Search for W-Associated Production of Single Top Quarks in CMS

The production of single top quarks at the LHC provides a unique window onto the measurement of the CKM matrix element IV_tbI without assuming 3~generation unitarity. The W-associated production of single top is a challenging channel due to the large overlap in phase space with t bar t production. We have developed a ratio method to reduce the systematic uncertainties in the presence of large t bar t backgrounds. The expected uncertainties and significance for a 60~pb pp to tW production cross section with 10 fb^-1 of CMS data are presented

ATP Released by Astrocytes Mediates Glutamatergic Activity-Dependent Heterosynaptic Suppression

AbstractExtracellular ATP released from axons is known to assist activity-dependent signaling between neurons and Schwann cells in the peripheral nervous system. Here we report that ATP released from astrocytes as a result of neuronal activity can also modulate central synaptic transmission. In cultures of hippocampal neurons, endogenously released ATP tonically suppresses glutamatergic synapses via presynaptic P2Y receptors, an effect that depends on the presence of cocultured astrocytes. Glutamate release accompanying neuronal activity also activates non-NMDA receptors of nearby astrocytes and triggers ATP release from these cells, which in turn causes homo- and heterosynaptic suppression. In CA1 pyramidal neurons of hippocampal slices, a similar synaptic suppression was also produced by adenosine, an immediate degradation product of ATP released by glial cells. Thus, neuron-glia crosstalk may participate in activity-dependent synaptic modulation

Original Article Downregulation of miR-129 in peripheral blood mononuclear cells is a diagnostic and prognostic biomarker in prostate cancer

Abstract: Objective: The present study was designed to explore the clinical values of microRNA-129 (miR-129) expression in peripheral blood mononuclear cells for prostate cancer patients and the role of miR-129 in the proliferation of prostate cancer. Methods: The peripheral blood mononuclear cells were isolated form blood simple from 98 patients confirmed with prostate cancer and 56 matched healthy volunteers. Reverse transcription quantitative real-time polymerase chain reaction (qRT-PCR) was employed to determine the expression level of miR-129 in peripheral blood mononuclear cells. Cox proportional hazards regression models and Kaplan-Meier analysis were used to evaluate the association of miR-129 expression with clinical and pathological characteristics of prostate cancer patients. The effect of miR-129 on the proliferation of prostate cancer cells in vitro was also determined. Results: Reverse transcription quantitative real-time polymerase chain reaction (qRT-PCR) results showed that the expression of miR-129 was dramatically down-regulated in peripheral blood mononuclear cells for prostate cancer patients in comparison with healthy controls (P<0.05). The decrease in miR-129 expression in peripheral blood mononuclear cells was significantly associated with aggressive clinical pathological features such as histological grade (P=0.010), high preoperative PSA level (P=0.002), pathological stage (P=0.011), high Gleason score (P=0.005), lymph node metastasis (P=0.002), angiolymphatic invasion (P=0.004), biochemical recurrence (P=0.001). The prostate cancer patients with a low miR-129 expression in peripheral blood mononuclear cells had an obviously shorter BCR-free survival compared with high miR-129 expression (P<0.001). The Cox multivariate analysis established that the miR-129 expression may be an independent prognostic factor for biochemical recurrence (BCR)-free survival prostate cancer patients (P=0.000). The results of in vitro CCK-8 assays, as well as proliferating cell nuclear antigen (PCNA) and phosphorylated histone-3 (P-H3) (markers of proliferation) indicated that miR-129 overexpression markedly retarded the proliferation of PC-3 and DU-145 cells. Conclusions: Our results provide the first evidence that the miR129is significantly downregulated in prostate cancer patients and multivariate analysis confirmed that miR-129 is a novel independent prognostic factor for prostate cancer. Overexpression of miR-129 exerts tumor suppressive functions and abrogates prostate cancer growth

Cytochrome P450 3A Enzymes Are Key Contributors for Hepatic Metabolism of Bufotalin, a Natural Constitute in Chinese Medicine Chansu

Bufotalin (BFT), one of the naturally occurring bufodienolides, has multiple pharmacological and toxicological effects including antitumor activity and cardiotoxicity. This study aimed to character the metabolic pathway(s) of BFT and to identify the key drug metabolizing enzyme(s) responsible for hepatic metabolism of BFT in human, as well as to explore the related molecular mechanism of enzymatic selectivity. The major metabolite of BFT in human liver microsomes (HLMs) was fully identified as 5β-hydroxylbufotalin by LC-MS/MS and NMR techniques. Reaction phenotyping and chemical inhibition assays showed that CYP3A4 and CYP3A5 were key enzymes responsible for BFT 5β-hydroxylation. Kinetic analyses demonstrated that BFT 5β-hydroxylation in both HLMs and human CYP3A4 followed the biphasic kinetics, while BFT 5β-hydroxylation in CYP3A5 followed substrate inhibition kinetics. Furthermore, molecular docking simulations showed that BFT could bind on two different ligand-binding sites on both CYP3A4 and CYP3A5, which partially explained the different kinetic behaviors of BFT in CYP3A4 and CYP3A5. These findings are very helpful for elucidating the phase I metabolism of BFT in human and for deeper understanding the key interactions between CYP3A enzymes and bufadienolides, as well as for the development of bufadienolide-type drugs with improved pharmacokinetic and safety profiles

Characterization of mammographic masses based on level set segmentation with new image features and patient information

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/134904/1/mp0630.pd

Inhibition of Asthma in OVA Sensitized Mice Model by a Traditional Uygur Herb Nepeta bracteata

Asthma is a chronic lung inflammation which affects many people. As current therapies for asthma mainly rely on administration of glucocorticoids and have many side effects, new therapy is needed. In this study, we investigated Nepeta bracteata Benth., a traditional Uygur Herb, for its therapeutics effect in OVA induced asthmatic mice model. Treatment of OVA sensitized asthma mice with extract from Nepeta bracteata Benth. demonstrated improved lung pathology, as well as reduced infiltration of eosinophil and neutrophil. Nepeta bracteata Benth. extract also contributed to the rebalance of Th17/Treg cell via decreasing the Th17 cell and increasing the Treg, which was corresponding with the inhibited Th17 cytokine response and increased IL-10 level. Moreover, the reduced TGF-β level and Smad2/3 protein level also suggested that Nepeta bracteata Benth. extract could inhibit TGF-β mediated airway remodelling as well. Taken together, these data suggested that Nepeta bracteata Benth. may be a novel candidate for future antiasthma drug development

JAG1 is correlated to suppressive immune microenvironment and predicts immunotherapy resistance in lung adenocarcinoma

BackgroundThe current exploration of the tumor immune microenvironment is enthusiastic, but few studies explored the impact of angiogenesis on the immune microenvironment. Immunotherapy combined with anti-angiogenesis therapy has become one of the first-line treatment for lung adenocarcinoma. Our study aimed to explore the reasons for resistance of immunotherapy, and explore markers for immunotherapy combined with anti-angiogenesis therapy.MethodsFirst, by unsupervised clustering of 36 angiogenesis-related genes in lung adenocarcinoma patients from TCGA database, AGS1 and AGS2 groups were distinguished with significantly different clinical outcomes. Secondly, the immune microenvironment and metabolic characteristics were analyzed. Next, we used the GDSC and GEO database to analyze therapeutic responses. Then, through multivariate Cox regression, the hub gene: JAG1, significantly related to prognosis was selected, and further verified by multi-omics data. Finally, we validated that patient with high JAG1 expression had a low immune-infiltrating tumor microenvironment through single-cell transcriptomic data.ResultsCompared with the AGS1 group, AGS2 showed an immune “cold” phenotype with lower lymphocyte infiltration, and was associated with worse prognoses. At the same time, the immunosuppressive TGF-β response was significantly higher in AGS2. Furthermore, the glycolysis ability of the AGS2 was stronger than AGS1. The expression of JAG1 was significantly higher in the AGS2, and was significantly negatively correlated with the degree of immune infiltration, accompanying with higher glycolytic capacity. The above results indicate that patients with high expression of JAG1 may lead to immunosuppressive phenotype due to its strong glycolytic capacity, thus making immunotherapy resistance.ConclusionPatients with high expression of JAG1 enhanced glycolytic capacity was likely to cause suppressed immune microenvironment. JAG1 may be a marker for resistance of immunotherapy. Combining anti-angiogenesis therapy could be considered to improve the prognosis of those patients

Highly polarized carbon nano-architecture as robust metal-free catalyst for oxygen reduction in polymer electrolyte membrane fuel cells

The final publication is available at Elsevier via http://dx.doi.org/10.1016/j.nanoen.2018.04.021 © 2018. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/Metal-free electrocatalysts have eluded widespread adoption in polymer electrolyte membrane fuel cells due to their far inferior catalytic activity than most non-precious metal-N-C counterparts (M-Nx-C) for oxygen reduction reaction (ORR), despite their distinct advantages over the M-Nx-C catalysts, including lower cost and higher durability. Herein, we develop a rational bottom-up engineering strategy to improve the ORR performance of a metal-free catalyst by constructing a three-dimensional ultrathin N, P dual-doped carbon nanosheet. The resultant catalyst represents unprecedented ORR performance with an onset potential of 0.91 V, half-wave potential of 0.79 V. Impressively, a maximum power output at 579 mW cm−2 is generated in the fuel cell test, the best among reported metal-free catalysts and outperforms most of the M-Nx-C catalysts. The outstanding catalytic performance results from the highly active polarized carbon sites which are induced by selective graphitic nitrogen and phosphorous dual doping. Our findings provide new directions for the exploration of alternatives to Pt and bring a renew interests in the metal-free catalysts.National Natural Science Foundation of China || (21633008, 21433003, U1601211, 21733004) National Science and Technology Major Project || (2016YFB0101202) Jilin Province Science and Technology Development Program || (20150101066JC, 20160622037JC, 20170203003SF, 20170520150JH) Hundred Talents Program of Chinese Academy of Sciences and the Recruitment Program of Foreign Experts || (WQ20122200077