising as a vehicle for robust delivery of compounds throughout solid tumours, which can be exploited for enhanced immunotherapy.

Jia Wei Xiao Yao San ameliorates chronic stress-induced depression-like behaviors in mice by regulating the gut microbiome and brain metabolome in relation to purine metabolism.

BACKGROUND: The pathogenesis of depression remains largely unknown. Accumulating evidence demonstrates the existence of a complex relationship between gut microbiome composition and brain functions. Jia Wei Xiao Yao San (JWXYS) is considered a potential antidepressant. However, the pharmacological mechanisms of JWXYS have not yet been clarified. PURPOSE: This study aimed to explore the effects of JWXYS on chronic stress-induced depression-like behaviors in mice. METHODS: A chronic restraint stress mouse model of depression was established. JWXYS was administered, and the responses of these mice to treatment were evaluated through several behavioral tests. The activity of astrocytes and microglia was detected by specific fluorescent labels. Inflammatory cytokines were quantified in intestinal and cerebral tissues. An integrated approach with full-length 16S rRNA sequencing and different types of untargeted metabolomics was conducted to investigate the relationship between the gut microbiome at the species level, metabolic brain functions, and JWXYS. RESULTS: We found that behavioral symptoms were associated with the relative abundance of Lactobacillus animalis. After JWXYS treatment, the relative abundance of Ileibacterium valens with enzymes potentially involved in purine metabolism was also described. The activation of astrocytes and microglia was negatively correlated with the relative abundance of L. animalis. Combined with network pharmacological analysis, several targets predicted based on JWXYS treatment focused on purine metabolism, which was also enriched from cerebral metabolites regulated by JWXYS. CONCLUSION: Our study suggests that L. animalis is involved in depression-like behaviors in mice. JWXYS increases the abundance of I. valens with potential enzymes in relation to cerebral purine metabolism, which is positively correlated with the activation of astrocytes in the amygdala.

Mannose-binding lectin and complement mediate follicular localization and enhanced immunogenicity of diverse protein nanoparticle immunogens.

Nanoparticle (NP) vaccine formulations promote immune responses through multiple mechanisms. We recently reported that mannose-binding lectin (MBL) triggers trafficking of glycosylated HIV Env-immunogen NPs to lymph node follicles. Here, we investigate effects of MBL and complement on NP forms of HIV and other viral antigens. MBL recognition of oligomannose on gp120 nanoparticles significantly increases antigen accumulation in lymph nodes and antigen-specific germinal center (GC) responses. MBL and complement also mediate follicular trafficking and enhance GC responses to influenza, HBV, and HPV particulate antigens. Using model protein nanoparticles bearing titrated levels of glycosylation, we determine that mannose patches at a minimal density of 2.1 × 10-3 mannose patches/nm2 are required to trigger follicular targeting, which increases with increasing glycan density up to at least ∼8.2 × 10-3 patches/nm2. Thus, innate immune recognition of glycans has a significant impact on humoral immunity, and these findings provide a framework for engineering glycan recognition to optimize vaccine efficacy.

Neoadjuvant STING Activation, Extended Half-life IL2, and Checkpoint Blockade Promote Metastasis Clearance via Sustained NK-cell Activation.

Combination immunotherapy treatments that recruit both innate and adaptive immunity have the potential to increase cancer response rates by engaging a more complete repertoire of effector mechanisms. Here, we combined intratumoral STimulator of INterferon Genes (STING) agonist therapy with systemically injected extended half-life IL2 and anti-PD-1 checkpoint blockade (hereafter CIP therapy) to drive innate and adaptive antitumor immunity in models of triple-negative breast cancer. Unlike treatment with the individual components, this trivalent immunotherapy halted primary tumor progression and led to long-term remission for a majority of animals in two spontaneously metastasizing orthotopic breast tumor models, though only as a neoadjuvant therapy but not adjuvant therapy. CIP therapy induced antitumor T-cell responses, but protection from metastatic relapse depended on natural killer (NK) cells. The combination of STING agonists with IL2/anti-PD-1 synergized to stimulate sustained granzyme and cytokine expression by lung-infiltrating NK cells. Type I IFNs generated as a result of STING agonism, combined with IL2, acted in a positive-feedback loop by enhancing the expression of IFNAR-1 and CD25 on lung NK cells. These results suggest that NK cells can be therapeutically targeted to effectively eliminate tumor metastases.See related Spotlight by Demaria, p. 3.