Neddylation, a newly identified post-translational modification, is significant for the activity and stability of target proteins. The exact role of neddylation in the pathogenesis of inflammatory bowel disease, specifically those mediated by dendritic cells (DCs), was still rarely reported. Here, we showed that inhibition of neddylation protected mice from mucosal inflammation. Targeting neddylation also inhibited DC maturation characterized by reduced cytokine production, down-regulated costimulatory molecules and suppressed capacity in allogeneic T cell stimulation. Additionally, inactivation of neddylation promotes caspase dependent apoptosis of DCs. These phenomena were attributed to the inactivation of mTOR, which was caused by Cullin-1 deneddylation induced Deptor accumulation. Together, our findings revealed that neddylation inhibition suppressed DC functions through mTOR signaling pathway and provided a potential therapeutic opportunity in inflammatory bowel diseases.

It has been established that mammalian target of Rapamycin (mTOR) inhibitors have anti-inflammatory effects in models of experimental colitis. However, the underlying mechanism is largely unknown. In this research, we investigate the anti-inflammatory effects of AZD8055, a potent mTOR inhibitor, on T cell response in dextran sulfate sodium (DSS)-induced colitis in mice, a commonly used animal model of inflammatory bowel diseases (IBD). Severity of colitis is evaluated by changing of body weight, bloody stool, fecal consistency, histology evaluation and cytokine expression. We find that AZD8055 treatment attenuates DSS-induced body weight loss, colon length shortening and pathological damage of the colon. And AZD8055 treatment decreases colonic expression of genes encoding the pro-inflammatory cytokines interferon-γ, interleukin (IL)-17A, IL-1β,IL-6 and tumor necrosis factor(TNF)-a and increases colonic expression of anti-inflammatory cytokines IL-10. We show that AZD8055 treatment decreases the percentages of CD4+ T cells and CD8+ T cells in spleen, lymph nodes and peripheral blood of mice. We also find that AZD8055 treatment significantly reduces the number of T helper 1(TH1) cells and TH17 cells and increases regulatory T (Treg) cells in the lamina propria and mesenteric lymph nodes. Furthermore, we demonstrates that AZD8055 suppresses the proliferation of CD4+ and CD8+ T cells and the differentiation of TH1/TH17 cells and expands Treg cells in vitro. The results suggest that, in experimental colitis, AZD8055 exerts anti-inflammatory effect by regulating T helper cell polarization and proliferation.

Grain number per panicle is a major component of rice yield that is typically controlled by many quantitative trait loci (QTLs). The identification of genes controlling grain number per panicle in rice would be valuable for the breeding of high-yielding rice. The Oryza glaberrima chromosome segment substitution line 9IL188 had significantly smaller panicles compared with the recurrent parent 9311. QTL analysis in an F2 population derived from a cross between 9IL188 and 9311 revealed that qgnp7(t), a major QTL located on the short arm of chromosome 7, was responsible for this phenotypic variation. Fine mapping was conducted using a large F3 population containing 2250 individuals that were derived from the F2 heterozygous plants. Additionally, plant height, panicle length, and grain number per panicle of the key F4 recombinant families were examined. Through two-step substitution mapping, qgnp7(t) was finally localized to a 41 kb interval in which eight annotated genes were identified according to available sequence annotation databases. Phenotypic evaluation of near isogenic lines (NIL-qgnp7 and NIL-qGNP7) indicated that qgnp7(t) has pleiotropic effects on rice plant architecture and panicle structure. In addition, yield estimation of NILs indicated that qGNP7(t) derived from 9311 is the favorable allele. Our results provide a foundation for isolating qgnp7(t). Markers flanking this QTL will be a useful tool for the marker-assisted selection of favorable alleles in O. glaberrima improvement programs.

Ursodeoxycholic acid (UDCA) is the hydrolysis of tauroursodeoxycholic acid, which is the main ingredient from bear gall that has functions including clearing heat and detoxification, and improving eyesight. However, whether UDCA has improving effects on diabetic retinopathy (DR) is not known. This study aims to observe the amelioration of UDCA on DR and its engaged mechanisms. The results of Evans blue permeation assay showed that UDCA (15, 30 mg/kg) reversed the breakdown of blood-retinal barrier (BRB) and the decreased expression of claudin-1 and claudin-19 in STZ-induced diabetic mice. UDCA reversed the reduced thickness of both inner nuclear layer (INL) and outer nuclear layer (ONL) in STZ-induced diabetic mice. UDCA reduced retinal ionized calcium-binding adapter molecule 1 (Iba1) expression in STZ-induced diabetic mice. UDCA reduced the expression of phosphorylated the inhibitor of nuclear factor κB kinase (IKK) and the nuclear translocation of p65 subunit of nuclear factor κB (NFκB) in retinas from STZ-induced diabetic mice. UDCA also reduced retinal expression of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), intercellular cell adhesion molecule-1 (ICAM-1), inducible nitric oxide synthase (iNOS) and vascular endothelial growth factor (VEGF) in STZ-induced diabetic mice. In conclusion, UDCA attenuates BRB breakdown during DR development via inhibiting retinal inflammation and reversing the reduced expression of tight junctions (TJs) including claudin-1 and claudin-19.

A better understanding of the immune profile of non-small cell lung cancer (NSCLC) and the immunomodulatory impact of chemotherapy is essential to develop current therapeutic approaches. Herein, we collected peripheral blood from 20 healthy donors and 50 patients with advanced NSCLC, before and after chemotherapy, followed by phenotypic analysis of lymphocyte subsets and assessment of the correlation between their post-chemotherapy levels and progression-free survival (PFS). Results showed that, before chemotherapy, the levels of CD8+ lymphocytes, PD-1+CD4+, Th2, and Th17 cells were elevated in patients' peripheral blood, in contrast to natural killer (NK) cells and Th1 cells. Besides, there was no remarkable difference in the frequency of PD-1+CD8+ cells between patients and healthy controls. After chemotherapy, the levels of CD8+ lymphocytes, NK, Th2, Th17, and Treg were declined, in contrast to the level of Th1 cells which was markedly increased. Importantly, chemotherapy had no impact on the frequencies of PD-1+CD8+ and PD-1+CD4+ cells. PFS was significantly better in patients with low percentage of PD-1+CD4+ T cells than those with high percentage. Patients with high content of Th1 cells showed longer PFS than those with low content. The low percentages of Th17 and Treg cells were correlated with longer PFS, even though the difference did not reach statistical significance. In conclusion, the imbalance of lymphocyte subsets is a hallmark of NSCLC. Furthermore, the high level of PD-1+CD4+ cells plays a crucial role in the progression of NSCLC and could be used as a prognostic marker; and the high level of Th1 could predict better clinical outcomes of chemotherapy.

Accumulating evidence shows that tigecycline, a first-in-class glycylcycline, has potential antitumour properties. Here, we found that tigecycline dramatically inhibited the proliferation of multiple myeloma (MM) cell lines RPMI-8226, NCI-H929 and U266 in a dose and time-dependent manner. Meanwhile, tigecycline also potently impaired the colony formation of these three cell lines. Mechanism analysis found that tigecycline led to cell cycle arrest at G0/G1 with down-regulation of p21, CDK2 and cyclin D1, rather than induced apoptosis, in MM cells. Importantly, we found that tigecycline induced autophagy and an autophagy inhibitor bafilomycin A1 further amplified the tigecycline-induced cytotoxicity, suggesting that autophagy plays a cytoprotective role in tigecycline-treated MM cells. Mechanisms modulating autophagy found that tigecycline enhanced the phosphorylation of AMPK, but did not decrease the phosphorylation of Akt, to inhibit the phosphorylation of mTOR and its two downstream effectors p70S6K1 and 4E-BP1. Tigecycline effectively inhibited tumour growth in the xenograft tumour model of RPMI-8226 cells. Autophagy also occurred in tigecycline-treated tumour xenograft, and autophagy inhibitor chloroquine and tigecycline had a synergistic effect against MM cells in vivo. Thus, our results suggest that tigecycline may be a promising candidate in the treatment of MM.

To investigate the prognostic value of the red blood cell distribution width(RDW) recovery from low levels at diagnosis after completion of first line therapy in mutiple myeloma (MM)patients,we enrolled 78 consecutive patients with MM and followed up from 2005 to 2016 in our hospital. The RDW was measured following completion of first-line therapy.The log-rank test, univariate analysis, and Cox regression analysis were used to evaluate the relationship between RDW and survival. We found that patients with an RDW ≥ 15.5% at diagnosis, as well as at completion of first-line therapy, had significantly lower progression-free survival (PFS) and overall survival(OS) rates than those with an RDW < 15.5%(P < 0.05).Patients with RDW that maintained more than 15.5% upon completion of therapy showed a shorter OS (P < 0.05) and PFS (P < 0.05) compared with patients with an RDW that decreased to a lower level.The multivariate analysis showed that RDW ≥ 15.5% after the completion of first-line therapy were an independent prognostic marker of poorer OS (P = 0.044) and PFS (P = 0.034). Therefore,we demonstrated that RDW at diagnosis, as well as at completion of first-line therapy is an independent predictor for mutiple myeloma patients.RDW maintained at high level, irrespective of whether RDW decreased to the cutoff value predicted an unfavorable prognosis in patients with MM.

This retrospective study determined the delayed-type hypersensitivity (DTH) skin test and safety of dendritic cell (DC) vaccine and cytokine-induced killer (CIK) cell immunotherapy and the survival compared to chemotherapy in 239 colorectal cancer (CRC) patients.

RNA-binding protein Musashi-2 (Msi2) is known to play a critical role in leukemogenesis and contributes to poor clinical prognosis in acute myeloid leukemia (AML). However, the effect of Msi2 silencing on treatment for AML still remains poorly understood. In this study, we used lentivirus-mediated RNA interference targeting Msi2 to investigate the resulting changes in cellular processes and the underlying mechanisms in AML cell lines as well as primary AML cells isolated from AML patients. We found that Msi2 was highly expressed in AML cells, and its depletion inhibited Ki-67 expression and resulted in decreased in vitro and in vivo proliferation. Msi2 silencing induced cell cycle arrest in G0/G1 phase, with decreased Cyclin D1 and increased p21 expression. Msi2 silencing induced apoptosis through down-regulation of Bcl-2 expression and up-regulation of Bax expression. Suppression of Akt, Erk1/2 and p38 phosphorylation also contributed to apoptosis mediated by Msi2 silencing. Finally, Msi2 silencing in AML cells also enhanced their chemosensitivity to daunorubicin. Conclusively, our data suggest that Msi2 is a promising target for gene therapy to optimize conventional chemotherapeutics in AML treatment.

Reaction-diffusion models were applied to gain insight into the aspects of biofilm infection and persistence by comparing mathematical simulations with the experimental data from varied bacterial biofilms. These comparisons, including three in vitro systems and two clinical investigations of specimens examined ex vivo, underscored the central importance of concentration gradients of metabolic substrates and the resulting physiological heterogeneity of the microorganisms. Relatively simple one-dimensional and two-dimensional (2D) models captured the: (1) experimentally determined distribution of specific growth rates measured in Pseudomonas aeruginosa cells within sputum from cystic fibrosis patients; (2) pattern of relative growth rate within aggregates of streptococcal biofilm harboured in an endocarditis vegetation; (3) incomplete penetration of oxygen into a Pseudomonas aeruginosa biofilm under conditions of exposure to ambient air and also pure oxygen; (4) localisation of anabolic activity around the periphery of P. aeruginosa cell clusters formed in a flow cell and attribution of this pattern to iron limitation; (5) very low specific growth rates, as small as 0.025 h-1, in the interior of cell clusters within a Klebsiella pneumoniae biofilm in a complex 2D domain of variable cell density.

Liver regeneration has become a new hotspot in the study of drug-induced liver injury (DILI). Baicalin has already been reported to alleviate acetaminophen (APAP)-induced acute liver injury in our previous study. This study aims to observe whether baicalin also promotes liver regeneration after APAP-induced liver injury and to elucidate its engaged mechanism. Baicalin alleviated APAP-induced hepatic parenchymal cells injury and enhanced the number of mitotic and proliferating cell nuclear antigen (PCNA)-positive hepatocytes in APAP-intoxicated mice. Baicalin increased hepatic PCNA and cyclinD1 expression in APAP-intoxicated mice. Baicalin induced the activation of NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome, leading to the increased hepatic expression of interleukin-18 (IL-18) and IL-1β in APAP-intoxicated mice. The results in vitro demonstrated that IL-18 promoted the proliferation of human normal liver L-02 cells. Moreover, the baicalin-provided promotion on liver regeneration in APAP-intoxicated mice was diminished after the application of NLRP3 inhibitor MCC950 and the recombinant mouse IL-18 binding protein (rmIL-18BP). Baicalin induced the cytosolic accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2), and increased the interaction between Nrf2 with Nlrp3, ASC and pro-caspase-1 in livers from APAP-intoxicated mice. Furthermore, the baicalin-provided NLRP3 inflammasome activation and promotion on liver regeneration after APAP-induced liver injury in wild-type mice were diminished in Nrf2 knockout mice. In conclusion, baicalin promoted liver regeneration after APAP-induced acute liver injury in mice via inducing Nrf2 accumulation in cytoplasm that led to NLRP3 inflammasome activation, and then caused the increased expression of IL-18, which induced hepatocytes proliferation.

To develop a fully automated AI system to quantitatively assess the disease severity and disease progression of COVID-19 using thick-section chest CT images.

Previous studies have provided evidence of the high expression of lactate dehydrogenase (LDH) in multiple solid tumors; however, its prognostic relationship with metastatic prostate cancer (mPCa) remains controversial. We performed a meta-analysis to better understand the prognostic potential of LDH in mPCa.

Parkinson's disease (PD) is a common neurodegenerative disease with movement and balance impairments. Although studies have reported improvement of motor symptoms with physical exercise, the mechanisms by which exercise is beneficial remains poorly understood. Our study addresses the exercise-induced changes to peripheral immune cells by interrogating the transcriptome of blood-derived leukocytes in PD patients before and after exercise. Patients attended 1 h exercise classes twice a week for 12 weeks. Leukocytes were collected at the beginning and end of the study for gene expression analysis by RNA-seq or quantitative real-time PCR. We correlated differentially expressed genes after exercise with clinical measures and analyzed the potential functions of gene changes with Kyoto Encyclopedia of Genes and Genomes pathway and Gene Ontology analysis. Exercise improved measures of movement and balance when compared with scores before the exercise program. Among the gene changes, Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analysis suggests that T-cell receptor signaling, T-cell activation, and T-cell migration pathways were downregulated, while the T-cell receptor signaling pathway was the most significantly correlated with clinical measures. To further investigate T-cell-related changes in PD leukocytes, we reanalyzed the differentially expressed genes from publicly available microarray data and found that genes in the T-cell activation, differentiation, and migration pathways were upregulated in PD samples compared to controls in a time-dependent manner. Together, our findings suggest that exercise rehabilitation may improve movement and balance in PD patients by reversing the upregulated T-cell activation pathways associated with PD. This study was registered with the Chinese Clinical Trial Registry under ChiCTR-TRC-14004707. Registered on May 27, 2014.

The pinna (or auricle) is part of the external ear, acting to capture and funnel sound toward the middle ear. The pinna is defective in a number of craniofacial syndromes, including Lacrimo-auriculo-dento-digital (LADD) syndrome, which is caused by mutations in FGF10 or its receptor FGFR2b. Here we study pinna defects in the Fgf10 knockout mouse. We show that Fgf10 is expressed in both the muscles and forming cartilage of the developing external ear, with loss of signaling leading to a failure in the normal extension of the pinna over the ear canal. Conditional knockout of Fgf10 in the neural crest fails to recapitulate this phenotype, suggesting that the defect is due to loss of Fgf10 from the muscles, or that this source of Fgf10 can compensate for loss in the forming cartilage. The defect in the Fgf10 null mouse is driven by a reduction in proliferation, rather than an increase in cell death, which can be partially phenocopied by inhibiting cell proliferation in explant culture. Overall, we highlight the mechanisms that could lead to the phenotype observed in LADD syndrome patients and potentially explain the formation of similar low-set and cup shaped ears observed in other syndromes.

San-Huang-Yi-Shen capsule (SHYS) has been used in the treatment of diabetic kidney disease (DKD) in clinics. However, the mechanism of SHYS on DKD remains unclear. In this study, we used a high-fat diet combined with streptozocin (STZ) injection to establish a rat model of DKD, and different doses of SHYS were given by oral gavage to determine the therapeutic effects of SHYS on DKD. Then, we studied the effects of SHYS on PINK1/Parkin-mediated mitophagy and the activation of NLRP3 inflammasome to study the possible mechanisms of SHYS on DKD. Our result showed that SHYS could alleviate DKD through reducing the body weight loss, decreasing the levels of fasting blood glucose (FBG), and improving the renal function, insulin resistance (IR), and inhibiting inflammatory response and oxidative stress in the kidney. Moreover, transmission electron microscopy showed SHYS treatment improved the morphology of mitochondria in the kidney. In addition, western blot and immunoflourescence staining showed that SHYS treatment induced the PINK1/Parkin-mediated mitophagy and inhibited the activation of NLRP3 signaling pathway. In conclusion, our study demonstrated the therapeutic effects of SHYS on DKD. Additionally, our results indicated that SHYS promoted PINK1/Parkin-mediated mitophagy and inhibited NLRP3 inflammasome activation to improve mitochondrial injury and inflammatory responses.

Mycobacterium abscessus is a fast growing Mycobacterium species mainly causing skin and respiratory infections in human. M. abscessus is resistant to numerous drugs, which is a major challenge for the treatment. In this study, we have sequenced the genomes of two clinical M. abscessus strains having rough and smooth morphology, using the single molecule real-time and Illumina HiSeq sequencing technology. In addition, we reported the first comparative methylome profiles of a rough and a smooth M. abscessus clinical strains. The number of N4-methylcytosine (4mC) and N6-methyladenine (6mA) modified bases obtained from smooth phenotype were two-fold and 1.6 fold respectively higher than that of rough phenotype. We have also identified 4 distinct novel motifs in two clinical strains and genes encoding antibiotic-modifying/targeting enzymes and genes associated with intracellular survivability having different methylation patterns. To our knowledge, this is the first report about genome-wide methylation profiles of M. abscessus strains and identification of a natural linear plasmid (15 kb) in this critical pathogen harboring methylated bases. The pan-genome analysis of 25 M. abscessus strains including two clinical strains revealed an open pan genome comprises of 7596 gene clusters. Likewise, structural variation analysis revealed that the genome of rough phenotype strain contains more insertions and deletions than the smooth phenotype and that of the reference strain. A total of 391 single nucleotide variations responsible for the non-synonymous mutations were detected in clinical strains compared to the reference genome. The comparative genomic analysis elucidates the genome plasticity in this emerging pathogen. Furthermore, the detection of genome-wide methylation profiles of M. abscessus clinical strains may provide insight into the significant role of DNA methylation in pathogenicity and drug resistance in this opportunistic pathogen.

To investigate whether the dynamic functional connectivity (dFC) of striatal-cortical circuits changes in juvenile myoclonic epilepsy (JME).

Liver fibrosis has been the focus and difficulty of medical research in the world and its concrete pathogenesis remains unclear. This study aims to observe the high-mobility group box 1 (HMGB1)-induced hepatic endothelial to mesenchymal transition (EndoMT) during the development of hepatic fibrosis, and further to explore the crucial involvement of Egr1 in this process.

Antibiotics are our primary approach to treating complex infections, yet we have a poor understanding of how these drugs affect microbial communities. To better understand antimicrobial effects on host-associated microbial communities we treated cultured sputum microbiomes from people with cystic fibrosis (pwCF, n = 24) with 11 different antibiotics, supported by theoretical and mathematical modeling-based predictions in a mucus-plugged bronchiole microcosm. Treatment outcomes we identified in vitro that were predicted in silico were: 1) community death, 2) community resistance, 3) pathogen killing, and 4) fermenter killing. However, two outcomes that were not predicted when antibiotics were applied were 5) community profile shifts with little change in total bacterial load (TBL), and 6) increases in TBL. The latter outcome was observed in 17.8% of samples with a TBL increase of greater than 20% and 6.8% of samples with an increase greater than 40%, demonstrating significant increases in community carrying capacity in the presence of an antibiotic. An iteration of the mathematical model showed that TBL increase was due to antibiotic-mediated release of pH-dependent inhibition of pathogens by anaerobe fermentation. These dynamics were verified in vitro when killing of fermenters resulted in a higher community carrying capacity compared to a no antibiotic control. Metagenomic sequencing of sputum samples during antibiotic therapy revealed similar dynamics in clinical samples. This study shows that the complex microbial ecology dictates the outcomes of antibiotic therapy against a polymicrobial infection.