Large-scale geographic patterns and environmental and anthropogenic drivers of wetland plant diversity in the Qinghai-Tibet Plateau.

BACKGROUND: The geographic patterns of plant diversity in the Qinghai-Tibet Plateau (QTP) have been widely studied, but few studies have focused on wetland plants. This study quantified the geographic patterns of wetland plant diversity in the QTP through a comprehensive analysis of taxonomic, phylogenetic and functional indices. METHODS: Based on a large number of floras, monographs, specimens and field survey data, we constructed a comprehensive dataset of 1,958 wetland plant species in the QTP. Species richness (SR), phylogenetic diversity (PD), functional diversity (FD), net relatedness index (NRI) and net functional relatedness index (NFRI) were used to assess the taxonomic, phylogenetic and functional diversity of wetland plants. We explored the relationships between the diversity indices and four categories of environmental variables (i.e. energy-water, climate seasonality, topography and human activities). We used four diversity indices, namely endemic species richness, weighted endemism, phylogenetic endemism and functional endemism, together with the categorical analysis of neo- and paleo-endemism (CANAPE), to identify the endemic centers of wetland plants in the QTP. RESULTS: SR, PD and FD were highly consistent and showed a decreasing trend from southeast to northwest, decreasing with increasing elevation. The phylogenetic structure of wetland plant assemblages in most parts of the plateau is mainly clustered. The functional structure of wetland plant assemblages in the southeast of the plateau is overdispersed, while the functional structure of wetland plant assemblages in other areas is clustered. Energy-water and climate seasonality were the two most important categories of variables affecting wetland plant diversity. Environmental variables had a greater effect on the functional structure of wetland plants than on the phylogenetic structure. This study identified seven endemic centres, mainly in the Himalayas and Hengduan Mountains. CONCLUSIONS: Climate and topography are the main factors determining the geographic distribution of wetland plant diversity at large scales. The majority of grid cells in the QTP with significant phylogenetic endemism were mixed and super-endemism. At large scales, compared to climate and topography, human activities may not have a negative impact on wetland plant diversity in the QTP.

The rise of baobab trees in Madagascar.

The baobab trees (genus Adansonia) have attracted tremendous attention because of their striking shape and distinctive relationships with fauna1. These spectacular trees have also influenced human culture, inspiring innumerable arts, folklore and traditions. Here we sequenced genomes of all eight extant baobab species and argue that Madagascar should be considered the centre of origin for the extant lineages, a key issue in their evolutionary history2,3. Integrated genomic and ecological analyses revealed the reticulate evolution of baobabs, which eventually led to the species diversity seen today. Past population dynamics of Malagasy baobabs may have been influenced by both interspecific competition and the geological history of the island, especially changes in local sea levels. We propose that further attention should be paid to the conservation status of Malagasy baobabs, especially of Adansonia suarezensis and Adansonia grandidieri, and that intensive monitoring of populations of Adansonia za is required, given its propensity for negatively impacting the critically endangered Adansonia perrieri.

Effects of Black Soldier Fly (Hermetia illucens L., BSF) Larvae Addition on In Vitro Fermentation Parameters of Goat Diets.

The purpose of this experiment was to evaluate the effects of different levels of BSF on rumen in vitro fermentation gas production, methane (CH4) production, ammonia nitrogen (NH3-N), and volatile fatty acids (VFAs). The experiment comprised four treatments, each with five replicates. The control group contained no BSF (BSF0), and the treatment groups contained 5% (BSF5), 10% (BSF10), and 15% (BSF15) BSF, respectively. Results showed that at 3 h, 9 h, and 24 h, gas production in BSF5 and BSF10 was significantly higher than in BSF0 and BSF15 (p < 0.05). Gas production in BSF5 and BSF10 was higher than in BSF0, while gas production in BSF15 was lower than in BSF0. At 6 h and 12 h, CH4 emission in BSF15 was significantly lower than in the other three groups (p < 0.05). There were no differences in the pH of in vitro fermentation after BSF addition (p > 0.05). At 3 h, NH3-N levels in BSF10 and BSF15 were significantly higher than in BSF0 and BSF5 (p < 0.05). At 6 h, NH3-N levels in BSF5 and BSF10 were significantly higher than in BSF0 and BSF15 (p < 0.05). Acetic acid, propionic acid, butyric acid, and total VFAs in BSF0, BSF5, and BSF10 were significantly higher than in BSF15 (p < 0.05). In conclusion, gas production, CH4 emission, NH3-N, acetic acid, propionic acid, butyric acid, and VFAs were highest in BSF5 and BSF10 and lowest in BSF15.

Climatic niche evolution and niche conservatism of Nymphaea species in Africa, South America, and Australia.

BACKGROUND: Interest in the evolution of climatic niches, particularly in understanding the potential adaptive responses of species under climate change, has increased both theoretically and within macroecological studies. These studies have provided valuable insights into how climatic traits of species influence their niche evolution. In this study, we aim to investigate whether niche conservatism plays a role in the species diversification of Nymphaea, a group of aquatic plants with a cosmopolitan distribution that is facing severe habitat loss. We will use climatic models and phylogenetic data for 23 species to reconstruct Nymphaea's niche evolution, measure niche overlap, and assess disparity through time while testing for evolutionary models. RESULTS: There was a lot of overlap in niches both within and between groups, especially for species that can be found in many places. The breadth and peaks of the niche profile varied depending on the bioclimatic variables, which suggested that the species evolved differently to cope with changes in climate. The analysis also showed that evolutionary changes happened across the phylogeny, with weak to moderate signals. The morphological disparity index (MDI) values indicated that there were disparities within subclades over time but not between or among them. Niche reconstruction and evolution analysis revealed both convergent and divergent evolution among various variables. For example, N. immutabilis, N. atrans, N. violancea, and N. nouchali evolved towards intermediate temperatures for bio2 and bio3 (isothermity) while moving towards extreme temperatures for bio8 and bio9 (wettest and driest average quarterly temperatures). CONCLUSION: Our study will improve our understanding of how changes in climatic niches are potentially driving the evolution of Nymphaea. It has significant scientific implications for the limits, assemblages, evolution, and diversification of species. This information is crucial for the ongoing efforts of conservation and management, particularly considering the inevitable effects of climate change.

Sex-specific circulating unconventional neutrophils determine immunological outcome of auto-inflammatory Behçet's uveitis.

Neutrophils are the most abundant immune cells that first respond to insults in circulation. Although associative evidence suggests that differences in neutrophils may be linked to the sex-specific vulnerability of inflammatory diseases, mechanistic links remain elusive. Here, we identified extensive sex-specific heterogeneity in neutrophil composition under normal and auto-inflammatory conditions at single-cell resolution. Using a combination of single-cell RNA sequencing analysis, neutrophil-specific genetic knockouts and transfer experiments, we discovered dysregulation of two unconventional (interferon-α responsive and T cell regulatory) neutrophil subsets leading to male-biased incidence, severity and poor prognosis of auto-inflammatory Behçet's uveitis. Genome-wide association study (GWAS) and exosome study revealed that male-specific negative effects of both genetic factors and circulating exosomes on unconventional neutrophil subsets contributed to male-specific vulnerability to disease. Collectively, our findings identify sex-specifically distinct neutrophil subsets and highlight unconventional neutrophil subsets as sex-specific therapeutic targets to limit inflammatory diseases.

The Cissus quadrangularis genome reveals its adaptive features in an arid habitat.

Cissus quadrangularis is a tetraploid species belonging to the Vitaceae family and is known for the Crassulacean acid metabolism (CAM) pathway in the succulent stem, while the leaves perform C3 photosynthesis. Here, we report a high-quality genome of C. quadrangularis comprising a total size of 679.2 Mb which was phased into two subgenomes. Genome annotation identified 51 857 protein-coding genes, while approximately 47.75% of the genome was composed of repetitive sequences. Gene expression ratios of two subgenomes demonstrated that the sub-A genome as the dominant subgenome played a vital role during the drought tolerance. Genome divergence analysis suggests that the tetraploidization event occurred around 8.9 million years ago. Transcriptome data revealed that pathways related to cutin, suberine, and wax metabolism were enriched in the stem during drought treatment, suggesting that these genes contributed to the drought adaption. Additionally, a subset of CAM-related genes displayed diurnal expression patterns in the succulent stems but not in leaves, indicating that stem-biased expression of existing genes contributed to the CAM evolution. Our findings provide insights into the mechanisms of drought adaptation and photosynthesis transition in plants.

Agaro-oligosaccharides mitigate deoxynivalenol-induced intestinal inflammation by regulating gut microbiota and enhancing intestinal barrier function in mice.

Agarose-derived agaro-oligosaccharides (AgaroS) have been extensively studied in terms of structures and bioactivities; they reportedly possess antioxidant and anti-inflammatory activities that maintain intestinal homeostasis and host health. However, the protective effects of AgaroS on deoxynivalenol (DON)-induced intestinal dysfunction remain unclear. We investigated the effects of AgaroS on DON-induced intestinal dysfunction in mice and explored the underlying protective mechanisms. In total, 32 mice were randomly allocated to four treatments (n = 8 each) for 28 days. From day 1 to day 21, the control (CON) and DON groups received oral phosphate-buffered saline (200 µL per day); the AgaroS and AgaroS + DON groups received 200 mg AgaroS per kg body weight once daily by orogastric gavage. Experimental intestinal injury was induced by adding DON (4.8 mg per kg body weight) via gavage from day 21 to day 28. Phosphate-buffered saline was administered once daily by gavage in the CON and AgaroS groups. Herein, AgaroS supplementation led to a higher final body weight and smaller body weight loss and a lower concentration of plasma inflammatory cytokines, compared with the DON group. The DON group showed a significantly reduced ileal villus height and villus height/crypt depth, compared with the CON and AgaroS + DON groups. However, AgaroS supplementation improved DON-induced intestinal injury in mice. Compared with the DON group, ileal and colonic protein expression levels of claudin, occludin, Ki67, and mucin2 were significantly higher in the AgaroS supplementation group. Colonic levels of the anti-inflammatory cytokine IL-1ß tended to be higher in the DON group than in the AgaroS + DON group. AgaroS altered the gut microbiota composition, accompanied by increased production of short-chain fatty acids in mice. In conclusion, our findings highlight a promising anti-mycotoxin approach whereby AgaroS alleviate DON-induced intestinal inflammation by modulating intestinal barrier functional integrity and gut microbiota in mice.

Seeing Your Stories: Visualization for Narrative Medicine.

Importance: Narrative medicine (NM), in which patient stories play a crucial role in their diagnosis and treatment, can potentially support a more holistic approach to patient care than traditional scientific ones. However, there are some challenges in the implementation of narrative medicine, for example, differences in understanding illnesses between physicians and patients and physicians' increased workloads and overloaded schedules. This paper first presents a review to explore previous visualization research for narrative medicine to bridge the gap between visualization researchers and narrative medicine experts and explore further visualization opportunities. Highlights: The review is conducted from 2 perspectives: (a) the contexts and domains in which visualization has been explored for narrative medicine and (b) the forms and solutions applied in these studies. Four applied domains are defined, including understanding patients from narrative records, medical communication, medical conversation training in education, and psychotherapy and emotional wellness enhancement. Conclusions: A future work framework illustrates some opportunities for future research, including groups of specific directions and future points for the 4 domains and 3 technological exploration opportunities (combination of narrative and medical data visualization, task-audience-based visual storytelling, and user-centered interactive visualization). Specifically, 3 directions of future work in medical communication (asynchronous online physician-patient communication, synchronous face-to-face medical conversation, and medical knowledge dissemination) were concluded.

Early predictors of bacterial pneumonia infection in children with congenital heart disease after cardiopulmonary bypass: a single-centre retrospective study.

OBJECTIVES: The objective of this study was to evaluate the early predictors of bacterial pneumonia infection in children with congenital heart disease (CHD) after cardiopulmonary bypass (CPB). DESIGN: Retrospective study. SETTING: A freestanding tertiary paediatric hospital in China. PARTICIPANTS: Patients admitted to the hospital due to CHD who underwent open-heart surgery. OUTCOME MEASURES: We retrospectively reviewed and analysed data from 1622 patients with CHD after CPB from June 2018 to December 2020 at the Children's Hospital of Nanjing Medical University. Enrolled patients were assigned to an infection group or a non-infection group according to the presence of postoperative bacterial pneumonia infection, and the differences in clinical indicators were compared. Potential predictors were analysed by multivariate logistic regression analysis and area under the curve (AUC) analysis. RESULTS: Among the 376 patients (23.2%) in the infection group, the three most common bacteria were Streptococcus pneumoniae in 67 patients (17.8%), Escherichia coli in 63 patients (16.8%) and Haemophilus influenzae in 53 patients (14.1%). The infection group exhibited a lower weight (8.0 (6.0-11.5) kg vs 11.0 (7.5-14.5) kg, p<0.001). In the infection group, procalcitonin (PCT) (ng/mL: 4.72 (1.38-9.52) vs 1.28 (0.47-3.74), p<0.001) and C reactive protein (CRP) (mg/L: 21.0 (12.1-32.0) vs 17.0 (10.0-27.0), p<0.001) levels were significantly greater than those in the non-infection group. Binary logistic regression analysis revealed that weight, PCT and CRP were independent risk factors for pulmonary bacterial infection after CPB. The AUCs of weight, PCT, CRP and PCT+CRP for predicting pulmonary bacterial infection after CPB were 0.632 (95% CI 0.600 to 0.664), 0.697 (95% CI 0.667 to 0.727), 0.586 (95% CI 0.554 to 0.618) and 0.694 (95% CI 0.664 to 0.724), respectively, and the cut-off values were ≤10.25 kg, ≥4.25 ng/mL, ≥6.50 mg/L and ≥0.20, respectively. The sensitivities were 69.7%, 54.0%, 93.9% and 70.2%, and the specificities were 53.5%, 77.7%, 19.4% and 59.1%, respectively. CONCLUSIONS: In our study, weight, PCT and CRP were found to be independent predictors of pulmonary bacterial infection after CPB. Moreover, PCT was the most specific predictor, and CRP was the most sensitive independent predictor that might be beneficial for the early diagnosis of pulmonary bacterial infection after CPB in patients with CHD.

Floral resource partitioning of coexisting bumble bees: Distinguishing species-, colony-, and individual-level effects.

Resource partitioning is considered a key factor in alleviating competitive interactions, enabling coexistence among consumer species. However, most studies have focused on resource partitioning between species, ignoring the potentially critical role of intraspecific variation in resource use. We investigated floral resource partitioning across species, colonies, and individuals in a species-rich bumblebee community in the diversification center of bumblebees. We used a total of 10,598 bumblebees belonging to 13 species across 5 years in the Hengduan Mountains of southwest China. First, we evaluated the influence of a comprehensive set of floral traits, including both those related to attractiveness (flower color and shape) and rewards (pollen, sugar ratio, nectar volume, sugar concentration, and amino acid content) on resource partitioning at the species level in bumblebee-plant networks. Then, we explored intraspecific resource partitioning on the colony and individual levels. Our results suggest that bumblebee species differ substantially in their use of the available floral resources, and that this mainly depends on flower attractiveness (floral color and shape). Interestingly, we also detected floral resource partitioning at the colony level within all commonest bumblebee species evaluated. In general, floral resource partitioning between bumblebee individuals decreased with species- and individual-level variation in body size (intertegular span). These results suggest that bumblebee species may coexist via the flexibility in their preferences for specific floral traits, which filters up to support the co-occurrence of high numbers of species and individuals in this global hotspot of species richness.

The choice of rice rotation system affects the composition of the soil fungal community and functional traits.

Plant rotation is a common practice in upland rice production. However, the effects of plant rotation on the interactions between rice plants, soil and underground ecosystems need to be studied further. Here, quantitative PCR and high-throughput pyrosequencing of the ITS region was applied to investigate the fungal abundance, diversity, and composition of fungal functional guilds in rice field soils and after different rotation practices ((rice-fallow (RF), rice-Chinese milk vetch (RV) and rice-wheat (RW)) and their relationship with rice yields. The results showed that the six-year RV and RW rotations increased fungal abundance by 42.7 %-69.2 % relative to RF, but decreased the soil bacterial-to-fungi ratio and fungal diversity. For the functional guilds, RV rotation significantly increased the relative abundance of soil saprotrophs and pathotrophs by 73.30 % and 32.94 %, respectively, while that of symbiotrophs was decreased by 35.96 %, compared to RF. RW rotation was found to significantly decrease all three fungal functional guilds, but increased the symbiotroph-saprotroph ratio. A structure equal model analysis indicated that the diversity of saprotrophs was significantly and negatively correlated with rice yield. Altogether, this work provides a detailed description of how the soil fungal community, including saprotrophic, symbiotrophic and pathotrophic functional guilds, responded to different upland rice rotation practices after eight years of application.

Ecological restoration reduces mercury in corn kernel and the distinction of mercury in corn plants in rural China - A case in Wuchuan mercury mining area.

Corn is a crucial crop in China and is widely cultivated in the mercury (Hg) mining region of Guizhou. This study analyzed the Hg content in soil and corn plant samples from the Wuchuan Hg mining area (WCMA) and the surrounding non-Hg mining regions (SNMR). The findings suggest that ongoing ecological rehabilitation and environmental conservation measures in the WCMA have significantly decreased the Hg content in corn kernels. The Hg concentration in different parts of the corn plant varied, being higher in the roots, tassels, and leaves and lower in kernels and stalks. Hg stored in corn plant growing in the WCMA primarily originates from the soil (55.4%), while in the SNMR, it mainly comes from the atmosphere (74.9%). Despite counted only about 7% of the total plant mass, corn roots play a crucial role in soil Hg pollution remediation when corn is used for remediation. Household corn residues burning release about 58.5% and 66.9% of the stored Hg in corn plants growing in the WCMA and the SNMR, respectively, into the atmosphere. Our findings indicate that corn cultivation acts as a reservoir for both soil and atmospheric Hg in the SNMR, while in the WCMA, it serves as a source of atmospheric Hg.

Plasma-derived exosomal protein SHP2 deficiency induces neutrophil hyperactivation in Behcet's uveitis.

To investigate the effect of plasma-derived exosomal proteins on neutrophil hyperactivation in Behcet's uveitis (BU), we treated neutrophils from healthy controls with plasma-derived exosomes from active BU patients, and determined the level of neutrophil activation by real-time quantitative PCR (RT-qPCR) and cytokine detection assay. The results revealed that exosomes from active BU patients could activate neutrophils as shown by increasing the expression levels of pro-inflammatory cytokines (IL-17 and IL-6), chemokines (IL-8 and MCP-1), and NETs (MPO and ELANE). Label-free quantitative proteomic analysis of plasma-derived exosomes from patients and healthy controls found a remarkably distinct protein profile and identified differentially expressed proteins (DEPs) between the two groups. The results of GO, KEGG, and GSEA enrichment analysis showed that DEPs were enriched in innate immune-mediated and neutrophil hyperactivation-related signaling pathways. The protein-protein interaction (PPI) analysis determined that SHP2 was a downregulated key hub protein in the exosomes of active BU patients. Knockdown of SHP2 in human neutrophil cell lines (NB4 cells) was shown to promote the secretion of pro-inflammatory cytokines, chemokines, and NETs. The converse effects were observed following SHP2 overexpression. In conclusion, we highlighted a pathogenic role of plasma-derived exosomal SHP2 deficiency in facilitating neutrophil activation and suggested that SHP2 might be an immunoprotective factor in BU pathologic process.

The chromosome-level genome of the submerged plant Cryptocoryne crispatula provides insights into the terrestrial-freshwater transition in Araceae.

Plant terrestrialization (i.e. the transition to a terrestrial environment) is a significant evolutionary event that has been intensively studied. While certain plant lineages, particularly in angiosperms, have re-adapted to freshwater habitats after colonizing terrene, however, the molecular mechanism of the terrestrial-freshwater (T-F) transition remains limited. Here, the basal monocot Araceae was selected as the study object to explore the T-F transition adaptation mechanism by comparative genomic analysis. Our findings revealed that the substitution rates significantly increased in the lineage of freshwater Araceae, which may promote their adaptation to the freshwater habitat. Additionally, 20 gene sets across all four freshwater species displayed signs of positive selection contributing to tissue development and defense responses in freshwater plants. Comparative synteny analysis showed that genes specific to submerged plants were enriched in cellular respiration and photosynthesis. In contrast, floating plants were involved in regulating gene expression, suggesting that gene and genome duplications may provide the original material for plants to adapt to the freshwater environment. Our study provides valuable insights into the genomic aspects of the transition from terrestrial to aquatic environments in Araceae, laying the groundwork for future research in the angiosperm.

11B NMR of the Morphological Evolution of Traditional Chinese Medicine Borax.

This article applies nuclear magnetic resonance technology to the study of boron-containing traditional Chinese medicine, in order to explore the morphological evolution of boron elements in traditional Chinese medicine. Borax is a traditional Chinese medicine with anti-corrosion, anti-inflammatory, antibacterial, and anticonvulsant effects. It is made by boiling, removing stones, and drying borax minerals like borate salts. This article introduces an 11B nuclear magnetic resonance method for identifying and characterizing boron-containing compounds in TCM. We applied this technology to borax aqueous solutions in different chemical environments and found that with boron mixed in the form of SP2 hybridization in equilateral triangles and SP3 hybridization in equilateral tetrahedra, the pH changes in alkaline environments significantly affected the ratio of the two. At the same time, it was found that in addition to the raw material peak, boron signals of other boron-containing compounds were also detected in 20 commercially available boron-containing TCM preparations. These new boron-containing compounds may be true pharmaceutical active ingredients, and adding them directly to the formula can improve quality and safety. This article describes the detection of 11B NMR in boron-containing traditional Chinese medicine preparations. It is simple, non-destructive, and can provide chemical fingerprint studies for boron-containing traditional Chinese medicine.

Age-induced Changes in Ginsenoside Accumulation and Primary Metabolic Characteristics of Panax Ginseng in Transplantation Mode.

Background: Ginseng (Panax ginseng Mayer) is an important natural medicine. However, a long culture period and challenging quality control requirements limit its further use. Although artificial cultivation can yield a sustainable medicinal supply, research on the association between the transplantation and chaining of metabolic networks, especially the regulation of ginsenoside biosynthetic pathways, is limited. Methods: Herein, we performed Liquid chromatography tandem mass spectrometry based metabolomic measurements to evaluate ginsenoside accumulation and categorise differentially abundant metabolites (DAMs). Transcriptome measurements using an Illumina Platform were then conducted to probe the landscape of genetic alterations in ginseng at various ages in transplantation mode. Using pathway data and crosstalk DAMs obtained by MapMan, we constructed a metabolic profile of transplantation Ginseng. Results: Accumulation of active ingredients was not obvious during the first 4 years (in the field), but following transplantation, the ginsenoside content increased significantly from 6-8 years (in the wild). Glycerolipid metabolism and Glycerophospholipid metabolism were the most significant metabolic pathways, as Lipids and lipid-like molecule affected the yield of ginsenosides. Starch and sucrose were the most active metabolic pathways during transplantation Ginseng growth. Conclusion: This study expands our understanding of metabolic network features and the accumulation of specific compounds during different growth stages of this perennial herbaceous plant when growing in transplantation mode. The findings provide a basis for selecting the optimal transplanting time.

Exploring the Timing of Disengagement From Nondriving Related Tasks in Scheduled Takeovers With Pre-Alerts: An Analysis of Takeover-Related Measures.

OBJECTIVES: This study aimed to investigate drivers' disengagement from nondriving related tasks (NDRT) during scheduled takeovers and to evaluate its impact on takeover performance. BACKGROUND: During scheduled takeovers, drivers typically have sufficient time to prepare. However, inadequate disengagement from NDRTs can introduce safety risks. METHOD: Participants experienced scheduled takeovers using a driving simulator, undergoing two conditions, with and without an NDRT. We assessed their takeover performance and monitored their NDRT disengagement from visual, cognitive, and physical perspectives. RESULTS: The study examined three NDRT disengagement timings (DTs): DT1 (disengaged before the takeover request), DT2 (disengaged after the request but before taking over), and DT3 (not disengaged). The impact of NDRT on takeover performance varied depending on DTs. Specifically, DT1 demonstrated no adverse effects; DT2 impaired takeover time, while DT3 impaired both takeover time and quality. Additionally, participants who displayed DT1 exhibited longer eye-off-NDRT duration and a higher eye-off-NDRT count during the prewarning stage compared to those with DT2 and DT3. CONCLUSION: Drivers can benefit from earlier disengagement from NDRTs, demonstrating resilience to the adverse effects of NDRTs on takeover performance. The disengagement of cognition is often delayed compared to that of eyes and hands, potentially leading to DT3. Moreover, visual disengagement from NDRTs during the prewarning stage could distinguish DT1 from the other two. APPLICATION: Our study emphasizes considering NDRT disengagement in designing systems for scheduled takeovers. Measures should be taken to promote early disengagement, facilitate cognitive disengagement, and employ visual disengagement during the prewarning period as predictive indicators of DTs.

4-Octyl Itaconate Inhibits Proinflammatory Cytokine Production in Behcet's Uveitis and Experimental Autoimmune Uveitis.

4-octyl itaconate (4-OI) is an anti-inflammatory metabolite that activates the nuclear-factor-E2-related factor 2 (NRF2) signaling. In the current work, we investigated whether 4-OI could affect the production of proinflammatory cytokines in Behcet's uveitis (BU) and experimental autoimmune uveitis (EAU). Peripheral blood mononuclear cells (PBMCs) of active BU patients and healthy individuals with in vitro 4-OI treatment were performed to assess the influence of 4-OI on the proinflammatory cytokine production. EAU was induced and used for investigating the influence of 4-OI on the proinflammatory cytokine production in vivo. The flow cytometry, qPCR, and ELISA were performed to detect proinflammatory cytokine expression. NRF2 signaling activation was evaluated by qPCR and western blotting (WB). Splenic lymphocyte transcriptome was performed by RNA sequencing. The NRF2 expression by BU patients-derived PBMCs was lower than that by healthy individuals. After treatment with 4-OI, the proportion of Th17 cells, along with the expression of proinflammatory cytokines (IL-17, TNF-α, MCP-1, and IL-6) by PBMCs, were downregulated, and anti-inflammatory cytokine (IL-10) expression was upregulated, although IFN-γ expression was unaffected. The EAU severity was ameliorated by 4-OI in association with a lower splenic Th1/Th17 cell proportion and increased nuclear NRF2 expression. Additionally, 4-OI downregulated a set of 248 genes, which were enriched in pathways of positive regulation of immune responses. The present study shows an inhibitory effect of 4-OI on the proinflammatory cytokine production in active BU patients and EAU mice, possibly mediated through activating NRF2 signaling. These findings suggest that 4-OI could act as a potential therapeutic drug for the treatment and prevention of BU in the future study.