Molecular basis of phenotypic plasticity in a marine ciliate.

Phenotypic plasticity, which involves phenotypic transformation in the absence of genetic change, may serve as a strategy for organisms to survive in complex and highly-fluctuating environments. However, its reaction norm, molecular basis, and evolution remain unclear in most organisms, especially microbial eukaryotes. In this study, we explored these questions by investigating the reaction norm, regulation, and evolution of phenotypic plasticity in the cosmopolitan marine free-living ciliates Glauconema spp., which undergo significant phenotypic changes in response to food shortages. This study led to the de novo assembly of macronuclear genomes using long-read sequencing, identified hundreds of differentially expressed genes associated with phenotypic plasticity in different life stages, validated the function of two of these genes, and revealed that the reaction norm of body shape in response to food density follows a power-law distribution. Purifying selection may be the dominant evolutionary force acting on the genes associated with phenotypic plasticity, and the overall data support the hypothesis that phenotypic plasticity is a trait maintained by natural selection. This study provides novel insight into the developmental genetics of phenotypic plasticity in non-model unicellular eukaryotes, and sheds light on the complexity and long evolutionary history of this important survival strategy.

ScRNA-seq revealed the tumor microenvironment heterogeneity related to the occurrence and metastasis in upper urinary tract urothelial carcinoma.

Metastasis is the greatest clinical challenge for UTUCs, which may have distinct molecular and cellular characteristics from earlier cancers. Herein, we provide single-cell transcriptome profiles of UTUC para cancer normal tissue, primary tumor lesions, and lymphatic metastases to explore possible mechanisms associated with UTUC occurrence and metastasis. From 28,315 cells obtained from normal and tumor tissues of 3 high-grade UTUC patients, we revealed the origin of UTUC tumor cells and the homology between metastatic and primary tumor cells. Unlike the immunomicroenvironment suppression of other tumors, we found no immunosuppression in the tumor microenvironment of UTUC. Moreover, it is imperative to note that stromal cells are pivotal in the advancement of UTUC. This comprehensive single-cell exploration enhances our comprehension of the molecular and cellular dynamics of metastatic UTUCs and discloses promising diagnostic and therapeutic targets in cancer-microenvironment interactions.

[Consumption status and growth trends of dairy products among children and adolescents in China from 1991 to 2018].

OBJECTIVE: To explore the dairy consumption among children and adolescents aged 7-17 in China. METHODS: 10 rounds of follow-up data from the "China Health and Nutrition Survey" from 1991 to 2018 were collected, and individuals aged 7-17 were selected as the study subjects. Dietary data was collected by using 3-day 24-hour dietary review method and household weighing accounting method(edible oils and seasonings). Dairy consumption was calculated by converting various dairy products into liquid milk intake using the China Food Composition. After excluding those with missing demographic information, missing data from the "3 days and 24 hours" dietary survey, and abnormal daily energy intake, 18 529 participants were included in the final analysis. Joinpoint regression model was used to analyze the trend of changes in dairy intake. RESULTS: The dairy consumption rate increased from 2.8% in 1991 to 42.3% in 2018, while it increased from 8.4% to 58.8% in urban and from 0.9% to 32.1% in rural areas. Meanwhile, the proportion of people whose dairy intake reaches the recommended intake(300 g/d) increased from 0.2% to 3.0%, and the proportion in rural area was 2.0%, which was lower than that in urban areas(4.9%). From 1991 to 2018, dairy intake increased at a rate of 12.97%(P=0.02), and the growth rate of urban and rural areas were 9.79%(P=0.03) and 15.67%(P<0.01), respectively. There was a faster growth trend from 1991-2004 compared to 2004-2018. The growth rate in urban and rural areas also showed different growth trends. CONCLUSION: The dairy intake of children and adolescents aged 7-17 in China improved significantly from 1991 to 2018, with higher consumption rate in urban areas than in rural areas, but it still need to be improved for health.

[Analysis of food carbon footprint and its socio-demographic disparities in China in 2018].

OBJECTIVE: To analyze food carbon footprint and its socio-demographic disparities among adults in China. METHODS: A total of 12 777 adults aged 18 years and above from the China Health and Nutrition Survey in 2018 who have completed dietary and socio-demographic data were analyzed. The information of food intake were collected by 24 h recalls combined with the weighing of household seasonings. Food consumption was converted into energy intake by the China Food Composition Table. Carbon footprint of 26 food groups were calculated by the food carbon footprint database based on life-cycle assessment(LCA), multinomial logit model was used to analyze the association of socio-demographic factors and food carbon footprint. RESULTS: Average food carbon footprint were decreased with increasing age while increased with increasing income and education levels, and was higher among male than that among female, was higher among urban residents than that among rural residents, was higher in the south than that in the north. Multinomial logit analysis showed that compared with people aged 18-44, the likelihood of occurring high carbon footprint in 60y and above group were 29%(OR=0.71, 95%CI 0.61-0.83) lower than that occurring low carbon footprint. Women were 11%(OR=0.89, 95%CI 0.81-0.99) and 25%(OR=0.75, 95%CI 0.67-0.84) less likely to appear medium and high carbon footprint than low carbon footprint, compared with their male counterparts. In comparison to people living in cities, rural dwellers were 24%(OR=0.76, 95%CI 0.69-0.85) and 38%(OR=0.62, 95%CI 0.55-0.70) less likely to appear medium and high carbon footprint than low carbon footprint. People in the south were 3.89 times(95%CI 3.52-4.30) and 11.35 times(95%CI 10.01-12.88) more likely to occur medium and high carbon footprint than low carbon footprint, compared with people in the north. Participants were more likely to occur medium carbon footprint and high carbon footprint with the increasing income level(OR>1), and were more likely to occur high carbon footprint with the increasing education level(OR>1). CONCLUSION: The food carbon footprint of adults in China in 2018 show different socio-demographic disparities, gender, income and education level are significant factors.

[Change of dietary pattern among young people aged 18-35 in China from 1989 to 2018].

OBJECTIVE: To analyze the dietary patterns changes of young people aged 18-35 in 15 provinces(autonomous regions, municipalities) from 1989 to 2018. METHODS: Using the data of China Health and Nutrition Survey, a total of 25 400 young people aged 18-35 with complete dietary and sociodemographic information from 1989 to 2018 in 15 provinces(autonomous regions, municipalities) were selected as the research objects. Nutrition survey was carried out by using 3 consecutive days of 24-hour review method combined with weighing accounting method. Energy and nutrient intake was calculated based on food composition list. The principal component cluster analysis was used to select food groups and K-mean cluster was uesd to extract dietary patterns. Dwass-Steel-Critchlow-Fligner was used to test the difference of food intake in different dietary patterns. Cochran-Armitage trend test was to analyze the change of dietary patterns with the years. Chi-square test was to analyze the difference of people with different dietary patterns in 2018. RESULTS: The dietary patterns of young people aged 18-35 in 15 provinces(autonomous regions, municipalities) were mainly divided into three categories: "traditional rice", "traditional pasta" and "high-quality protein". In 2018, the proportion of "traditional rice" dietary patterns was higher for men than for women, and the proportion of "high-quality protein" dietary patterns was lower than for women. The proportion of "traditional pasta" dietary pattern in people aged 25-35 was higher than that aged 18-24, and the proportion of "high-quality protein" dietary pattern was lower than that aged 18-24. The proportion of people in urban with "traditional rice" dietary pattern was lower than that in rural areas, and the proportion of "high-quality protein" dietary pattern was higher than that in rural areas. The northern region was dominated by "traditional pasta" dietary pattern, while the southern region was dominated by "traditional rice" dietary pattern, and the proportion of people with "high-quality protein" dietary pattern was higher in the northern region than in the southern region. With the increase of education level and income level, the proportion of people with "high-quality protein" dietary pattern showed an increasing trend. From 1989 to 2018, the "traditional rice" dietary pattern had always maintained a high proportion among young people aged 18-35 in 15 provinces(autonomous regions, municipalities) in China, and the "traditional pasta" dietary pattern had been decreasing since 2009, and the "high-quality protein" dietary pattern had significantly increased since 2011. CONCLUSION: From 1989 to 2018, the proportion of young people aged 18-35 with reasonable dietary pattern has increased in 15 provinces(autonomous regions, municipalities), but the traditional dietary pattern still needs to be improved.

Exploring the multifaceted role of RASGRP1 in disease: immune, neural, metabolic, and oncogenic perspectives.

RAS guanyl releasing protein 1 (RASGRP1) is a guanine nucleotide exchange factor (GEF) characterized by the presence of a RAS superfamily GEF domain. It functions as a diacylglycerol (DAG)-regulated nucleotide exchange factor, specifically activating RAS through the exchange of bound GDP for GTP. Activation of RAS by RASGRP1 has a wide range of downstream effects at the cellular level. Thus, it is not surprising that many diseases are associated with RASGRP1 disorders. Here, we present an overview of the structure and function of RASGRP1, its crucial role in the development, expression, and regulation of immune cells, and its involvement in various signaling pathways. This review comprehensively explores the relationship between RASGRP1 and various diseases, elucidates the underlying molecular mechanisms of RASGRP1 in each disease, and identifies potential therapeutic targets. This study provides novel insights into the role of RASGRP1 in insulin secretion and highlights its potential as a therapeutic target for diabetes. The limitations and challenges associated with studying RASGRP1 in disease are also discussed.

Association between CD4+ T cells ATP levels and disease progression in patients with non­small cell lung cancer.

Introducing the exploration of stimulated CD4+ cells adenosine triphosphate (sATPCD4) levels for immune monitoring post non-small cell lung cancer (NSCLC) chemotherapy, the present study aimed to investigate its efficacy in gauging the potential risk of disease progression (PD) in patients with NSCLC. Therefore, a total of 89 patients with advanced NSCLC, who underwent chemotherapy between August 15 2022 and August 30 2023 at the Fifth Affiliated Hospital of Guangzhou Medical University (Guangzhou, China), were retrospectively studied. Patients were divided into the PD (n=21) and disease stability (non-PD; n=68) groups and their clinical data were compared. The thresholds for predicting PD were identified using receiver operating characteristics (ROC) curves. Multivariate logistic regression analysis was carried out to assess the association between peripheral blood markers and the incidence of PD. Therefore, post-chemotherapy, significant differences in white blood cell count, non-stimulated CD4+ cells ATP and sATPCD4 levels were obtained between patients in the PD and non-PD groups (P<0.05). In addition, sATPCD4 levels were notably decreased in the PD group compared with the non-PD group. Furthermore, ROC analysis revealed that the predictive threshold for PD was 224.5 ng/ml [area under the curve=0.887; 95% confidence interval, 0.811-0.963]. Additionally, patients with low immunity (ATP <224.5 ng/ml) exhibited a higher risk of PD compared with the high-immunity group (ATP >224.5 ng/ml; P<0.0001). Finally, multivariate logistic regression analysis suggested that sATPCD4 could serve as an independent factor for predicting NSCLC progression. Overall, the current study predicted that immune function could be possibly associated with the risk of PD in patients with NSCLC.

Design, Synthesis, Bioactive Evaluation, and Molecular Dynamics Simulation of Novel 4H-Pyrano[3,2-c]pyridine Analogues as Potential Sterol 14α-Demethylase (CYP51) Inhibitors.

To discover potential sterol 14α-demethylase (CYP51) inhibitors, thirty-four unreported 4H-pyrano[3,2-c]pyridine derivatives were designed and synthesized. The assay results indicated that most compounds displayed significant fungicidal activity against Sclerotinia sclerotiorum, Colletotrichum lagenarium, Botrytis cinerea, Penicillium digitatum, and Fusarium oxysporum at 16 µg/mL. The half maximal effective concentration (EC50) values of compounds 7a, 7b, and 7f against B. cinerea were 0.326, 0.530, and 0.610, respectively. Namely, they had better antifungal activity than epoxiconazole (EC50 = 0.670 µg/mL). Meanwhile, their half maximal inhibitory concentration (IC50) values against CYP51 were 0.377, 0.611, and 0.748 µg/mL, respectively, representing that they also possessed better inhibitory activities than epoxiconazole (IC50 = 0.802 µg/mL). The fluorescent quenching tests of proteins showed that 7a and 7b had similar quenching patterns to epoxiconazole. The molecular dynamics simulations indicated that the binding free energy of 7a and epoxiconazole to CYP51 was -35.4 and -27.6 kcal/mol, respectively.

Arrayed in vivo barcoding for multiplexed sequence verification of plasmid DNA and demultiplexing of pooled libraries.

Sequence verification of plasmid DNA is critical for many cloning and molecular biology workflows. To leverage high-throughput sequencing, several methods have been developed that add a unique DNA barcode to individual samples prior to pooling and sequencing. However, these methods require an individual plasmid extraction and/or in vitro barcoding reaction for each sample processed, limiting throughput and adding cost. Here, we develop an arrayed in vivo plasmid barcoding platform that enables pooled plasmid extraction and library preparation for Oxford Nanopore sequencing. This method has a high accuracy and recovery rate, and greatly increases throughput and reduces cost relative to other plasmid barcoding methods or Sanger sequencing. We use in vivo barcoding to sequence verify >45 000 plasmids and show that the method can be used to transform error-containing dispersed plasmid pools into sequence-perfect arrays or well-balanced pools. In vivo barcoding does not require any specialized equipment beyond a low-overhead Oxford Nanopore sequencer, enabling most labs to flexibly process hundreds to thousands of plasmids in parallel.

Integrative analyses on the ciliates Colpoda illuminate the life history evolution of soil microorganisms.

Microorganisms play a central role in sustaining soil ecosystems and agriculture, and these functions are usually associated with their complex life history. Yet, the regulation and evolution of life history have remained enigmatic and poorly understood, especially in protozoa, the third most abundant group of organisms in the soil. Here, we explore the life history of a cosmopolitan species-Colpoda steinii. Our analysis has yielded a high-quality macronuclear genome for C. steinii, with size of 155 Mbp and 37,123 protein-coding genes, as well as mean intron length of ~93 bp, longer than most other studied ciliates. Notably, we identify two possible whole-genome duplication events in C. steinii, which may account for its genome being about twice the size of C. inflata's, another co-existing species. We further resolve the gene expression profiles in diverse life stages of C. steinii, which are also corroborated in C. inflata. During the resting cyst stage, genes associated with cell death and vacuole formation are upregulated, and translation-related genes are downregulated. While the translation-related genes are upregulated during the excystment of resting cysts. Reproductive cysts exhibit a significant reduction in cell adhesion. We also demonstrate that most genes expressed in specific life stages are under strong purifying selection. This study offers a deeper understanding of the life history evolution that underpins the extraordinary success and ecological functions of microorganisms in soil ecosystems.IMPORTANCEColpoda species, as a prominent group among the most widely distributed and abundant soil microorganisms, play a crucial role in sustaining soil ecosystems and promoting plant growth. This investigation reveals their exceptional macronuclear genomic features, including significantly large genome size, long introns, and numerous gene duplications. The gene expression profiles and the specific biological functions associated with the transitions between various life stages are also elucidated. The vast majority of genes linked to life stage transitions are subject to strong purifying selection, as inferred from multiple natural strains newly isolated and deeply sequenced. This substantiates the enduring and conservative nature of Colpoda's life history, which has persisted throughout the extensive evolutionary history of these highly successful protozoa in soil. These findings shed light on the evolutionary dynamics of microbial eukaryotes in the ever-fluctuating soil environments. This integrative research represents a significant advancement in understanding the life histories of these understudied single-celled eukaryotes.

Novel Pyrido[4,3-d]pyrimidine Derivatives as Potential Sterol 14α-Demethylase Inhibitors: Design, Synthesis, Inhibitory Activity, and Molecular Modeling.

Thirty-four new pyrido[4,3-d]pyrimidine analogs were designed, synthesized, and characterized. The crystal structures for compounds 2c and 4f were measured by means of X-ray diffraction of single crystals. The bioassay results showed that most target compounds exhibited good fungicidal activities against Pyricularia oryzae, Rhizoctonia cerealis, Sclerotinia sclerotiorum, Botrytis cinerea, and Penicillium italicum at 16 µg/mL. Compounds 2l, 2m, 4f, and 4g possessed better fungicidal activities than the commercial fungicide epoxiconazole against B. cinerea. Their half maximal effective concentration (EC50) values were 0.191, 0.487, 0.369, 0.586, and 0.670 µg/mL, respectively. Furthermore, the inhibitory activities of the bioactive compounds were determined against sterol 14α-demethylase (CYP51). The results displayed that they had prominent activities. Compounds 2l, 2m, 4f, and 4g also showed better inhibitory activities than epoxiconazole against CYP51. Their half maximal inhibitory concentration (IC50) values were 0.219, 0.602, 0.422, 0.726, and 0.802 µg/mL, respectively. The results of molecular dynamics (MD) simulations exhibited that compounds 2l and 4f possessed a stronger affinity to CYP51 than epoxiconazole.

Emerging Chemistry for Wide-Temperature Sodium-Ion Batteries.

The shortage of resources such as lithium and cobalt has promoted the development of novel battery systems with low cost, abundance, high performance, and efficient environmental adaptability. Due to the abundance and low cost of sodium, sodium-ion battery chemistry has drawn worldwide attention in energy storage systems. It is widely considered that wide-temperature tolerance sodium-ion batteries (WT-SIBs) can be rapidly developed due to their unique electrochemical and chemical properties. However, WT-SIBs, especially for their electrode materials and electrolyte systems, still face various challenges in harsh-temperature conditions. In this review, we focus on the achievements, failure mechanisms, fundamental chemistry, and scientific challenges of WT-SIBs. The insights of their design principles, current research, and safety issues are presented. Moreover, the possible future research directions on the battery materials for WT-SIBs are deeply discussed. Progress toward a comprehensive understanding of the emerging chemistry for WT-SIBs comprehensively discussed in this review will accelerate the practical applications of wide-temperature tolerance rechargeable batteries.

Design, Synthesis, Antifungal Activity, and Molecular Docking Studies of Novel Chiral Isoxazoline-Benzofuran-Sulfonamide Derivatives.

Succinate dehydrogenase (SDH) is one of the most important molecular targets for the development of novel fungicides. With the emerging problem of resistance in plant fungal pathogens, novel compounds with high fungicidal activity need to be developed, but the study of chiral pesticides for the inhibition of highly destructive plant pathogens has been rarely reported in recent years. Therefore, a series of novel chiral isoxazoline-benzofuran-sulfonamide derivatives were designed to investigate potential novel antifungal molecules. The chiral target compound 3a was cultured as a single crystal and confirmed using X-ray diffraction. All the target compounds were tested for antifungal activity, and compounds 3c, 3i, 3s, and 3r were found to have significant antifungal effects against S. sclerotiorum with EC50 values of 0.42 mg/L, 0.33 mg/L, 0.37 mg/L, and 0.40 mg/L, respectively, which were superior to the commercial fungicide fluopyram (EC50 = 0.47 mg/L). The IC50 value of compound 3i against the SDH of S. sclerotiorum was 0.63 mg/mL, which was further demonstrated by enzyme activity assays. Scanning electron microscopy showed that 3i had a significant inhibitory effect on S. sclerotiorum. In addition, the fluorescence quenching analysis assay indicated that compound 3i had a similar effect with the positive control fluopyram. Molecular docking exhibited that target compounds with chiral configuration had better affinity than racemic configuration, and 3i possessed stronger action than fluopyram, which was in keeping with the in vitro test results. These results would provide a basis and reference for the development of novel chiral fungicides.

Theoretical Investigation on Dialumenes toward Dihydrogen Activation: Mechanism and Ligand Effect.

Herein, we report a computation study based on the density functional theory calculations to understand the mechanism and ligand effect of the base-stabilized dialumenes toward dihydrogen activation. Among all of the examined modes of dihydrogen activation using the base-stabilized dialumene, we found that the concerted 1,2-hydrogenation of the Al═Al double bond is kinetically more preferable. The concerted 1,2-hydrogenation of the Al═Al double bond adopts an electron-transfer model with certain asynchrony. That is, the initial electron donation from the H-H σ bonding orbital to the empty 3p orbital of the Al1 center is followed by the backdonation from the lone pair electron of the Al2 center to the H-H σ antibonding orbital. Combined with the energy decomposition analysis on the transition states of the concerted 1,2-hydrogenation of the Al═Al double bond and the topographic steric mapping analysis on the free dialumenes, we ascribe the higher reactivity of the aryl-substituted dialumene over the silyl-substituted analogue in dihydrogen activation to the stronger electron-withdrawing effect of the aryl group, which not only increases the flexibility of the Al═Al double bond but also enhances the Lewis acidity of the Al═Al core. Consequently, the aryl-substituted dialumene fragment suffers less geometric deformation, and the orbital interactions between the dialumene and dihydrogen moieties are more attractive during the 1,2-hydrogenation process. Moreover, our calculations also predict that the Al═Al double bond has a good tolerance with the stronger electron-withdrawing group (-CF3) and the weaker σ-donating N-heterocyclic carbene (NHC) analogue (e.g., triazol carbene and NHSi). The reactivity of the dialumene in dihydrogen activation can be further improved by introducing these groups as the supporting ligand and the stabilizing base on the Al═Al core, respectively.

[Changes in mild cognitive impairment and sociodemographic disparity among adults aged 55 years and above in 4 provinces of China].

OBJECTIVE: To investigate the changes in mild cognitive impairment(MCI) and sociodemographic disparity among adults aged 55 years and above in 4 provinces of China. METHODS: A total of 4687 adults aged 55 years and above from Community-based Cohort Study on Nervous System Disease who did not have Alzheimer's disease, participated in both rounds of the survey, and had complete baseline sociodemographic data and two rounds of data on cognitive function were selected. Generalized estimation equations were used to analyse the effect of sociodemographic factors on MCI. RESULTS: The detection rates of MCI in adults aged 55 years and above without Alzheimer's disease in 4 provinces of China in 2018 and 2020 were 48.56% and 42.56% respectively. MCI occurred in 30.11% of those with normal cognition(NC) at baseline, and 44.24% of those with MCI at baseline reverted to NC. The risk of MCI increased and the likelihood of MCI reversion decreased with increasing age and decreasing per capita monthly household income. In the baseline NC population, the risk of MCI in the junior high school and above group was 35% lower than that in the illiterate group(RR=0.65, 95%CI 0.53-0.80), the risk of MCI was lower in those living in rural areas(RR=0.56, 95%CI 0.49-0.65), and the risk of MCI was 1.17 times(95%CI 1.03-1.32) higher in those with a history of chronic diseases than in those without it. In the baseline MCI population, the likelihood of MCI reversion increased with education, the likelihood of MCI reversion was 1.04 times higher for workers than for non-workers(95%CI 1.00-1.08). CONCLUSION: The incidence and reversal rates of MCI were high in adults aged ≥55 years in four provinces of China. Advanced age, low education and low income level are risk factors for cognitive dysfunction.

High glucose intake exacerbates experimental autoimmune prostatitis through mitochondrial reactive oxygen species-dependent TGF-ß activation-mediated Th17 differentiation.

Chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) is a common inflammatory immune disease of the urogenital system. High glucose intake is considered to be a potential promoter of autoimmune diseases. However, the influence of high glucose intake on CP/CPPS is unknown. This research aimed to explore the influences of high glucose intake on experimental autoimmune prostatitis (EAP), a valid animal model of CP/CPPS, and the underlying mechanism. NOD mice received 20% glucose water or normal water treatment during EAP induction. EAP severity and Th17 cell responses were evaluated. Then, we explored the effects of an IL-17A neutralizing antibody, an inhibitor of TGF-ß, the reactive oxygen species (ROS) inhibitor NAC, and the mitochondrial ROS (mtROS) antioxidant MitoQ on glucose-fed EAP mice. The results demonstrated that high glucose intake aggravated EAP severity and promoted Th17 cell generation, which could be ameliorated by the neutralization of IL-17A. In vitro experiments showed that high dextrose concentrations promoted Th17 cell differentiation through mtROS-dependent TGF-ß activation. Treatment with TGF-ß blockade, NAC, or MitoQ suppressed Th17 cell generation both in vivo and in vitro, resulting in the amelioration of EAP manifestations caused by high glucose intake. This study revealed that high glucose intake exacerbates EAP through mtROS-dependent TGF-ß activation-mediated Th17 differentiation. Our results may provide insights into the molecular mechanisms underlying the detrimental effects of an environmental factor, such as high glucose intake, on CP/CPPS.

Protective effect of Tetrandrine on optic nerve by inhibiting glial activation through NF-κB pathway.

Introduction: This study aimed to explore the effect and molecular mechanism of Tetrandrine (Tet) onlipopolysaccharide (LPS)-induceduveitis andoptic nerve injury in vivo and in vitro. Methods: Uveitis was induced by LPS injected into the hindlimb foot pad of Wistar rats and was intervened by retroeyeball injection of Tet (100 nM, 1 µM or 10 µM).The anterior segment inflammation was observed by slit lamp. Tunelassay was used to detect the survival state of ganglion cells and nuclear layers of inner and outer. The detection of characteristic markers in different activation states of glial cells were performed by qualitative and quantitative test of immunofluorescence and western blotting. Also, western blotting was used to detect the expression of inflammatory factors in retina and the activation of nuclear factor kappa B (NF-κB) signal pathway. Meanwhile, routine blood test and function of liver and renal were performed. Results: The ciliary hyperemia was obvious, and the iris vessels were dilated and tortuous in rats with LPS-induced uveitis. Tet-pretreated obviously elieved these symptoms. In addition, the dilation and hyperemia in Tet group were alleviated compared with LPS group, and the inflammatory scores in Tetgroup were significantly lower than those of LPS group. TUNEL Staining showed that the number ofretinal ganglion cell (RGCs) in Tetgroup was slightly less than that in normal group, but significantly more than that in LPS group, and the cells arranged orderly. Besides, the number of apoptotic cells was significantly less than that in LPS group. Tet reduced LPS-activated gliocyte in a dose-dependent manner. Tumour necrosis factor alpha (TNF-α), interleukin (IL)-1ß, interferon gamma (γ-IFN) and IL-2 in retina were increased by LPS but decreased significantly viaTet-pretreatment. Moreover, LPS activate NF-κB signal pathway, while Tet efficiently inhibited this effect.Furthermore, injection of Tet did not damage theroutineblood, liver and kidney. Conclusions: Retrobulbar injection of Tet significantly alleviatedLPS-induced uveitisand optic nerve injuryof rats by activating gliocyte and NF-κB signaling pathway.

The predictive value of peripheral blood CD4 cells ATP concentration for immune-related adverse events in advanced non-small cell lung cancer patients.

OBJECTIVE: Lung cancer with the highest incidence and mortality in the world. Immune checkpoint inhibitors (ICIs), can bring long-term survival benefits to patients, but also can bring immune-related adverse events (irAEs) in some patients during therapy. Therefore, the aim of this study was to investigate the predictive effect of peripheral blood WBC, NLR, sATPCD4 and nATPCD4 on irAEs in advanced non-small cell lung cancer (NSCLC). METHODS: Clinical data of 112 patients with advanced NSCLC who were treated with PD -1/PD -L1 inhibitor in the Fifth Affiliated Hospital of Guangzhou Medical University from December 15, 2019 to April 30, 2023 were retrospectively analyzed. These patients were divided into the irAEs group (n = 27) and non-irAEs group (n = 85). The clinical data of the two groups were compared. Receiver operating characteristic (ROC) curves were drawn to determine the threshold value of baseline peripheral blood parameters to predict the occurrence of irAEs. Multivariate logistic regression analysis was used to explore the relationship between peripheral blood markers and the incidence of irAEs. RESULTS: The patient characteristics have no significant difference between irAEs and non-irAEs group. But the baseline peripheral blood WBC, sATPCD4 and nATPCD4 of patients in the irAEs group were higher than those in the non-irAEs group (p < 0.05), and the NLR in irAEs group was similar to in the non-irAEs group (p = 0.639).Univariate analysis showed that high WBC, sATPCD4 and nATPCD4 may the risk factors for the occurrence of irAEs (p < 0.05). Multivariate logistic regression analysis showed that high sATPCD4 and nATPCD4 were independent risk factors for the occurrence of irAEs (p < 0.05). The best critical values of WBC, sATPCD4 and nATPCD4 before treatment for predicting the occurrence of irAEs were 8.165 × 109cells/L (AUC = 0.705) ,484.5 ng/mL (AUC = 0.777), and 156 ng/mL (AUC = 0.840), respectively. CONCLUSIONS: sATPCD4 and nATPCD4 were independent risk factors for the occurrence of irAEs in advanced NSCLC patients. This discovery provides a new method to predict the occurrence of irAEs in patients. Based on the prediction results, corresponding treatment measures can be taken to reduce the incidence of adverse events.

Injectable hydrogels embedded with chitosan nanoparticles coated with hyaluronic acid for sequential release of dual drugs.

An effective treatment for some disease, such as the model disease acute retinal necrosis (ARN), requires a combination of different drugs which should be administered at a certain interval. The precise sequential and long-term drug release are the critical questions. In this work, the as-prepared chitosan nanoparticles (CS-NPs) coated with hyaluronic acid (HA) were embedded in the aldehyde ß-cyclodextrin (ACD)/aminated hyaluronic acid (NHA) hydrogels to synthesize injectable hydrogels loaded with dual drugs named DEX-CS-NPs/GCV-Gel and HA-DEX-CS-NPs/GCV-Gel. In the first 24 h and 48 h, the releases of DEX from DEX-CS-NPs/GCV-Gel were 128.5 % and 82.8 % faster than those from HA-DEX-CS-NPs/GCV-Gel, respectively. There was no DEX released from HA-DEX-CS-NPs/GCV-Gel at the first 7 h, which has never been reported before, although some hydrogel systems loaded with different drugs release different drugs simultaneously at different rate which have been well studied. This is a good start of a precise sequence release. The composite hydrogels possessed appropriate rheology, gel time, degradation performance, and ideal cytocompatibility. The injectable hydrogel loaded with dual drugs presenting a precise sequential and long-term release has great potential in the treatment of diseases requiring combinations of drugs being released sequentially at different treating stages.