Recapitulation of HIV-1 Neutralization Breadth in Plasma by the Combination of Two Broadly Neutralizing Antibodies from Different Lineages in the Same SHIV-Infected Rhesus Macaque.

Viral infection generally induces polyclonal neutralizing antibody responses. However, how many lineages of antibody responses can fully represent the neutralization activities in sera has not been well studied. Using the newly designed stable HIV-1 Env trimer as hook, we isolated two distinct broadly neutralizing antibodies (bnAbs) from Chinese rhesus macaques infected with SHIV1157ipd3N4 for 5 years. One lineage of neutralizing antibodies (JT15 and JT16) targeted the V2-apex in the Env trimers, similar to the J038 lineage bnAbs identified in our previous study. The other lineage neutralizing antibody (JT18) targeted the V3 crown region in the Env, which strongly competed with human 447-52D. Each lineage antibody neutralized a different set of viruses. Interestingly, when the two neutralizing antibodies from different lineages isolated from the same macaque were combined, the mixture had a neutralization breath very similar to that from the cognate sera. Our study demonstrated that a minimum of two different neutralizing antibodies can fully recapitulate the serum neutralization breadth. This observation can have important implications in AIDS vaccine design.

Immobilized NRG1 Accelerates Neural Crest like Cell Differentiation Toward Functional Schwann Cells Through Sustained Erk1/2 Activation and YAP/TAZ Nuclear Translocation.

Neural Crest cells (NC) are a multipotent cell population that give rise to a multitude of cell types including Schwann cells (SC) in the peripheral nervous system (PNS). Immature SC interact with neuronal axons via the neuregulin 1 (NRG1) ligand present on the neuronal surface and ultimately form the myelin sheath. Multiple attempts to derive functional SC from pluripotent stem cells have met challenges with respect to expression of mature markers and axonal sorting. Here, they hypothesized that sustained signaling from immobilized NRG1 (iNRG1) might enhance the differentiation of NC derived from glabrous neonatal epidermis towards a SC phenotype. Using this strategy, NC derived SC expressed mature markers to similar levels as compared to explanted rat sciatic SC. Signaling studies revealed that sustained NRG1 signaling led to yes-associated protein 1 (YAP) activation and nuclear translocation. Furthermore, NC derived SC on iNRG1 exhibited mature SC function as they aligned with rat dorsal root ganglia (DRG) neurons in an in vitro coculture model; and most notably, aligned on neuronal axons upon implantation in a chick embryo model in vivo. Taken together their work demonstrated the importance of signaling dynamics in SC differentiation, aiming towards development of drug testing platforms for de-myelinating disorders.

Environment-responsive dendrobium polysaccharide hydrogel embedding manganese microsphere as a post-operative adjuvant to boost cascaded immune cycle against melanoma.

Rationale: Surgical resection is a primary treatment for solid tumors, but high rates of tumor recurrence and metastasis post-surgery present significant challenges. Manganese (Mn2+), known to enhance dendritic cell-mediated cancer immunotherapy by activating the cGAS-STING pathway, has potential in post-operative cancer management. However, achieving prolonged and localized delivery of Mn2+ to stimulate immune responses without systemic toxicity remains a challenge. Methods: We developed a post-operative microenvironment-responsive dendrobium polysaccharide hydrogel embedded with Mn2+-pectin microspheres (MnP@DOP-Gel). This hydrogel system releases Mn2+-pectin microspheres (MnP) in response to ROS, and MnP shows a dual effect in vitro: promoting immunogenic cell death and activating immune cells (dendritic cells and macrophages). The efficacy of MnP@DOP-Gel as a post-surgical treatment and its potential for immune activation were assessed in both subcutaneous and metastatic melanoma models in mice, exploring its synergistic effect with anti-PD1 antibody. Result: MnP@DOP-Gel exhibited ROS-responsive release of MnP, which could exert dual effects by inducing immunogenic cell death of tumor cells and activating dendritic cells and macrophages to initiate a cascade of anti-tumor immune responses. In vivo experiments showed that the implanted MnP@DOP-Gel significantly inhibited residual tumor growth and metastasis. Moreover, the combination of MnP@DOP-Gel and anti-PD1 antibody displayed superior therapeutic potency in preventing either metastasis or abscopal brain tumor growth. Conclusions: MnP@DOP-Gel represents a promising drug-free strategy for cancer post-operative management. Utilizing this Mn2+-embedding and ROS-responsive delivery system, it regulates surgery-induced immune responses and promotes sustained anti-tumor responses, potentially increasing the effectiveness of surgical cancer treatments.

Defective Diamane: A Superior Sensor for Toxic Gases Capture and Detection with Excellent Selectivity, Sensitivity, and Reversibility at Room Temperature.

The toxic gases emitted from industrial production have caused significant damage to the environment and human health, necessitating efficient gas sensors for their detection and removal. In this work, first-principles calculations are employed to investigate the potential application of diamanes for high-performance toxic gas sensors. The results show that nine gas molecules (CO, CO2, NO, NO2, NH3, SO2, N2, O2, and H2O) are physisorbed on pristine diamane by weak van der Waals interactions. After introducing H/F defects, diamane can effectively capture specific toxic gases (CO, NO, NO2, and SO2) in the presence of interfering gases (N2, O2, and H2O), suggesting excellent selectivity and anti-interference ability. Orbital hybridization and significant charge redistribution between gas molecules and defective diamane dominate the enhanced adsorbate-substrate interactions. More importantly, the high sensitivity and good reversibility of defective diamane for detecting CO, NO, and SO2 molecules enable its reuse as a superior resistance-type gas sensor. Our calculations provide valuable insights into the potential of defective diamane for detecting toxic gases and shed light on the practical application of novel carbon-based materials in the gas-sensing field.

Oxygen-Terminated Polycrystalline Boron-Doped Diamond Superhydrophobic Surface with Excellent Mechanical and Thermal Stabilities.

Superhydrophobic surfaces are of great interest because of their remarkable properties. Due to its maximal hardness and chemical inertness, diamond film has great potential in fabricating robust superhydrophobic surfaces. In the present study, an oxygen-terminated polycrystalline boron-doped diamond (O-PBDD) superhydrophobic surface with micro/nano-hierarchical porous structures is developed. The preparation method is very simple, requiring only sputtering and dewetting procedures. The former involves sputtering gold and copper particles onto the hydrogen-terminated polycrystalline boron-doped diamond (H-PBDD) to form gold/copper films, whereas the latter involves placing the samples in an atmospheric tube furnace to form hierarchical pores. By controlling the etching parameters, the wettability of the O-PBDD surface can be adjusted from hydrophilic to superhydrophobic, which is significantly different to the normal hydrophilicity feature of O-termination diamonds. The water contact angle of the obtained O-PBDD surface can reach 165 ± 5°, which is higher than the superhydrophobic diamond surfaces that are reported in the literature. In addition, the O-PBDD surface exhibits excellent durability; it can maintain satisfactory superhydrophobicity even after high-pressure, high-temperature, and sandpaper friction tests. This work provides a new research direction for fabricating robust superhydrophobic materials with diamond film.

Assessment of toxic effects of thallium on the earthworm Eisenia fetida using the biomarker response index.

Thallium (Tl), though not essential for biological systems, is widely used in industrial activities, resulting in soil pollution and adverse effects on soil biota. Systematic toxicological studies on Tl, especially concerning soil organisms, are relatively rare. This research evaluates the toxic effects of Tl on earthworms by measuring oxidative stress biomarkers, such as superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST), malondialdehyde (MDA), and 8-hydroxydeoxyguanosine (8-OHdG), and by assessing the expression of functional genes, such as heat shock protein 70 (Hsp70), metallothionein (MT), and annetocin (ANN). Additionally, this study employs the Biomarker Response Index (BRI) and two-way ANOVA to comprehensively assess the cumulative toxicity of Tl in earthworms. The findings indicate that Tl exposure significantly exacerbates oxidative stress and cellular damage in earthworms, particularly under conditions of high concentration and prolonged exposure. BRI results demonstrate a continuous decline in the physiological state of earthworms with increasing Tl concentration and exposure duration. Two-way ANOVA reveals significant dose-responsive increases in SOD and CAT activities, as well as in ANN gene expression. Apart from GST activity, other biomarkers significantly increased over time, and the changes in biomarkers such as SOD, CAT, MDA, and 8-OHdG were significantly influenced by dose and time. LSD post hoc tests show significant effects of dose, time, and their interactions on all biomarkers except for GST. These findings are valuable for gaining a deeper understanding of the ecological risks of Tl in soil environments and its potential threats to soil biota, aiding in the management of ecological risks associated with Tl-contaminated soils.

Xuebijing improves intestinal microcirculation dysfunction in septic rats by regulating the VEGF-A/PI3K/Akt signaling pathway.

BACKGROUND: This study aims to explore whether Xuebijing (XBJ) can improve intestinal microcirculation dysfunction in sepsis and its mechanism. METHODS: A rat model of sepsis was established by cecal ligation and puncture (CLP). A total of 30 male SD rats were divided into four groups: sham group, CLP group, XBJ + axitinib group, and XBJ group. XBJ was intraperitoneally injected 2 h before CLP. Hemodynamic data (blood pressure and heart rate) were recorded. The intestinal microcirculation data of the rats were analyzed via microcirculation imaging. Enzyme-linked immunosorbent assay (ELISA) kits were used to detect the serum levels of interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor-α (TNF-α) in the rats. Histological analysis and transmission electron microscopy were used to analyze the injury of small intestinal microvascular endothelial cells and small intestinal mucosa in rats. The expression of vascular endothelial growth factor A (VEGF-A), phosphoinositide 3-kinase (PI3K), phosphorylated PI3K (p-PI3K), protein kinase B (Akt), and phosphorylated Akt (p-Akt) in the small intestine was analyzed via Western blotting. RESULTS: XBJ improved intestinal microcirculation dysfunction in septic rats, alleviated the injury of small intestinal microvascular endothelial cells and small intestinal mucosa, and reduced the systemic inflammatory response. Moreover, XBJ upregulated the expression of VEGF-A, p-PI3K/total PI3K, and p-Akt/total Akt in the rat small intestine. CONCLUSION: XBJ may improve intestinal microcirculation dysfunction in septic rats possibly through the VEGF-A/PI3K/Akt signaling pathway.

Error compensation for near optical coaxial phase measuring deflectometry with refraction error model.

Phase measuring deflectometry (PMD) is a key measurement technology for specular surfaces form measurement. Compared with conventional PMD techniques, the near optical coaxial PMD (NCPMD) can achieve compact configuration, light weight and reducing measurement error caused by shadows of the surface structures through utilizing a plate beamsplitter. However, the introduction of the plate beamsplitter will affect the measurement accuracy of the NCPMD system. The refraction of the plate beamsplitter needs to be considered. In this work, a virtual system of NCPMD was established, and an error model of the NCPMD system by considering the refraction influence of the plate beamsplitter was presented to analyze the shape reconstruction error caused by the plate beamsplitter. Moreover, the calibration method of the beamsplitter and the ray tracing algorithm to achieve error compensation of the beamsplitter were proposed. The proposed error compensation method can effectively improve the measurement accuracy of NCPMD system which has been confirmed by surface measurement experiments.

Soil pH amendment alters the abundance, diversity, and composition of microbial communities in two contrasting agricultural soils.

Soil microorganisms are the most active participants in terrestrial ecosystems, and have key roles in biogeochemical cycles and ecosystem functions. Despite the extensive research on soil pH as a key predictor of microbial community and composition, a limitation of these studies lies in determining whether bacterial and/or fungal communities are directly or indirectly influenced by pH. We conducted a controlled laboratory experiment to investigate the effects of soil pH amendment (+/- 1-2 units) with six levels on soil microbial communities in two contrasting Chinese agricultural soils (pH 8.43 in Dezhou, located in the North China Plain, Shandong vs pH 6.17 in Wuxi, located in the Taihu Lake region, Jiangsu, east China). Results showed that the fungal diversity and composition were related to soil pH, but the effects were much lower than the effects of soil pH on bacterial community in two soils. The diversity and composition of bacterial communities were more closely associated with soil pH in Wuxi soils compared to Dezhou soils. The alpha diversity of bacterial communities peaked near in situ pH levels in both soils, displaying a quadratic fitting pattern. Redundancy analysis and variation partition analysis indicated that soil pH affected bacterial community and composition by directly imposing a physiological constraint on soil bacteria and indirectly altering soil characteristics (e.g., nutrient availability). The study also examined complete curves of taxa relative abundances at the phylum and family levels in response to soil pH, with most relationships conforming to a quadratic fitting pattern, indicating soil pH is a reliable predictor. Furthermore, soil pH amendment affected the transformation of nitrogen and the abundances of functional genes involved in the nitrogen cycle, and methane production and consumption. Overall, results from this study would enhance our comprehension of how soil microorganisms in contrasting farmlands will respond to soil pH changes, and would contribute to more effective soil management and conservation strategies. IMPORTANCE: This study delves into the impact of soil pH on microbial communities, investigating whether pH directly or indirectly influences bacterial and fungal communities. The research involved two contrasting soils subjected to a 1-2 pH unit amendment. Results indicate bacterial community composition was shaped by soil pH through physiological constraints and nutrient limitations. We found that most taxa relative abundances at the phylum and family levels responded to pH with a quadratic fitting pattern, indicating that soil pH is a reliable predictor. Additionally, soil pH was found to significantly influence the predicted abundance of functional genes involved in the nitrogen cycle as well as in methane production and consumption processes. These insights can contribute to develop more effective soil management and conservation strategies.

Quantitative Assessment of True Vocal Fold Movement by the Lateral-Approach Laryngeal Ultrasonography: A Pilot Study.

BACKGROUND/OBJECTIVES: Ultrasonography is a new method for subjective and qualitative assessment of true vocal fold movement, and true vocal fold visualization with the lateral approach could be better than that with the anterior approach. Our aim was to explore the feasibility of lateral-approach ultrasonography in objective and quantitative assessment of true vocal fold movement. METHODS: The lateral-approach laryngeal ultrasonography was performed during calm breathing and breath-holding on young healthy adult volunteers in Shanghai, China. The morphology and anatomical position of false vocal fold, true vocal fold, and arytenoid cartilage were observed and measured through the ultrasonic self-contained measurement function. All parameters, including the distance from false vocal fold to thyroid cartilage lamina, true vocal fold length, and the distance from true vocal fold to thyroid cartilage lamina, were obtained at the end of the calm inspiratory and breath-holding phases. Data were analyzed using a t test (P < 0.05). RESULTS: Forty healthy adult volunteers (age 20 to 34 years, body mass index 19.5 to 23.8 kg/m2, 20 males and 20 females) with satisfactory ultrasonic images were included in the study. There were no significant differences in all laryngeal parameters between the left and right sides in either phase (P > 0.05). From the end of the calm inspiratory phase to the breath-holding phase, changes in all laryngeal parameters were significantly different (P < 0.05), regardless of gender. CONCLUSIONS: This study demonstrated that the lateral-approach laryngeal ultrasonography seemed feasible to quantify and objectively assess true vocal fold movement, utilizing differences between laryngeal parameters before and after true vocal fold movement.

Intestinal lysozyme engagement of Salmonella Typhimurium stimulates the release of barrier-impairing InvE and Lpp1.

Lysozyme is a ß-1,4-glycosidase that hydrolyzes the polysaccharide backbone of bacterial cell walls. With an additional bactericidal function mediated by a separate protein domain, lysozyme is considered a uniquely important antimicrobial molecule contributing to the host's innate immune response to infection. Elevated lysozyme production is found in various inflammatory conditions while patients with genetic risks for inflammatory bowel diseases demonstrate abnormal lysozyme expression, granule packaging, and secretion in Paneth cells. However, it remains unclear how a gain- or loss-of-function in host lysozyme may impact the host inflammatory responses to pathogenic infection. We challenged Lyz1-/- and ectopic Lyz1-expressing (Villin-Lyz1TG) mice with S. Typhimurium and then comprehensively assessed the inflammatory disease progression. We conducted proteomics analysis to identify molecules derived from human lysozyme-mediated processing of live Salmonella. We examined the barrier-impairing effects of these identified molecules in human intestinal epithelial cell monolayer and enteroids. Lyz1-/- mice are protected from infection in terms of morbidity, mortality, and barrier integrity, whereas Villin-Lyz1TG mice demonstrate exacerbated infection and inflammation. The growth and invasion of Salmonella in vitro are not affected by human or chicken lysozyme, whereas lysozyme encountering of live Salmonella stimulates the release of barrier-disrupting factors, InvE-sipC and Lpp1, which directly or indirectly impair the tight junctions. The direct engagement of host intestinal lysozyme with an enteric pathogen such as Salmonella promotes the release of virulence factors that are barrier-impairing and pro-inflammatory. Controlling lysozyme function may help alleviate the inflammatory progression.

Preparation, structural analysis of alcohol aroma compounds/ß-cyclodextrin inclusion complexes and the application in strawberry preservation.

The dynamic combination of aromas and cyclodextrins is an important means to achieve their stability and controllability, and accurately revealing their interaction rules is the key to designing and constructing high-quality aroma nanocarriers. In this study, the inclusion mechanism between alcohol aroma compounds with different structures and ß-cyclodextrin (ß-CD) was studied by combining molecular dynamics simulation and experimental methods. Results showed that the selected alcohol aroma compounds formed inclusion complexes (ICs) with ß-CD in a 1:1 ratio, while alcohol aroma compounds containing cyclic structures were more tightly bound to ß-CD. Van der Waals forces were the primary forces driving the formation and stabilization of the ICs. Cinnamyl alcohol/ß-CD ICs showed the most significant antimicrobial effect and notably prolonged the shelf life of strawberries. This study aimed to provide theoretical support for precisely designing and preparing highly stable flavours and fragrances, as well as expanding their application range.

DrugSK: A Stacked Ensemble Learning Framework for Predicting Drug Combinations of Multiple Diseases.

Combination therapy is an important direction of continuous exploration in the field of medicine, with the core goals of improving treatment efficacy, reducing adverse reactions, and optimizing clinical outcomes. Machine learning technology holds great promise in improving the prediction of drug synergy combinations. However, most studies focus on single disease-oriented collaborative predictive models or involve excessive feature categories, making it challenging to predict the majority of new drugs. To address these challenges, the DrugSK comprehensive model was developed, which utilizes SMILES-BERT to extract structural information from 3492 drugs and trains on reactions from 48,756 drug combinations. DrugSK is an integrated learning model capable of predicting interactions among various drug categories. First, the primary learner is trained from the initial data set. Random forest, support vector machine, and XGboost model are selected as primary learners and logistic regression as secondary learners. A new data set is then "generated" to train level 2 learners, which can be thought of as a prediction for each model. Finally, the results are filtered using logistic regression. Furthermore, the combination of the new antibacterial drug Drafloxacin with other antibacterial agents was tested. The synergistic effect of Drafloxacin and Isavuconazonium in the fight against Candida albicans has been confirmed, providing enlightenment for the clinical treatment of skin infection. DrugSK's prediction is accurate in practical application and can also predict the probability of the outcome. In addition, the tendency of Drafloxacin and antifungal drugs to be synergistic was found. The development of DrugSK will provide a new blueprint for predicting drug combination synergies.

General In Situ Engineering of Carbon-Based Materials on Carbon Fiber for In Vivo Neurochemical Sensing.

Developing real-time, dynamic, and in situ analytical methods with high spatial and temporal resolutions is crucial for exploring biochemical processes in the brain. Although in vivo electrochemical methods based on carbon fiber (CF) microelectrodes are effective in monitoring neurochemical dynamics during physiological and pathological processes, complex post modification hinders large-scale productions and widespread neuroscience applications. Herein, we develop a general strategy for the in situ engineering of carbon-based materials to mass-produce functional CFs by introducing polydopamine to anchor zeolitic imidazolate frameworks as precursors, followed by one-step pyrolysis. This strategy demonstrates exceptional universality and design flexibility, overcoming complex post-modification procedures and avoiding the delamination of the modification layer. This simplifies the fabrication and integration of functional CF-based microelectrodes. Moreover, we design highly stable and selective H+, O2, and ascorbate microsensors and monitor the influence of CO2 exposure on the O2 content of the cerebral tissue during physiological and ischemia-reperfusion pathological processes.

Association between serum neuron-specific enolase at admission and the risk of delayed neuropsychiatric sequelae in adults with carbon monoxide poisoning: A meta-analysis.

Delayed neuropsychiatric sequelae (DNS) significantly impact the quality of life in patients following acute carbon monoxide poisoning (COP). This systematic review and meta-analysis aimed to assess the relationship between serum neuron-specific enolase (NSE) levels at admission and the risk of DNS in adults after acute COP. Relevant observational studies with longitudinal follow-up were identified through searches in PubMed, Embase, Web of Science, Wanfang, and China National Knowledge Infrastructure databases. The random-effects model was used to aggregate results, accounting for potential heterogeneity. Nine cohort studies, including 1501 patients, were analyzed, with 254 (16.9%) developing DNS during follow-up. The pooled data indicated that elevated serum NSE in the early phase was linked to a higher risk of subsequent DNS (odds ratio per 1 ng/mL increase in NSE: 1.10, 95% confidence interval: 1.06 to 1.15, P < 0.001). Moderate heterogeneity (I2 = 46%) among the studies was entirely attributed to one study with the longest follow-up duration (22.3 months; I2 = 0% after excluding this study). Subgroup analyses based on country, study design, sample size, age, sex, admission carboxyhemoglobin levels, DNS incidence, follow-up duration, and quality score yielded consistent results (P for subgroup differences all > 0.05). In summary, high serum NSE levels in the early phase of acute COP are associated with an increased risk of developing DNS during follow-up.

High-Performance Anode Material Based on Zinc Naphthalocyanine/Graphene Composite.

Transition metal oxides are a potential anode material owing to their high theoretical capacity. Nonetheless, their large volume changes and low electrical conductivities lead to poor cycling performance and rate capabilities. In this article, an effective strategy is proposed and developed for preparing a ZnO/N-doped graphene composite (ZnNc/GO-5). The key point of this strategy is to use zinc tetra tert-butyl-naphthalocyanine (ZnNc) as a codoped source of N atoms and zinc ions, and graphene oxide (GO) which is combined with ZnNc by π-π deposition as a carbon matrix. After calcination, ZnO microcrystals coated with N-doped graphene are obtained. The unique features of the composite and synergistic effect between N-doped reduced graphene oxide and ZnO microcrystals enable good electrochemical performance by the composites when used in lithium-ion batteries. As an anode material, the as-synthesized ZnNc/GO-5 composite delivers a high first capacity of 1942.9 mAh g-1 and excellent cyclic stability of 861.4 mAh g-1 after 150 cycles at 100 mA g-1. This strategy may offer a new method of designing the anode materials of lithium-ion batteries and promote the practical use of organic molecules in next-generation lithium-ion batteries.

Inhibition of cIAP1/2 reduces RIPK1 phosphorylation in pulmonary endothelial cells and alleviate sepsis-induced lung injury and inflammatory response.

Acute respiratory distress syndrome (ARDS)/acute lung injury (ALI) is a severe complication of sepsis characterized by acute respiratory distress, hypoxemia, and diffuse bilateral pulmonary infiltrates. The regulation of RIPK1 is an important part of the inflammatory response, and cIAP1/2 serves as the E3 ubiquitin ligase for RIPK1. In this study, we investigated the effect and mechanism of cIAP1/2 inhibition on sepsis-induced lung injury. Our results showed that cIAP1/2 inhibition can alleviate sepsis-induced lung injury and reduce the inflammatory response, which is accompanied by downregulation of RIPK1 phosphorylation and ubiquitination. Additionally, cIAP1/2 inhibition led to the up-regulation of programmed cell death, including apoptosis, necroptosis, and pyroptosis, and inhibiting these three cell death pathways can further reduce the inflammatory response, which is similar to the recently discovered programmed cell death pathway PANoptosis. Our findings suggest that cIAP1/2 and PANoptosis inhibition may be a new strategy for treating sepsis-induced lung injury and provide important references for further exploring the mechanism of sepsis-induced lung injury and identifying new therapeutic targets.

Smad4 deficiency inhibits lung metastases through enhancing phagocytosis of lung interstitial macrophages.

Smad4, a critical mediator of TGF-ß signaling, plays a pivotal role in regulating various cellular functions, including immune responses. In this study, we investigated the impact of Smad4 knockout specifically in macrophages on anti-tumor immunity, focusing on lung metastasis of B16 melanoma cells. Using a mouse model with Smad4 knockout in macrophages established via Lyz2-cre mice and Smad4 flox/flox mice, we demonstrated a significant inhibition of B16 metastasis in the lungs. Interestingly, the inhibition of tumor growth was found to be independent of adaptive immunity, as no significant changes were observed in the numbers or activities of T cells, B cells, or NK cells. Instead, Smad4 knockout led to the emergence of an MCHIIlow CD206high subset of lung interstitial macrophages, characterized by enhanced phagocytosis function. Our findings highlight the crucial role of Smad4 in modulating the innate immune response against tumors and provide insights into potential therapeutic strategies targeting lung interstitial macrophages to enhance anti-tumor immunity.

Lactobacillus rhamnosus GG Stimulates Dietary Tryptophan-Dependent Production of Barrier-Protecting Methylnicotinamide.

BACKGROUND & AIMS: Lacticaseibacillus rhamnosus GG (LGG) is the world's most consumed probiotic but its mechanism of action on intestinal permeability and differentiation along with its interactions with an essential source of signaling metabolites, dietary tryptophan (trp), are unclear. METHODS: Untargeted metabolomic and transcriptomic analyses were performed in LGG monocolonized germ-free mice fed trp-free or -sufficient diets. LGG-derived metabolites were profiled in vitro under anaerobic and aerobic conditions. Multiomic correlations using a newly developed algorithm discovered novel metabolites tightly linked to tight junction and cell differentiation genes whose abundances were regulated by LGG and dietary trp. Barrier-modulation by these metabolites were functionally tested in Caco2 cells, mouse enteroids, and dextran sulfate sodium experimental colitis. The contribution of these metabolites to barrier protection is delineated at specific tight junction proteins and enterocyte-promoting factors with gain and loss of function approaches. RESULTS: LGG, strictly with dietary trp, promotes the enterocyte program and expression of tight junction genes, particularly Ocln. Functional evaluations of fecal and serum metabolites synergistically stimulated by LGG and trp revealed a novel vitamin B3 metabolism pathway, with methylnicotinamide (MNA) unexpectedly being the most robust barrier-protective metabolite in vitro and in vivo. Reduced serum MNA is significantly associated with increased disease activity in patients with inflammatory bowel disease. Exogenous MNA enhances gut barrier in homeostasis and robustly promotes colonic healing in dextran sulfate sodium colitis. MNA is sufficient to promote intestinal epithelial Ocln and RNF43, a master inhibitor of Wnt. Blocking trp or vitamin B3 absorption abolishes barrier recovery in vivo. CONCLUSIONS: Our study uncovers a novel LGG-regulated dietary trp-dependent production of MNA that protects the gut barrier against colitis.