Cancer Associated Fibroblasts Promote Tumor Growth and Metastasis by Modulating the Tumor Immune Microenvironment in a 4T1 Murine Breast Cancer Model

BACKGROUND:Local inflammation associated with solid tumors commonly results from factors released by tumor cells and the tumor stroma, and promotes tumor progression. Cancer associated fibroblasts comprise a majority of the cells found in tumor stroma and are appealing targets for cancer therapy. Here, our aim was to determine the efficacy of targeting cancer associated fibroblasts for the treatment of metastatic breast cancer. METHODOLOGY/PRINCIPAL FINDINGS:We demonstrate that cancer associated fibroblasts are key modulators of immune polarization in the tumor microenvironment of a 4T1 murine model of metastatic breast cancer. Elimination of cancer associated fibroblasts in vivo by a DNA vaccine targeted to fibroblast activation protein results in a shift of the immune microenvironment from a Th2 to Th1 polarization. This shift is characterized by increased protein expression of IL-2 and IL-7, suppressed recruitment of tumor-associated macrophages, myeloid derived suppressor cells, T regulatory cells, and decreased tumor angiogenesis and lymphangiogenesis. Additionally, the vaccine improved anti-metastatic effects of doxorubicin chemotherapy and enhanced suppression of IL-6 and IL-4 protein expression while increasing recruitment of dendritic cells and CD8(+) T cells. Treatment with the combination therapy also reduced tumor-associated Vegf, Pdgfc, and GM-CSF mRNA and protein expression. CONCLUSIONS/SIGNIFICANCE:Our findings demonstrate that cancer associated fibroblasts promote tumor growth and metastasis through their role as key modulators of immune polarization in the tumor microenvironment and are valid targets for therapy of metastatic breast cancer

Finding and proving the exact ground state of a generalized Ising model by convex optimization and MAX-SAT

This paper was supported primarily by the US Department of Energy (DOE) under Contract No. DE-FG02-96ER45571. In addition, some of the test cases for ground states were supported by the Office of Naval Research under contract N00014-14-1-0444.Lattice models, also known as generalized Ising models or cluster expansions, are widely used in many areas of science and are routinely applied to the study of alloy thermodynamics, solid-solid phase transitions, magnetic and thermal properties of solids, fluid mechanics, and others. However, the problem of finding and proving the global ground state of a lattice model, which is essential for all of the aforementioned applications, has remained unresolved for relatively complex practical systems, with only a limited number of results for highly simplified systems known. In this paper, we present a practical and general algorithm that provides a provable periodically constrained ground state of a complex lattice model up to a given unit cell size and in many cases is able to prove global optimality over all other choices of unit cell. We transform the infinite-discrete-optimization problem into a pair of combinatorial optimization (MAX-SAT) and nonsmooth convex optimization (MAX-MIN) problems, which provide upper and lower bounds on the ground state energy, respectively. By systematically converging these bounds to each other, we may find and prove the exact ground state of realistic Hamiltonians whose exact solutions are difficult, if not impossible, to obtain via traditional methods. Considering that currently such practical Hamiltonians are solved using simulated annealing and genetic algorithms that are often unable to find the true global energy minimum and inherently cannot prove the optimality of their result, our paper opens the door to resolving longstanding uncertainties in lattice models of physical phenomena. An implementation of the algorithm is available at https://github.com/dkitch/maxsat-isingPublisher PDFPeer reviewe

Automatic Determination of Stellar Atmospheric Parameters and Construction of Stellar Spectral Templates of the Guoshoujing Telescope (LAMOST)

A number of spectroscopic surveys have been carried out or are planned to study the origin of the Milky Way. Their exploitation requires reliable automated methods and softwares to measure the fundamental parameters of the stars. Adopting the ULySS package, we have tested the effect of different resolutions and signal-to-noise ratios (SNR) on the measurement of the stellar atmospheric parameters (effective temperature Teff, surface gravity log g, and metallicity [Fe/H]). We show that ULySS is reliable to determine these parameters with medium-resolution spectra (R~2000). Then, we applied the method to measure the parameters of 771 stars selected in the commissioning database of the Guoshoujing Telescope (GSJT). The results were compared with the SDSS/SEGUE Stellar Parameter Pipeline (SSPP), and we derived precisions of 167 K, 0.34 dex, and 0.16 dex for Teff, log g and [Fe/H] respectively. Furthermore, 120 of these stars are selected to construct the primary stellar spectra template library (Version 1.0) of GSJT, and will be deployed as basic ingredients for the GSJT automated parametrization pipeline.Comment: 23 pages, 15 figures, accepted by RA

PAI-1 Exacerbates White Adipose Tissue Dysfunction and Metabolic Dysregulation in High Fat Diet-Induced Obesity

Background: Plasminogen activator inhibitor (PAI)-1 levels and activity are known to increase during metabolic syndrome and obesity. In addition, previous studies have implicated PAI-1 in adipose tissue (AT) expansion while also contributing to insulin resistance. As inflammation is also known to occur in AT during obesity, we hypothesized that in a high-fat diet (HFD)-induced obese mouse model PAI-1 contributes to macrophage-mediated inflammation and metabolic dysfunction.Methods: Four- to five-weeks-old male C57B6/6J mice were fed a HFD (45%) for 14 weeks, while age-matched control mice were fed a standard laboratory chow diet (10% fat). Additional studies were performed in PAI-1 knockout mice and wild type mice treated with an inhibitor (PAI-039) of PAI-1. Macrophage polarization were measured by real time PCR.Results: HFD mice showed increased expression of PAI-1 in visceral white AT (WAT) that also displayed increased macrophage numbers. PAI-1 deficient mice exhibited increased numbers of anti-inflammatory macrophages in WAT and were resistant to HFD-induced obesity. Similarly, pharmacological inhibition of PAI-1 using PAI-039 significantly decreased macrophage infiltration in WAT and improved metabolic status in HFD-induced wild-type mice. Importantly, the numbers of M1 macrophages appeared to be increased by the HFD and decreased by either genetic PAI-1 depletion or PAI-039 treatment.Conclusions: Collectively, our findings provide support for PAI-1 contributing to the development of inflammation in adipose tissue and explain the mechanism of inflammation modulated by PAI-1 in the disordered metabolism in HFD-induced obesity

Reduced nitrogenase efficiency dominates response of the globally important nitrogen fixer Trichodesmium to ocean acidification

工业革命以来，海洋吸收了约三分之一人为排放的CO2，以迄今3亿年来最快的速度酸化（CO2升高、pH下降），这势必影响海洋生态系统的关键过程和功能。研究团队创新性地从区分海洋酸化过程中CO2上升和pH下降的双重效应入手，揭示了海水CO2升高的正效应小于pH下降的负效应，故酸化的净效应为抑制束毛藻的固氮作用。这是因为酸化引起束毛藻胞质 pH下降，从而降低固氮酶效率、干扰胞内pH稳态、影响细胞产能。在上述研究工作的基础上，进一步系统地测定了固氮和光合系统蛋白的表达量及其含铁量，建立了一个束毛藻的“资源最优化分配”细胞模型。实现了实验数据和数值模型的紧密结合：实验数据是构筑模型的坚实基础，并提高了模型的预测水平；通过模型模拟，加深了对实验发现的认知，并对实验结论进行了时空拓展。 罗亚威博士和史大林博士为论文的共同第一作者和共同通讯作者，史大林课题组的洪海征教授、研究助理沈容和博士生张福婷为共同作者。论文的共同作者还包括美国佛罗里达州立大学助理教授Sven Kranz博士和乔治亚大学副教授Brian Hopkinson博士。【Abstract】The response of the prominent marine dinitrogen (N2)-fixing cyanobacteria Trichodesmium to ocean acidification (OA) is critical to understanding future oceanic biogeochemical cycles. Recent studies have reported conflicting findings on the effect of OA on growth and N2 fixation of Trichodesmium. Here, we quantitatively analyzed experimental data on how Trichodesmium reallocated intracellular iron and energy among key cellular processes in response to OA, and integrated the findings to construct an optimality-based cellular model. The model results indicate that Trichodesmium growth rate decreases under OA primarily due to reduced nitrogenase efficiency. The downregulation of the carbon dioxide (CO2)-concentrating mechanism under OA has little impact on Trichodesmium, and the energy demand of anti-stress responses to OA has a moderate negative effect. We predict that if anthropogenic CO2 emissions continue to rise, OA could reduce global N2 fixation potential of Trichodesmium by 27% in this century, with the largest decrease in iron-limiting regions.This work was funded by the National Key R&D Program of China (2016YFA0601404 and 2016YFA0601203), NSFC (41476093, 41721005, 41890802, 31861143022 and 41376116), and the MEL internal research fund (MELRI1502).本项研究得到了国家重点研发计划（2016YFA0601404 和2016YFA0601203）以及国家自然科学基金系列项目（41476093, 41721005, 41890802, 31861143022 和41376116）的资助

Sediment Provenance of the Nansha Trough Since 40 ka B.P. in the South China Sea: Evidence From δ13Corg, TOC and Pollen Composition

Geochemical proxies in organic matter (OM) are considered to be reliable proxies for deciphering types of paleo-vegetation (C3 plants and C4 plants) and their abundance. The contributions of total organic carbon (TOC), stable carbon isotopes (δ13Corg), total nitrogen (TN) and organic carbon to total nitrogen ratios (C/N) were obtained from a gravity core NS07-25 (6°39.945′ N, 113°32.936′ E, water depth 2006 m), extracted from the southern South China Sea (SCS). These data were used to reconstruct the climate changes of the Nansha Trough since 40 ka B.P. by comparing them with pollen data from the same core, and this comparison provides better sediment provenance details in the study area. During the periods between 37 and 27 ka, and from 12.5 ka to modern day, the majority of terrestrial sediment received from Borneo, and some climatic events have been governed by aeolian fluxes from mid-latitude areas (mainland China). These periods were relatively humid, compared to 27–12.5 ka, where the majority of terrestrial sediment came from the Sunda Shelf through riverine pathways. This study serves as the first study to correlate deep oceanic pollen and geochemical proxies in order to identify the weaken terrestrial OM signals in the deep ocean

Identification of blood biomarkers of rheumatoid arthritis by transcript profiling of peripheral blood mononuclear cells from the rat collagen-induced arthritis model

Rheumatoid arthritis (RA) is a chronic debilitating autoimmune disease that results in joint destruction and subsequent loss of function. To better understand its pathogenesis and to facilitate the search for novel RA therapeutics, we profiled the rat model of collagen-induced arthritis (CIA) to discover and characterize blood biomarkers for RA. Peripheral blood mononuclear cells (PBMCs) were purified using a Ficoll gradient at various time points after type II collagen immunization for RNA preparation. Total RNA was processed for a microarray analysis using Affymetrix GeneChip technology. Statistical comparison analyses identified differentially expressed genes that distinguished CIA from control rats. Clustering analyses indicated that gene expression patterns correlated with laboratory indices of disease progression. A set of 28 probe sets showed significant differences in expression between blood from arthritic rats and that from controls at the earliest time after induction, and the difference persisted for the entire time course. Gene Ontology comparison of the present study with previous published murine microarray studies showed conserved Biological Processes during disease induction between the local joint and PBMC responses. Genes known to be involved in autoimmune response and arthritis, such as those encoding Galectin-3, Versican, and Socs3, were identified and validated by quantitative TaqMan RT-PCR analysis using independent blood samples. Finally, immunoblot analysis confirmed that Galectin-3 was secreted over time in plasma as well as in supernatant of cultured tissue synoviocytes of the arthritic rats, which is consistent with disease progression. Our data indicate that gene expression in PBMCs from the CIA model can be utilized to identify candidate blood biomarkers for RA

Anion Redox Chemistry in the Cobalt Free 3d Transition Metal Oxide Intercalation Electrode Li[Li0.2_{0.2}Ni0.2_{0.2}Mn0.6_{0.6}]O2_2

Conventional intercalation cathodes for lithium batteries store charge in redox reactions associated with the transition metal cations, e.g., Mn3+/4+ in LiMn2O4, and this limits the energy storage of Li-ion batteries. Compounds such as Li[Li0.2Ni0.2Mn0.6]O2 exhibit a capacity to store charge in excess of the transition metal redox reactions. The additional capacity occurs at and above 4.5 V versus Li+/Li. The capacity at 4.5 V is dominated by oxidation of the O2– anions accounting for ?0.43 e–/formula unit, with an additional 0.06 e–/formula unit being associated with O loss from the lattice. In contrast, the capacity above 4.5 V is mainly O loss, ?0.08 e–/formula. The O redox reaction involves the formation of localized hole states on O during charge, which are located on O coordinated by (Mn4+/Li+). The results have been obtained by combining operando electrochemical mass spec on 18O labeled Li[Li0.2Ni0.2Mn0.6]O2 with XANES, soft X-ray spectroscopy, resonant inelastic X-ray spectroscopy, and Raman spectroscopy. Finally the general features of O redox are described with discussion about the role of comparatively ionic (less covalent) 3d metal–oxygen interaction on anion redox in lithium rich cathode materials

The LAMOST Complete Spectroscopic Survey of Pointing Area (LaCoSSPAr) in the Southern Galactic Cap I. The Spectroscopic Redshift Catalog

We present a spectroscopic redshift catalog from the LAMOST Complete Spectroscopic Survey of Pointing Area (LaCoSSPAr) in the Southern Galactic Cap (SGC), which is designed to observe all sources (Galactic and extra-galactic) by using repeating observations with a limiting magnitude of $r=18.1~mag$ in two $20~deg^2$ fields. The project is mainly focusing on the completeness of LAMOST ExtraGAlactic Surveys (LEGAS) in the SGC, the deficiencies of source selection methods and the basic performance parameters of LAMOST telescope. In both fields, more than 95% of galaxies have been observed. A post-processing has been applied to LAMOST 1D spectrum to remove the majority of remaining sky background residuals. More than 10,000 spectra have been visually inspected to measure the redshift by using combinations of different emission/absorption features with uncertainty of $\sigma_{z}/(1+z)<0.001$. In total, there are 1528 redshifts (623 absorption and 905 emission line galaxies) in Field A and 1570 redshifts (569 absorption and 1001 emission line galaxies) in Field B have been measured. The results show that it is possible to derive redshift from low SNR galaxies with our post-processing and visual inspection. Our analysis also indicates that up to 1/4 of the input targets for a typical extra-galactic spectroscopic survey might be unreliable. The multi-wavelength data analysis shows that the majority of mid-infrared-detected absorption (91.3%) and emission line galaxies (93.3%) can be well separated by an empirical criterion of $W2-W3=2.4$. Meanwhile, a fainter sequence paralleled to the main population of galaxies has been witnessed both in $M_r$/$W2-W3$ and $M_*$/$W2-W3$ diagrams, which could be the population of luminous dwarf galaxies but contaminated by the edge-on/highly inclined galaxies ($\sim30\%$).Comment: 19 pages, 14 figures, 2 MRT, accepted by ApJ