Summary Pyruvate kinase isoform M2 (PKM2) is a glycolysis enzyme catalyzing conversion of phosphoenolpyruvate (PEP) to pyruvate with transferring a phosphate from PEP to ADP. We report here that PKM2 localizes to the cell nucleus. The levels of nuclear PKM2 correlate with cell proliferation. PKM2 activates transcription of MEK5 by phosphorylating stat3 at Y705. In vitro phosphorylation assays show that PKM2 is a protein kinase using PEP as phosphate donor. ADP competes with the protein substrate binding, indicating that the substrate may bind to the ADP site of PKM2. Our experiments suggest that PKM2 dimer is an active protein kinase, while the tetramer is an active pyruvate kinase. Expression a PKM2 mutant that exists as a dimer promotes cell proliferation, indicating that protein kinase activity of PKM2 plays a role in promoting cell proliferation. Our study reveals an important link between metabolism alteration and gene expression during tumor transformation and progression.

Although a multitude of promising anti-cancer drugs have been developed over the past 50 years, effective delivery of the drugs to diseased cells remains a challenge. Recently, nanoparticles have been used as drug delivery vehicles due to their high delivery efficiencies and the possibility to circumvent cellular drug resistance. However, the lack of biocompatibility and inability to engineer spatially addressable surfaces for multi-functional activity remains an obstacle to their widespread use. Here we present a novel drug carrier system based on self-assembled, spatially addressable DNA origami nanostructures that confronts these limitations. Doxorubicin, a well-known anti-cancer drug, was noncovalently attached to DNA origami nanostructures through intercalation. A high level of drug loading efficiency was achieved, and the complex exhibited prominent cytotoxicity not only to regular human breast adenocarcinoma cancer cells (MCF 7), but more importantly to doxorubicin-resistant cancer cells, inducing a remarkable reversal of phenotype resistance. With the DNA origami drug delivery vehicles, the cellular internalization of doxorubicin was increased, which contributed to the significant enhancement of cell-killing activity to doxorubicin-resistant MCF 7 cells. Presumably, the activity of doxorubicin-loaded DNA origami inhibits lysosomal acidification, resulting in cellular redistribution of the drug to action sites. Our results suggest that DNA origami has immense potential as an efficient, biocompatible drug carrier and delivery vehicle in the treatment of cancer.

The Large sky Area Multi-Object Fiber Spectroscopic Telescope (LAMOST) general survey is a spectroscopic survey that will eventually cover approximately half of the celestial sphere and collect 10 million spectra of stars, galaxies and QSOs. Objects in both the pilot survey and the first year regular survey are included in the LAMOST DR1. The pilot survey started in October 2011 and ended in June 2012, and the data have been released to the public as the LAMOST Pilot Data Release in August 2012. The regular survey started in September 2012, and completed its first year of operation in June 2013. The LAMOST DR1 includes a total of 1202 plates containing 2 955 336 spectra, of which 1 790 879 spectra have observed signalto-noise ratio (SNR) ≥ 10. All data with SNR ≥ 2 are formally released as LAMOST DR1 under the LAMOST data policy. This data release contains a total of 2 204 696 spectra, of which 1 944 329 are stellar spectra, 12 082 are galaxy spectra and 5017 are quasars. The DR1 not only includes spectra, but also three stellar catalogs with measured parameters: late A,FGK-type stars with high quality spectra (1 061 918 entries), A-type stars (100 073 entries), and M-type stars (121 522 entries). This paper introduces the survey design, the observational and instrumental limitations, data reduction and analysis, and some caveats. A description of the FITS structure of spectral files and parameter catalogs is also provided.

Using the "standard pair" technique of paring stars of almost nil and high extinction but otherwise of almost identical stellar parameters from the Sloan Digital Sky Survey (SDSS), and combing the SDSS, Galaxy Evolution Explore (GALEX), Two Micro All Sky Survey (2MASS) and Wide-field Infrared Survey Explorer (WISE) photometry ranging from the far ultraviolet (UV) to the mid-infrared (mid-IR), we have measured dust reddening in theH − Ks, Ks − W 1 and W 1 − W 2 colors for thousands of Galactic stars. The measurements, together with the E(B − V ) values given by Schlegel et al. (1998), allow us to derive the observed, model-free reddening coefficients for those colors. The results are compared with previous measurements and the predictions of a variety of Galactic reddening laws. We find that 1) The dust reddening map of Schlegel et al. (1998) over-estimates E(B − V ) by about 14 per cent, consistent with the recent work of Schlafly et al. (2010) and Schlafly & Finkbeiner (2011); 2) After accounted for the differences in reddening normalization, the newly deduced reddening coefficients for colors F U V − N U V, N U V − u, u − g, g − r, r − i, i − z, z − J, J − H and H − Ks differ by respectively −1640%, 15.5%, 12.6%, −0.8%, 3.4%, −0.7%, 3.5%, 2.5% and 1.4% from the predictions of Fitzpatrick reddening law (Fitzpatrick 1999) for an assumed total-to-selective extinction ratio R(V ) = 3.1, and by respectively −1730%, 13.0%, 8.1%, 10.0%, 8.0%, −13.5%, −1.7%, −6.7% and −17.1% from the predictions of CCM reddening law (Cardelli et al. 1989); and 3) All the new reddening coefficients, except those for N U V − u and u − g, prefer the R(V ) = 3.1 Fitzpatrick reddening law rather than the R(V ) = 3.1 CCM and O'Donnell (O'Donnell 1994) reddening laws. Using the Ks-band extinction coefficient predicted by the R(V ) = 3.1 Fitzpatrick law and the observed reddening coefficients, we have deduced new extinction coefficients for the F U V, N U V, u, g, r, i, z, J, H, W 1 and W 2 passbands. We recommend that the new reddening and extinction coefficients should be used in the future and an update of the Fitzpatrick reddening law in the UV is probably necessary. We stress however that the F U V -and N U V -band coefficients should be used with caution given their relatively large measurement uncertainties. Finally, potential applications of the "standard pair" technique with the LAMOST Galactic surveys are discussed.

Background —Antiphospholipid (aPL) antibodies are associated with thrombosis in patients diagnosed with antiphospholipid syndrome (APS) and enhance thrombus formation in vivo in mice, but the mechanism of thrombosis by aPL is not completely understood. Although aPL antibodies have been shown to inhibit protein C activation and activate endothelial cells (ECs) in vitro, no study has examined whether these antibodies activate ECs in vivo. Therefore, human affinity-purified aPL (ap aPL) antibodies from APS patients were tested in a mouse model of microcirculation using the cremaster muscle that allows direct microscopic examination of thrombus formation and adhesion of white blood cells (WBCs) to ECs as an indication of EC activation in vivo. Adhesion molecule expression on human umbilical vein endothelial cells (HUVECs) after aPL exposure was performed to confirm EC activation in vitro. Methods and Results —All 6 ap aPL antibodies significantly increased the expression of VCAM-1 (2.3- to 4.4-fold), with one of the antibodies also increasing the expression of E-selectin (1.6-fold) on HUVECs in vitro. In the in vivo experiments, each ap aPL antibody except for 1 preparation increased WBC sticking (mean number of WBCs ranged from 22.7 to 50.6) compared with control (14.4), which correlated with enhanced thrombus formation (mean thrombus size ranged from 1098 to 6476 versus 594 μm 2 for control). Conclusions —Activation of ECs by aPL antibodies in vivo may create a prothrombotic state on ECs, which may be the first pathophysiological event of thrombosis in APS.

Macrophages are important tumor-infiltrating cells and play pivotal roles in tumor growth and metastasis. Macrophages participate in immune responses to tumors in a polarized manner: classic M1 macrophages produce interleukin (IL) 12 to promote tumoricidal responses, whereas M2 macrophages produce IL10 and help tumor progression. The mechanisms governing macrophage polarization are unclear. Here, we show that the M2-like tumor-associated macrophages (TAM) have a lower level of Notch pathway activation in mouse tumor models. Forced activation of Notch signaling increased M1 macrophages which produce IL12, no matter whether M1 or M2 inducers were applied. When Notch signaling was blocked, the M1 inducers induced M2 response in the expense of M1. Macrophages deficient in canonical Notch signaling showed TAM phenotypes. Forced activation of Notch signaling in macrophages enhanced their antitumor capacity. We further show that RBP-J-mediated Notch signaling regulates the M1 versus M2 polarization through SOCS3. Therefore, Notch signaling plays critical roles in the determination of M1 versus M2 polarization of macrophages, and compromised Notch pathway activation will lead to the M2-like TAMs. These results provide new insights into the molecular mechanisms of macrophage polarization and shed light on new therapies for cancers through the modulation of macrophage polarization through the Notch signaling. Cancer Res; 70(12); 4840-9. ©2010 AACR.

Mucin-type O-linked oligosaccharides (O-glycans) are primary components of the intestinal mucins thatform the mucus gel layer overlying the gut epithelium. Impaired expression of intestinal O-glycans has been observed in patients with ulcerative colitis (UC), but its role in the etiology of this disease is unknown. Here, we report that mice with intestinal epithelial cell-specific deficiency of core 1-derived O-glycans, the predominant form of O-glycans, developed spontaneous colitis that resembled human UC, including massive myeloid infiltrates and crypt abscesses. The colitis manifested in these mice was also characterized by TNF-producing myeloid infiltrates in colon mucosa in the absence of lymphocytes, supporting an essential role for myeloid cells in colitis initiation. Furthermore, induced deletion of intestinal core 1-derived O-glycans caused spontaneous colitis in adult mice. These data indicate a causal role for the loss of core 1-derived O-glycans in colitis. Finally, we detected a biosynthetic intermediate typically exposed in the absence of core 1 O-glycan, Tn antigen, in the colon epithelium of a subset of UC patients. Somatic mutations in the X-linked gene that encodes core 1 β1,3-galactosyltransferase-specific chaperone 1 (C1GALT1C1, also known as Cosmc), which is essential for core 1 O-glycosylation, were found in Tn-positive epithelia. These data suggest what we believe to be a new molecular mechanism for the pathogenesis of UC.

Safe and effective vaccines offer the best intervention for disease control. One strategy to maximize vaccine immunogenicity without compromising safety is to rationally design molecular complexes that mimic the natural structure of immunogenic microbes, but without the disease-causing components. Here we use highly programmable DNA nanostructures as platforms to assemble a model antigen and CpG adjuvants together into nanoscale complexes with precise control of the valency and spatial arrangement of each element. Our results from immunized mice show that compared to a mixture of antigen and CpG molecules, the assembled antigen-adjuvant-DNA complexes induce strong and long-lasting antibody responses against the antigen without stimulating a reaction to the DNA nanostructure itself. This result demonstrates the potential of DNA nanostructures to serve as general platforms for the rational design and construction of a variety of vaccines.