A GAPDH serotonylation system couples CD8+ T cell glycolytic metabolism to antitumor immunity.

Apart from the canonical serotonin (5-hydroxytryptamine [5-HT])-receptor signaling transduction pattern, 5-HT-involved post-translational serotonylation has recently been noted. Here, we report a glyceraldehyde-3-phosphate dehydrogenase (GAPDH) serotonylation system that promotes the glycolytic metabolism and antitumor immune activity of CD8+ T cells. Tissue transglutaminase 2 (TGM2) transfers 5-HT to GAPDH glutamine 262 and catalyzes the serotonylation reaction. Serotonylation supports the cytoplasmic localization of GAPDH, which induces a glycolytic metabolic shift in CD8+ T cells and contributes to antitumor immunity. CD8+ T cells accumulate intracellular 5-HT for serotonylation through both synthesis by tryptophan hydroxylase 1 (TPH1) and uptake from the extracellular compartment via serotonin transporter (SERT). Monoamine oxidase A (MAOA) degrades 5-HT and acts as an intrinsic negative regulator of CD8+ T cells. The adoptive transfer of 5-HT-producing TPH1-overexpressing chimeric antigen receptor T (CAR-T) cells induced a robust antitumor response. Our findings expand the known range of neuroimmune interaction patterns by providing evidence of receptor-independent serotonylation post-translational modification.

ZL006 mitigates anxiety-like behaviors induced by closed head injury through modulation of the neural circuit from the medial prefrontal cortex to amygdala.

Closed head injury is a prevalent form of traumatic brain injury with poorly understood effects on cortical neural circuits. Given the emotional and behavioral impairments linked to closed head injury, it is vital to uncover brain functional deficits and their driving mechanisms. In this study, we employed a robust viral tracing technique to identify the alteration of the neural pathway connecting the medial prefrontal cortex to the basolateral amygdala, and we observed the disruptions in neuronal projections between the medial prefrontal cortex and the basolateral amygdala following closed head injury. Remarkably, our results highlight that ZL006, an inhibitor targeting PSD-95/nNOS interaction, stands out for its ability to selectively reverse these aberrations. Specifically, ZL006 effectively mitigates the disruptions in neuronal projections from the medial prefrontal cortex to basolateral amygdala induced by closed head injury. Furthermore, using chemogenetic approaches, we elucidate that activating the medial prefrontal cortex projections to the basolateral amygdala circuit produces anxiolytic effects, aligning with the therapeutic potential of ZL006. Additionally, ZL006 administration effectively mitigates astrocyte activation, leading to the restoration of medial prefrontal cortex glutamatergic neuron activity. Moreover, in the context of attenuating anxiety-like behaviors through ZL006 treatment, we observe a reduction in closed head injury-induced astrocyte engulfment, which may correlate with the observed decrease in dendritic spine density of medial prefrontal cortex glutamatergic neurons.

Molecular classification reveals the sensitivity of lung adenocarcinoma to radiotherapy and immunotherapy: multi-omics clustering based on similarity network fusion.

BACKGROUND: Due to individual differences in tumors and immune systems, the response rate to immunotherapy is low in lung adenocarcinoma (LUAD) patients. Combinations with other therapeutic strategies improve the efficacy of immunotherapy in LUAD patients. Although radioimmunotherapy has been demonstrated to effectively suppress tumors, the underlying mechanisms still need to be investigated. METHODS: Total RNA from LUAD cells was sequenced before and after radiotherapy to identify differentially expressed radiation-associated genes. The similarity network fusion (SNF) algorithm was applied for molecular classification based on radiation-related genes, immune-related genes, methylation data, and somatic mutation data. The changes in gene expression, prognosis, immune cell infiltration, radiosensitivity, chemosensitivity, and sensitivity to immunotherapy were assessed for each subtype. RESULTS: We used the SNF algorithm and multi-omics data to divide TCGA-LUAD patients into three subtypes. Patients with the CS3 subtype had the best prognosis, while those with the CS1 and CS2 subtypes had poorer prognoses. Among the strains tested, CS2 exhibited the most elevated immune cell infiltration and expression of immune checkpoint genes, while CS1 exhibited the least. Patients in the CS2 subgroup were more likely to respond to PD-1 immunotherapy. The CS2 patients were most sensitive to docetaxel and cisplatin, while the CS1 patients were most sensitive to paclitaxel. Experimental validation of signature genes in the CS2 subtype showed that inhibiting the expression of RHCG and TRPA1 could enhance the sensitivity of lung cancer cells to radiation. CONCLUSIONS: In summary, this study identified a risk classifier based on multi-omics data that can guide treatment selection for LUAD patients.

Celastrol reduces lung inflammation induced by multiwalled carbon nanotubes in mice via NF-κb-signaling pathway.

Multiwalled carbon nanotubes (MWCNTs) have numerous applications in the field of carbon nanomaterials. However, the associated toxicity concerns have increased significantly because of their widespread use. The inhalation of MWCNTs can lead to nanoparticle deposition in the lung tissue, causing inflammation and health risks. In this study, celastrol, a natural plant medicine with potent anti-inflammatory properties, effectively reduced the number of inflammatory cells, including white blood cells, neutrophils, and lymphocytes, and levels of inflammatory cytokines, such as IL-1ß, IL-6, and TNF-α, in mice lungs exposed to MWCNTs. Moreover, celastrol inhibited the activation of the NF-κB-signaling pathway. This study confirmed these findings by demonstrating comparable reductions in inflammation upon exposure to MWCNTs in mice with the deletion of NF-κB (P50-/-). These results indicate the utility of celastrol as a promising pharmacological agent for preventing MWCNT-induced lung tissue inflammation.

Associations between multiple metal exposure and fertility in women: A nested case-control study.

Metal pollution can cause a decline in female fertility, however, previous studies have focused more on the effect of a single metal on fertility. In this study, we evaluated the effect of metal mixtures on female fertility based on nested case-control samples. The plasma levels of 22 metal elements from 180 women were determined by an inductively coupled plasma mass spectrometer (ICP-MS). Minimum absolute contraction and selection operator (LASSO) penalty regression selected metals with the greatest influence on clinical outcome. Logistic regression was used to analyze the correlation between single metals and fertility while a Bayesian kernel function regression (BKMR) model was used to analyze the effect of mixed metals. Eight metals (Calcium (Ca), Chromium (Cr), Cobalt (Co), Copper (Cu), Zinc (Zn), Rubidium (Rb), Strontium (Sr) and Zirconium (Zr)) were selected by LASSO regression for subsequent analysis. After adjusting for covariates, the logistic model showed that Cu (Odds Ratio(OR):0.33, 95% CI: 0.13 - 0.84) and Co (OR:0.38, 95% CI: 0.15 -0.94) caused a significant reduction in fertility, and identified the protective effect of Zn (OR: 2.96, 95% CI:1.21 -7.50) on fertility. Trend tests showed that increased Cr, Cu, and Rb levels were associated with reduced fertility. The BKMR model showed that Cr, Co, Cu, and Rb had a nonlinear relationship with fertility decline when controlling for the concentrations of other metals and suggested that Cu and Cr might exert an influence on fertility. Analysis showed a negative correlation between Cu, Cr, Co, Rb, and fertility, and a positive correlation between Zn and fertility. Furthermore, we found evidence for the interaction between Cu and Cr. Our findings require further validation and may identify new mechanisms in the future.

Autophagy impairment is involved in midazolam-induced lipid droplet accumulation and consequent phagocytosis decrease in BV2 cells.

An increasing number of experimental and clinical observation suggest that the use of anaesthetics is closely associated with postoperative central nervous system (CNS) complications, such as delirium and cognitive dysfunction. Brain energy rescue is an emerging therapeutic strategy for central nervous system disease (CNSDs). However, the effect of anaesthetics on nerve cell energy utilisation, especially microglia, and its potential effects on cell function still unclear. Elucidating the effects of anaesthetics on lipid droplets, which are specific lipid storage organs, and phagocytosis of microglia is crucial to discover a new therapeutic concept for postoperative CNS complications. Here, we studied the effects of the commonly used anaesthetic midazolam on lipid droplets and phagocytosis in immortalised microglial BV2 cells. Lipid droplets were assessed by flow cytometry and triglyceride quantification. The phagocytosis of BV2 cells was evaluated by detecting their phagocytosis by latex beads. Additionally, the autophagy of BV2 cells was evaluated by western blot and observation under microscopy. Our results showed that midazolam caused lipid droplet accumulation and reduced phagocytosis in BV2 cells, and inhibition of lipid droplet accumulation partially restored phagocytosis. Furthermore, midazolam blocks autophagic degradation by increasing phosphorylated TFEB in BV2 cells, inhibition of midazolam-increased phosphorylated TFEB might contribute to the improvement of autophagic flux by rapamycin. Moreover, promoting autophagy reverse the lipid droplet accumulation and phagocytosis decrease. This study suggests autophagy is a target for attenuating lipid droplet accumulation, normal degradation of lipid droplets is important for maintaining microglia phagocytosis and attenuating the side effects of midazolam on the CNS.

Effect of refractive status on retinal nerve fiber layer thickness in Chinese Population.

PURPOSE: To evaluate the relationship between retinal nerve fiber layer (RNFL) thickness and other related parameters measured by spectral-domain optical coherence tomography and the refractive error of eyes. METHODS: A total of 5394 subjects were enrolled in this population-based cohort study, who were divided into three groups by refractive state after they underwent a standardized ophthalmic examination: emmetropia (the absolute value should range from 0 to 0.5 D), low-moderate myopia (the absolute value of myopic error should range from 0.5 to 6 D), and high myopia (the absolute value of myopic error should be over than 6 D). R 3.6.1 software was adopted for statistical analysis. RESULTS: Two thousand five hundred fifty-two subjects (4548 eyes) were collected in this study, with an average age of 53.14 ± 10.64 years. There were significant differences among groups in average central corneal curvature, spherical equivalent, and axial length (P < 0.001). The measurements of average retinal nerve fiber layer (RNFL) were 113.95 ± 10.62 µm, 112.97 ± 11.59 µm, and 101.88 ± 15.67 µm, respectively, in the emmetropia, low-moderate, and high myopia groups (P < 0.001). Meanwhile, there was a decreasing trend of cup area, cup volume, disc area, and rim area in the high myopia group compared with the emmetropia group (P < 0.001). CONCLUSION: The measurements of RNFL thickness vary greatly with refractive error, and this study indicated that it is of great significance for the accurate diagnosis of glaucoma to establish an individualized RNFL thickness database.

Association of Systemic Immune Inflammation Index with Estimated Pulse Wave Velocity, Atherogenic Index of Plasma, Triglyceride-Glucose Index, and Cardiovascular Disease: A Large Cross-Sectional Study.

In the U.S. general population, there is a lack of understanding regarding the association between the systemic immune inflammation (SII) index and estimated pulse wave velocity (ePWV), atherogenic index of plasma (AIP), and triglyceride-glucose (TyG) index and cardiovascular disease (CVD). As a result, the objective of our research was to investigate the association between the SII index and ePWV, AIP, and TyG index and incident CVD. We used the National Health and Nutrition Examination Survey (NHANES) data from 1999 to 2018 to conduct this study. The correlation between the SII index and ePWV, AIP, and TyG index was examined using generalized additive models with smooth functions. In addition, the association between SII index and triglyceride (TC), high-density lipoprotein cholesterol (HDL-C), and fast glucose (FBG) also were explored. Finally, we further performed multivariable logistic regression analysis, restricted cubic spline (RCS) plots, and subgroup analysis to study the connection between the SII index and CVD. Our analysis included 17389 subjects from the NHANES database. A substantial positive association existed between SII, WV, and the TyG index. In addition, with the increase of the SII index, AIP showed a trend of decreasing first, then rising, and then decreasing. The SII index was inversely and linearly associated with triglyceride (TG), while positively and linearly associated with fast glucose (FBG). However, high-density lipoprotein cholesterol (HDL-C) had a tendency of first declining, then climbing, and finally falling with the rise in the SII index. After adjusting for potential confounders, compared with the lowest quartiles, the odds ratios with 95% confidence intervals for CVD across the quartiles were 0.914 (0.777, 1.074), 0.935 (0.779, 1.096), and 1.112 (0.956, 1.293) for SII index. The RCS plot showed an inverse U-shaped curve relationship between the SII index and CVD. Overall, this study found a strong correlation between a higher SII index and ePWV and the TyG index. Additionally, these cross-sectional data also revealed a U-shaped connection between the SII index and CVD.

Celastrol alleviates oxidative stress induced by multi-walled carbon nanotubes through the Keap1/Nrf2/HO-1 signaling pathway.

Multi-walled carbon nanotubes (MWCNTs) mainly induce oxidative stress through the overproduction of reactive oxygen species (ROS), which can lead to cytotoxicity. Celastrol, a plant-derived compound, can exert antioxidant effects by reducing ROS production. Our results indicated that exposure to MWCNTs decreased cell viability and increased ROS production. Nrf2 knockdown (kd) led to increased ROS production and enhanced MWCNT-induced cytotoxicity. Keap1-kd led to decreased ROS production and attenuated cytotoxicity. Treatment with celastrol significantly decreased ROS production and promoted Keap1 protein degradation through the lysosomal pathway, thereby enhancing the translocation of Nrf2 from the cytoplasm to the nucleus and increasing HO-1 expression. The in vivo results showed that celastrol could alleviate the inflammatory damage of lung tissues, increase the levels of the antioxidants, GSH and SOD, as well as promote the expression of the antioxidant protein, HO-1 in MWCNT-treated mice. Celastrol can alleviate MWCNT-induced oxidative stress through the Keap1/Nrf2/HO-1 signaling pathway.

Neutrophils extracellular traps and ferroptosis in diabetic wounds.

Wound healing is an extremely complex process involving multiple levels of cells and tissues. It is mainly completed through four stages: haemostasis, inflammation, proliferation, and remodelling. When any one of these stages is impaired, it may lead to delayed healing or even transformation into chronic refractory wounds. Diabetes is a kind of common metabolic disease that affects approximately 500 million people worldwide, 25% of whom develop skin ulcers that break down repeatedly and are difficult to heal, making it a growing public health problem. Neutrophils extracellular traps and ferroptosis are new types of programmed cell death identified in recent years and have been found to interact with diabetic wounds. In this paper, the normal wound healing and interfering factors of the diabetic refractory wound were outlined. The mechanism of two kinds of programmed cell death was also described, and the interaction mechanism between different types of programmed cell death and diabetic refractory wounds was discussed.

Endothelium-Specific GTP Cyclohydrolase I Overexpression Restores Endothelial Function in Aged Mice.

This study tested the hypothesis that endothelium-specific GTP cyclohydrolase I (GTPCH I) overexpression (Tg-GCH) restores age-associated endothelial dysfunction in vivo. Aortic GTPCH I expression and serum nitric oxide (NO) release were measured in young and aged mice. Aortic rings from young and aged wild-type (WT) mice and aged Tg-GCH mice were suspended for isometric tension recording. A hind limb ischemia model was used to measure blood flow recovery. Aged mice showed reduced GTPCH I expression in the aorta and decreased NO levels in serum. Compared with aged WT mice, Tg-GCH significantly elevated NO levels in serum in aged Tg-GCH mice, restored the impaired aortic relaxation in response to acetylcholine, and significantly elevated aortic constriction in response to L-NAME. Importantly, aged Tg-GCH mice displayed a significant increase in blood flow recovery compared with aged WT mice. GTPCH I reduction contributes to aging-associated endothelial dysfunction, which can be retarded by Tg-GCH.

Burden of visual impairment in mainland China: the Handan Eye Study and Beijing Eye Study.

PURPOSE: To determine the impact of visual impairment (VI) on health-related quality of life (HRQoL) and to compare the health burden of VI in different areas in mainland China. METHODS: A cohort of 6830 people from rural villages and a cohort of 3251 people from an urban city were included to receive comprehensive ophthalmologic examinations and complete the European Quality of Life-5 Dimensions 3 Levels (EQ-5D-3L) questionnaire. For urban and rural populations, a unified VI grouping standard was adopted: the eyes were classified into normal group, mild-moderate group, and severe group according to WHO standards, and then divided into 6 groups considering both eyes. We estimated the effects of VI on the EQ-5D index score using linear regression models and the association between VI and self-reported EQ-5D health problems using logistic regression models. Associations were assessed by the Spearman correlation coefficient. RESULTS: The prevalence of VI and the index scores of EQ-5D-3L for each subgroup of VI were higher for the rural cohort. In these two cohorts, the severity of VI in rural population (Spearman r = 0.205; p < 0.0001) and urban population (Spearman r = 0.164; p < 0.0001) is correlated with the EQ-5D index score. In the rural cohort, the difference in index scores with bilateral severe VI compared to those without VI, after adjusting for covariates, was - 0.053 for the rural cohort and - 0.084 for the urban cohort, respectively. In the rural cohort, the odds ratio for bilateral severe VI was 4.39 for mobility, 6.33 for self-care, and 5.88 for usual activities. The incidence of anxiety or depression and pain or discomfort in the urban cohort was greater; the OR for bilateral severe VI in the urban cohort was 4.75. CONCLUSIONS: VI has a negative impact on HRQoL in the rural and urban areas of China, especially in urban population. It is also more likely to cause anxiety or depression among the urban cohort, which deserves special attention.

[Mechanism of Chuanxiong Rhizoma-Paeoniae Radix Rubra drug pair on intervention of cerebral ischemia based on network pharmacology-molecular docking].

Cerebral ischemia is one of the most common diseases in China, and the drug pair of Chuanxiong Rhizoma and Paeoniae Radix Rubra can intervene in cerebral ischemia to reduce the inflammatory response of cerebral ischemia and apoptosis. To reveal the intervention mechanism of Chuanxiong Rhizoma-Paeoniae Radix Rubra drug pair on cerebral ischemia systematically, computer network pharmacology technology was used in this paper to predict the target and signaling pathway of the drug pair on the intervention of cerebral ischemia, and then the molecular docking technology was used to further analyze the mechanism of the intervention. The target results were then verified by the rat cerebral ischemia model. The target network results showed that the active compounds of Chuanxiong Rhizoma-Paeoniae Radix Rubra for cerebral ischemic disease contained 30 compounds, 38 targets and 9 pathways. The main compounds included phenolic acids in Chuanxiong Rhizoma and monoterpene glycosides in Paeoniae Radix Rubra. The key targets involved mitogen-activated protein kinase 1(MAPK1), steroid receptor coactivator(SRC), epidermal growth factor receptor(EGFR), mitogen-activated protein kinase 14(MAPK14), caspase-3(CASP3), caspase-7(CASP7), estrogen receptor 1(ESR1), and mitogen-activated protein kinase 8(MAPK8), etc. The target gene functions were biased towards protein kinase activity, protein autophosphorylation, peptidyl-serine phosphorylation and protein serine/threonine kinase activity, etc. The important KEGG pathways involved Ras signaling pathway, ErbB signaling pathway and VEGF signaling pathway. Molecular docking results showed that catechin, oxypaeoniflorin, albiflorin, paeoniflorin and benzoylpaeoniflorin had strong binding ability with MAPK1, SRC, EGFR, MAPK14 and CASP7. MCAO rat experimental results showed that Chuanxiong Rhizoma-Paeoniae Radix Rubra significantly improved the cerebral ischemia injury and interstitial edema, and significantly reduced the activation of caspase-7 and the phosphorylation of ERK1/2. The Chuanxiong Rhizoma-Paeoniae Radix Rubra drug pair alleviated cerebral ischemia injury through a network model of multi-phenotype intervention by promoting cell proliferation and differentiation, reducing inflammatory factor expression, protecting nerve cells from death and figh-ting against neuronal cell apoptosis, with its action signaling pathway most related to Ras signaling pathway, ErbB signaling pathway and VEGF signaling pathway. This study provides the basis for clinical intervention of Chuanxiong Rhizoma-Paeoniae Radix Rubra drug pair on cerebral ischemia, and also provides ideas for the modernization of drug pairs.

[Clinical features of children with periodic fever, aphthous stomatitis, pharyngitis, and adenitis syndrome: an analysis of 13 cases].

OBJECTIVE: To study the clinical features of children with periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) syndrome, a polygenic and multifactorial autoinflammatory disease with unknown pathogenesis. METHODS: A retrospective analysis was performed on the medical data of 13 children with PFAPA syndrome. RESULTS: All 13 children had disease onset within the age of 3 years, with a mean age of onset of (14±10) months. They all had periodic fever, with 8-18 attacks each year. The mean interictal period of fever was (30±5) days. Pharyngitis, cervical adenitis, and aphthous stomatitis were the three cardinal symptoms, with incidence rates of 100% (13/13), 85% (11/13), and 38% (5/13) respectively. There were increases in white blood cells, C-reactive protein, and erythrocyte sedimentation rate during fever. Of all the 13 children, 6 underwent whole exome sequencing and 7 underwent panel gene detection for autoinflammatory disease, and the results showed single heterozygous mutations in the MEFV gene in 6 children (46%). Recurrent fever in all children gradually returned to normal without antibiotics. Ten children were treated with a single dose of glucocorticoids, and fever was relieved after treatment. Of all the children, 4 were treated with cimetidine, among whom 2 had response; 4 children were treated with colchicine, among whom 2 had response and 2 were withdrawn from the drug due to adverse reactions. Tonsillectomy was performed for 2 children, among whom 1 was followed up for 3 years without recurrence and 1 still had recurrence. CONCLUSIONS: For children with unexplained periodic fever with early onset accompanied by pharyngitis, cervical adenitis, aphthous stomatitis, elevated inflammatory indices, and good response to glucocorticoids, PFAPA syndrome should be considered. This disorder has good prognosis, and early diagnosis can avoid the long-term repeated use of antibiotics.

Multiparametric MRI Evaluation of Liposomal Prostaglandins E1 Intervention on Hepatic Warm Ischemia-Reperfusion Injury in Rabbits.

BACKGROUND: Liposomal prostaglandin E1 (Lipo-PGE1) treatment should protect against hepatic warm ischemia-reperfusion injury (WIRI). Improved methods are needed for the noninvasive evaluation of hepatic responses to prophylactic Lipo-PGE1 pretreatment approaches. PURPOSE: To demonstrate that multiparametric MRI measurements permit noninvasive differentiation of Lipo-PGE1 treatment outcomes in a hepatic WIRI animal model. STUDY TYPE: Animal study. ANIMAL MODEL: Seventy rabbits were randomly divided into a sham-operated group (A0), warm ischemia groups experiencing increasing periods of ischemia (A1-A3), and corresponding intervention groups (I1-I3) (n = 10 for each group). FIELD STRENGTH/SEQUENCE: Imaging was performed at 3T using a multiecho gradient echo (GRE) sequence (repetition time / echo time [TR/TE], 75/2.57-24.25 msec) for R2* blood oxygenation level-dependent (BOLD) measurements, free-breathing single-shot echo-planar imaging (ss-EPI) sequence with two b-values (0 and 500 s/mm2 ) in 12 diffusion directions for diffusion tensor imaging (DTI), and a free-breathing ss-EPI sequence with eight b-values (0 to 800 s/mm2 ) for intravoxel incoherent motion (IVIM) measurements. ASSESSMENT: The BOLD-derived parameter (R2*), DTI-derived parameters (ADC, FA), and IVIM-derived parameters (Dslow, Dfast, and PF) were calculated for comparisons between treatment groups and correlation to ALT, AST, and LDH levels. STATISTICAL TESTS: One-way analysis of variance (ANOVA), independent sample t-test, Spearman correlation, and receiver operating characteristic (ROC) analysis were performed. RESULTS: Histopathology confirmed the validity of the WIRI model and the efficacy of intervention with clear structure and morphology differences between the different ischemia times and between the Lipo-PGE1 treatment and control groups. Prolonged warm ischemia times resulted in higher R2* and FA values and gradually lower ADC, Dslow, Dfast, and PF values (all P < 0.05). The R2* and FA values were lower, and the ADC, Dslow, Dfast, and PF values were higher in the Lipo-PGE1 intervention groups compared with those in the warm ischemia group for each paired time. However, none of the parameters reached the levels of the A0 group (all P < 0.05). As the warm ischemia time increased, additional parameters demonstrated significant differences between warm ischemia time groups and corresponding intervention groups. At the shortest (30 min), middle (40 min), and longest (60 min) ischemia times, three, four, and five parameters were significantly different between the WIRI and intervention groups, respectively (all P < 0.05). ADC, Dslow, Dfast, and PF values were negatively correlated, while R2* and FA values were positively correlated with serum ALT (|r| = 0.312-0.606) and AST (|r| = 0.432-0.602) (all P < 0.05). ADC and Dfast values showed negative correlations, and R2* showed positive correlations with serum LDH (|r| = 0.323-0.542, all P < 0.05). ROC analysis showed that DTI yielded the strongest diagnostic performance for evaluating the improvement of WIRI. DATA CONCLUSION: Multiparametric MRI can serve as a noninvasive radiologic evaluation for monitoring the protective impact of Lipo-PGE1 therapy on hepatic WIRI. LEVEL OF EVIDENCE: 1 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2020;52:217-228.

Effects of biochar and foliar application of selenium on the uptake and subcellular distribution of chromium in Ipomoea aquatica in chromium-polluted soils.

The potential toxicity of Cr to plants poses a severe threat to human health. Biochar and Se can reduce the absorption of Cr and its phytotoxicity in plants, but the associated mechanisms at subcellular levels have not been addressed in depth. A study was designed to investigate the effects of biochar, foliar application of Se, and their combination on the physicochemical and biological properties of the soil, Cr availability, Cr absorption, and Cr subcellular distribution in each part of the plant, and biomass and quality of two water spinach (Ipomoea aquatica) genotypes. The results showed that biochar, Se, and their combination increased the organic matter content and available NPK nutrients in the soil and improved the urease, phosphatase, catalase, and sucrase activities in the soil. Furthermore, they also increased the number of bacteria, actinomycetes, and fungi in the soil, were conducive to dry matter accumulation in I. aquatica, and increased the contents of soluble sugar and soluble protein in its leaves. The Cr contents in the roots and shoots of I. aquatica under different treatments were reduced compared with those in the control group. The content of Cr(VI) in the root-soil of I. aquatica with low Cr accumulation and the contents of Cr in various parts of I. aquatica were lower than those in I. aquatica with high Cr accumulation, and the absorbed Cr was mainly accumulated in the roots. Cr was mainly distributed in the cell walls and soluble fractions of the roots, stems, and leaves of I. aquatica and was less distributed in the organelles. Biochar and Se helped to increase the proportion of Cr in the cell walls of the roots and soluble fractions of the leaves of I. aquatica. The effects of improving the soil properties, passivating and inhibiting Cr absorption by I. aquatica, and reducing the Cr proportion in the organelles of biochar were superior to those of Se application. The foliar application of Se and biochar had no synergistic effect on inhibiting Cr absorption by I. aquatica. Based on these findings, the application of biochar in Cr-contaminated soil or foliar application of Se with low Cr-accumulating plants may be effective means of reducing the Cr absorption by plants and its toxicity to ensure the safe production of agricultural products in Cr-contaminated regions.

Growing networks with communities: A distributive link model.

Evolution and popularity are two keys of the Barabasi-Albert model, which generates a power law distribution of network degrees. Evolving network generation models are important as they offer an explanation of both how and why complex networks (and scale-free networks, in particular) are ubiquitous. We adopt the evolution principle and then propose a very simple and intuitive new model for network growth, which naturally evolves modular networks with multiple communities. The number and size of the communities evolve over time and are primarily subjected to a single free parameter. Surprisingly, under some circumstances, our framework can construct a tree-like network with clear community structures-branches and leaves of a tree. Results also show that new communities will absorb a link resource to weaken the degree growth of hub nodes. Our models have a common explanation for the community of regular and tree-like networks and also breaks the tyranny of the early adopter; unlike the standard popularity principle, newer nodes and communities will come to dominance over time. Importantly, our model can fit well with the construction of the SARS-Cov-2 haplotype evolutionary network.

CBX3 promotes glioma U87 cell proliferation and predicts an unfavorable prognosis.

BACKGROUND: Chromobox protein homolog 3 (CBX3) is one of the heterochromatin protein 1 (HP1) family members. Among multiple cancers, it is usually overexpressed. However, the mechanism and function of CBX3 in glioma remain incompletely illustrated. METHODS: The expression level of CBX3 as well as its correlation with glioma are detected through TCGA and Oncomine database. The expressions of CBX3 mRNA and protein in glioma tissues and normal brain tissues have been identified by qRT-PCR and Western blot. The prognostic role of CBX3 has been assessed in a retrospective cohort study. Additionally, the correlation between CBX3 expression and the clinicopathological characteristics of glioma patients were also discussed. To better understand the role of CBX3 in glioma, a lentiviral vector expressing CBX3-shRNA and cyclin dependent kinase inhibitor 1A (CDKN1A) siRNA were established and transfected into the glioma U87 cells. Besides, the CBX3 and CDKN1A expression levels in glioma U87 cells after transfected with CBX3-shRNA were gauged by qRT-PCR and Western blot. CCK-8, colony formation and EdU assays have been applied to evaluate the influence of CBX3 on U87 cells proliferation, and flow cytometry has been applied to manage the changes in cell cycle and cell apoptosis after transfection with CBX3-shRNA. Xenograft tumors have been examined in vivo for the carcinogenic effects and prognostic value of CBX3 in glioma tissues. RESULTS: In the present study, CBX3 was demonstrated to be highly expressed in human glioma tissues, and high CBX3 expression predicted the dismal recurrence-free survival (RFS) and poor overall survival (OS) for glioma patients. High CBX3 expression was dependent on the tumor size, Karnofsky performance scale (KPS) score, WHO grade, recurrence and survival status. Moreover, CBX3 expression knockdown could remarkably suppress the proliferation and colony formation ability of U87 cells, which was achieved through blocking cell arrest at G0/G1 phase and inducing apoptosis. Additionally, our findings also suggested that, compared with shRNA-Ctrl transfection, the mRNA and protein expression levels of CDKN1A have been dramatically up-regulated in vitro after transfection with shRNA-CBX3. Consistent with the results of in vitro assays, the outcomes of xenograft assay and immunohistochemistry (IHC) also indicated that, the tumor growth and Ki-67 expression level were restrained in response to CBX3 inhibition, while the CDKN1A expression level in vivo was up-regulated. Down-regulation of CDKN1A expression partially restored the ability of cell proliferation in the U87 cells, which was inhibited by shRNA-CBX3 CONCLUSIONS: In conclusion, results of the current research suggest that a high CBX3 expression level predicts the poor prognosis for glioma patients. CBX3 can stimulate the growth of glioma U87 cells through targeting CDKN1A and CBX3 may become a novel target in the clinical treatment for glioma.

[Research progress on Chinese herbal medicine fermentation and profile of active substances derived].

Chinese herbal medicines( CHMs) are a class of preparations made from natural plants that pose health beneficial properties as well as illness prevention functions. Thanks to a panel of salutary features,such as comprehensive immunological enhancement and inhibition of pathogenic bacteria,negligible side-effects,inappreciable drug-resistance,CHMs have been taken as one of the costeffective candidates for antibiotics substitutions. Through probiotics fermentation,the enzymatic hydrolysis of matrixes of CHMs enables easier release of the active ingredient as well as endows less toxicity of the preparations derived. During fermentation,the macromolecule or polymers forms of the active ingredient can be cut down to smaller molecule,which favors the transmembrane transport and improve adsorption of the active ingredients by the tissues. Other than the enzymatic benefits,probiotics can produce metabolites that inhibit pathogenic bacteria propagation,which may function synergically with the inhibitory effects of the CHMs preparations to fight the target pathogens. In addition,the oligosaccharide like components of CHMs can promote the growth of probiotics in intestinal environment which may largely facilitate the gut health. To summarize,the fermentation of CHMs using probiotics brings about the biochemical reactions and elevates the health beneficial effects by synergy of the microbial and herbal activities. It has been proved to be one of promising approaches as to antibiotic substitutions,particularly in livestock and poultry breeding industries. This review covered the recent progress of CHMs fermentation on the aspects of microbial strains,patterns of fermentation and active substances from fermentation of CHMs and their potency,respectively.

Persistency of Enlarged Autolysosomes Underscores Nanoparticle-Induced Autophagy in Hepatocytes.

The diverse biological effects of nanomaterials form the basis for their applications in biomedicine but also cause safety issues. Induction of autophagy is a cellular response after nanoparticles exposure. It may be beneficial in some circumstances, yet autophagy-mediated toxicity raises an alarming concern. Previously, it has been reported that upconversion nanoparticles (UCNs) elicit liver damage, with autophagy contributing most of this toxicity. However, the detailed mechanism is unclear. This study reveals persistent presence of enlarged autolysosomes in hepatocytes after exposure to UCNs and SiO2 nanoparticles both in vitro and in vivo. This phenomenon is due to anomaly in the autophagy termination process named autophagic lysosome reformation (ALR). Phosphatidylinositol 4-phosphate (PI(4)P) relocates onto autolysosome membrane, which is a key event of ALR. PI(4)P is then converted into phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2 ) by phosphatidylinositol-4-phosphate 5-kinase. Clathrin is subsequently recruited by PI(4,5)P2 and leads to tubule budding of ALR. Yet it is observed that PI(4)P cannot be converted in nanoparticle-treated hepatocytes cells. Exogenous supplement of PI(4,5)P2 suppresses the enlarged autolysosomes in vitro. Abolishment of these enlarged autolysosomes by autophagy inhibitor relieves the hepatotoxicity of UCNs in vivo. The results provide evidence for disrupted ALR in nanoparticle-treated hepatocytes, suggesting that the termination of nanoparticle-induced autophagy is of equal importance as the initiation.