The accumulation of myeloid-derived suppressor cells (MDSCs) has been observed in solid tumors and is correlated with tumor progression; however, the underlying mechanism is still poorly understood. ...In this study, we identified a mechanism by which tumor cells induce MDSC accumulation and expansion in the bladder cancer (BC) microenvironment via CXCL2/MIF-CXCR2 signaling. Elevated expression of CXCL2 and MIF and an increased number of CD33
MDSCs were detected in BC tissues, and these increases were significantly associated with advanced disease stage and poor patient prognosis (P<0.01). A positive association was observed between CXCL2 or MIF expression and the number of tumor-infiltrating CD33
MDSCs (P<0.01). Subsequently, we demonstrated that CD45
CD33
CD11b
HLA-DR
MDSCs from fresh BC tissues displayed high levels of suppressive molecules, including Arg1, iNOS, ROS, PDL-1 and P-STAT3, and stronger suppression of T-cell proliferation. Interestingly, these CD45
CD33
CD11b
HLA-DR
MDSCs exhibited increased CXCR2 expression compared with that in peripheral blood from BC patients or healthy controls (P<0.05). Chemotaxis assay revealed that bladder cancer cell line J82 induced MDSC migration via CXCL2/MIF-CXCR2 signaling in vitro. Mechanistic studies demonstrated that J82-induced MDSC trafficking and CXCR2 expression were associated with increased phosphorylation of p38, ERK and p65. Conversely, inhibition of the phosphorylation of p38, ERK or p65 decreased J82-induced MDSC trafficking and CXCR2 expression. CXCL2/MIF-stimulated activation of the mitogen-activated protein kinase and nuclear factor kappa B pathways in MDSCs was MyD88 dependent. Overall, our results identify the CXCL2/MIF-CXCR2 axis as an important mediator in MDSC recruitment and as predictors and potential therapeutic targets in BC patients.
Owing to the unknown high-order unstable motion, it is difficult to realise the motion compensation for inverse synthetic aperture radar manoeuvring targets. By modelling the envelope shifting and ...phase modulation into two different high-order polynomial functions against observation time, a novel parametric ISAR motion compensation method is proposed based on polynomial coefficients estimation via particle swarm optimiser (PSO). The average range profile energy and the image contrast are chosen as the fitness functions for envelope alignment and phase auto-focusing, respectively. Furthermore, the polynomial order of phase auto-focusing is chosen higher than that of envelope alignment to meet the accuracy need of phase compensation. Besides, in order to speed up the convergence and ensure that the estimated parameters converge to the global optimisation, a least-square fitting pre-processing is also proposed to determine the target motion order and initialise the best particle at first. Finally, the results based on both numerical experiments and real data are all provided to demonstrate the effectiveness of the proposed PSO-based parametric methods.
In order to rescale an inverse synthetic aperture radar image into a homogeneous range cross-range domain, a novel method is proposed to estimate rotation velocity (RV) by exploiting the phase slope ...difference of two prominent scatterers on a complex image. Firstly, two prominent scatterers are automatically extracted in a range-Doppler image via watershed method. Subsequently, the signal obtained by the two scatterers is divided into two equal segments, each of which provides an estimation of the phase slope via phase unwrapping and the least-square fitting. Finally, the target RV can be estimated based on the difference of the two phase slopes. The proposed method can be implemented automatically, and is more computationally efficient than the traditional methods. Finally, the results based on simulation data and real data are provided, to demonstrate the effectiveness of the proposed method.
The mechanisms underlying hypermethylation of tumor-suppressor gene promoters in cancer is not well understood. Here, we report that lysine acetylation of the oncogenic transcription factor STAT3 is ...elevated in tumors. We also show that genetically altering STAT3 at Lys685 reduces tumor growth, which is accompanied by demethylation and reactivation of several tumor-suppressor genes. Moreover, mutating STAT3 at Lys685 disrupts DNA methyltransferase 1–STAT3 interactions in cultured tumor cells and in tumors. These observations are confirmed by treatment with an acetylation inhibitor, resveratrol. Furthermore, reduction of acetylated STAT3 in triple-negative breast cancer cells leads to demethylation and activation of the estrogen receptor-α gene, sensitizing the tumor cells to antiestrogens. Our results also demonstrate a correlation between STAT3 acetylation and methylation of estrogen receptor-α in melanoma, which predicts melanoma progression. Taken together, these results suggest a role of STAT3 acetylation in regulating CpG island methylation, which may partially explain aberrant gene silencing in cancer. These findings also provide a rationale for targeting acetylated STAT3 for chemoprevention and cancer therapy.
Summary Background A severe form of encephalitis associated with antibodies against NR1–NR2 heteromers of the NMDA receptor was recently identified. We aimed to analyse the clinical and immunological ...features of patients with the disorder and examine the effects of antibodies against NMDA receptors in neuronal cultures. Methods We describe the clinical characteristics of 100 patients with encephalitis and NR1–NR2 antibodies. HEK293 cells ectopically expressing single or assembled NR1–NR2 subunits were used to determine the epitope targeted by the antibodies. Antibody titres were measured with ELISA. The effect of antibodies on neuronal cultures was determined by quantitative analysis of NMDA-receptor clusters. Findings Median age of patients was 23 years (range 5–76 years); 91 were women. All patients presented with psychiatric symptoms or memory problems; 76 had seizures, 88 unresponsiveness (decreased conciousness), 86 dyskinesias, 69 autonomic instability, and 66 hypoventilation. 58 (59%) of 98 patients for whom results of oncological assessments were available had tumours, most commonly ovarian teratoma. Patients who received early tumour treatment (usually with immunotherapy) had better outcome (p=0·004) and fewer neurological relapses (p=0·009) than the rest of the patients. 75 patients recovered or had mild deficits and 25 had severe deficits or died. Improvement was associated with a decrease of serum antibody titres. The main epitope targeted by the antibodies is in the extracellular N-terminal domain of the NR1 subunit. Patients' antibodies decreased the numbers of cell-surface NMDA receptors and NMDA-receptor clusters in postsynaptic dendrites, an effect that could be reversed by antibody removal. Interpretation A well-defined set of clinical characteristics are associated with anti-NMDA-receptor encephalitis. The pathogenesis of the disorder seems to be mediated by antibodies. Funding National Institutes for Health, University of Pennsylvania Institute for Translational Medicine, Lankenau Institute for Medical Research, Foederer Foundation of the Children's Hospital of Philadelphia.
Necroptosis is a caspase-independent form of cell death that is triggered by activation of the receptor interacting serine/threonine kinase 3 (RIPK3) and phosphorylation of its pseudokinase substrate ...mixed lineage kinase-like (MLKL), which then translocates to membranes and promotes cell lysis. Activation of RIPK3 is regulated by the kinase RIPK1. Here we analyze the contribution of RIPK1, RIPK3, or MLKL to several mouse disease models. Loss of RIPK3 had no effect on lipopolysaccharide-induced sepsis, dextran sodium sulfate-induced colitis, cerulein-induced pancreatitis, hypoxia-induced cerebral edema, or the major cerebral artery occlusion stroke model. However, kidney ischemia-reperfusion injury, myocardial infarction, and systemic inflammation associated with A20 deficiency or high-dose tumor necrosis factor (TNF) were ameliorated by RIPK3 deficiency. Catalytically inactive RIPK1 was also beneficial in the kidney ischemia-reperfusion injury model, the high-dose TNF model, and in A20(-/-) mice. Interestingly, MLKL deficiency offered less protection in the kidney ischemia-reperfusion injury model and no benefit in A20(-/-) mice, consistent with necroptosis-independent functions for RIPK1 and RIPK3. Combined loss of RIPK3 (or MLKL) and caspase-8 largely prevented the cytokine storm, hypothermia, and morbidity induced by TNF, suggesting that the triggering event in this model is a combination of apoptosis and necroptosis. Tissue-specific RIPK3 deletion identified intestinal epithelial cells as the major target organ. Together these data emphasize that MLKL deficiency rather than RIPK1 inactivation or RIPK3 deficiency must be examined to implicate a role for necroptosis in disease.
Graphitic overlayers on metals have commonly been considered as inhibitors for surface reactions due to their chemical inertness and physical blockage of surface active sites. In this work, however, ...we find that surface reactions, for instance, CO adsorption/desorption and CO oxidation, can take place on Pt(111) surface covered by monolayer graphene sheets. Surface science measurements combined with density functional calculations show that the graphene overlayer weakens the strong interaction between CO and Pt and, consequently, facilitates the CO oxidation with lower apparent activation energy. These results suggest that interfaces between graphitic overlayers and metal surfaces act as 2D confined nanoreactors, in which catalytic reactions are promoted. The finding contrasts with the conventional knowledge that graphitic carbon poisons a catalyst surface but opens up an avenue to enhance catalytic performance through coating of metal catalysts with controlled graphitic covers.
Significance Carbon deposits have been widely observed on metal surfaces in a variety of catalytic reactions, and the graphitic carbon species are often considered as inhibitors for surface reactions. We demonstrate here that CO adsorption and oxidation can occur on Pt surface covered by monolayer graphene, showing that the space between graphene overlayer and metal surface can act as a two-dimensional (2D) nanoreactor. Inside, CO oxidation happens with lower activation barrier due to the confinement effect of the graphene cover. This finding reminds us to reconsider the role of graphitic carbon in metal-catalyzed surface reactions and further provides a way to design novel catalysts.
Summary Background China has experienced a remarkable epidemiological and demographic transition during the past three decades. Far less is known about this transition at the subnational level. ...Timely and accurate assessment of the provincial burden of disease is needed for evidence-based priority setting at the local level in China. Methods Following the methods of the Global Burden of Disease Study 2013 (GBD 2013), we have systematically analysed all available demographic and epidemiological data sources for China at the provincial level. We developed methods to aggregate county-level surveillance data to inform provincial-level analysis, and we used local data to develop specific garbage code redistribution procedures for China. We assessed levels of and trends in all-cause mortality, causes of death, and years of life lost (YLL) in all 33 province-level administrative units in mainland China, all of which we refer to as provinces, for the years between 1990 and 2013. Findings All provinces in mainland China have made substantial strides to improve life expectancy at birth between 1990 and 2013. Increases ranged from 4·0 years in Hebei province to 14·2 years in Tibet. Improvements in female life expectancy exceeded those in male life expectancy in all provinces except Shanghai, Macao, and Hong Kong. We saw significant heterogeneity among provinces in life expectancy at birth and probability of death at ages 0–14, 15–49, and 50–74 years. Such heterogeneity is also present in cause of death structures between sexes and provinces. From 1990 to 2013, leading causes of YLLs changed substantially. In 1990, 16 of 33 provinces had lower respiratory infections or preterm birth complications as the leading causes of YLLs. 15 provinces had cerebrovascular disease and two (Hong Kong and Macao) had ischaemic heart disease. By 2013, 27 provinces had cerebrovascular disease as the leading cause, five had ischaemic heart disease, and one had lung cancer (Hong Kong). Road injuries have become a top ten cause of death in all provinces in mainland China. The most common non-communicable diseases, including ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and cancers (liver, stomach, and lung), contributed much more to YLLs in 2013 compared with 1990. Interpretation Rapid transitions are occurring across China, but the leading health problems and the challenges imposed on the health system by epidemiological and demographic change differ between groups of Chinese provinces. Localised health policies need to be implemented to tackle the diverse challenges faced by local health-care systems. Funding China National Science & Technology Pillar Program 2013 (2013BAI04B02) and Bill & Melinda Gates Foundation.
Summary Currently, osteoarthritis (OA) is considered a disease of the entire joint, which is not simply a process of wear and tear but rather abnormal remodelling and joint failure of an organ. The ...bone–cartilage interface is therefore a functioning synergistic unit, with a close physical association between subchondral bone and cartilage suggesting the existence of biochemical and molecular crosstalk across the OA interface. The crosstalk at the bone–cartilage interface may be elevated in OA in vivo and in vitro . Increased vascularisation and formation of microcracks associated with abnormal bone remodelling in joints during OA facilitate molecular transport from cartilage to bone and vice versa . Recent reports suggest that several critical signalling pathways and biological factors are key regulators and activate cellular and molecular processes in crosstalk among joint compartments. Therapeutic interventions including angiogenesis inhibitors, agonists/antagonists of molecules and drugs targeting bone remodelling are potential candidates for this interaction. This review summarised the premise for the presence of crosstalk in bone–cartilage interface as well as the current knowledge of the major signalling pathways and molecular interactions that regulate OA progression. A better understanding of crosstalk in bone–cartilage interface may lead to development of more effective strategies for treating OA patients.
seedling-vigor is important for crop establishment. There have been reported quantitative trait locus (QTL) analyses on seedling-vigor related morphological traits. However, physiological ...understanding of these detected QTLs is rather limited. In this study, we employed a recombinant inbred population to detect QTLs for seedling-vigor traits and physiological traits related to seedling-vigor. Germination rate and seedling growth were measured to quantify seedling-vigor. Total amylase activity, alpha-amylase activity, reducing sugar content, root activity and seed weight were determined. Correlations were observed between the seedling-vigor and physiological traits. QTL analysis reveals that the intervals of RG393-C1087-RZ403 on chromosome 3, C246-RM26-C1447 and R830-R3166-RG360-C734b on chromosome 5, and the interval of Waxy on chromosome 6 are the four main chromosomal regions controlling seedling-vigor. Several QTLs for amylase activities, reducing sugar content and root activity were localized in the similar regions as the QTLs for seedling-vigor. The results suggest that these traits were under the control of pleiotropic and/or closely linked QTLs. The implications of the results in the understanding of the physiological basis of seedling-vigor were discussed.
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