16 research outputs found
A High Intrinsic Peculiarity Rate Among Type Ia Supernovae
We have compiled a sample of 45 Type Ia supernovae (SNe Ia) discovered by the
Lick Observatory Supernova Search (LOSS) and the Beijing Astronomical
Observatory Supernova Survey (BAOSS), and determined the rate of
spectroscopically peculiar SNe Ia (i.e., SN 1986G-like, SN 1991bg-like, and SN
1991T-like objects) and the luminosity function of SNe Ia. Because of the
nature of the two surveys (distance-limited with small baselines and deep
limiting magnitudes), nearly all SNe Ia have been discovered in the sample
galaxies of LOSS and BAOSS; thus, the observed peculiarity rate and luminosity
function of SNe Ia are intrinsic. We find that 369% of nearby SNe Ia are
peculiar; specifically, the luminosity function of SNe Ia consists of 20% SN
1991T-like, 64% normal, and 16% SN 1991bg-like objects. We have compared our
results to those found by earlier studies, and to those found at high redshift.
The apparent dearth of SN 1991T-like objects at high redshift may be due to
extinction, and especially to the difficulty of recognizing them from spectra
obtained past maximum brightness or from spectra with low signal-to-noise
ratios. Implications of the high peculiarity rate for the progenitor systems of
SNe Ia are also briefly discussed.Comment: 20 pages, 7 figures, accepted for publication in the Ap
Shear-induced Notch-Cx37-p27 axis arrests endothelial cell cycle to enable arterial specification
Establishment of a functional vascular network is rate-limiting in embryonic development, tissue repair and engineering. During blood vessel formation, newly generated endothelial cells rapidly expand into primitive plexi that undergo vascular remodeling into circulatory networks, requiring coordinated growth inhibition and arterial-venous specification. Whether the mechanisms controlling endothelial cell cycle arrest and acquisition of specialized phenotypes are interdependent is unknown. Here we demonstrate that fluid shear stress, at arterial flow magnitudes, maximally activates NOTCH signaling, which upregulates GJA4 (commonly, Cx37) and downstream cell cycle inhibitor CDKN1B (p27). Blockade of any of these steps causes hyperproliferation and loss of arterial specification. Re-expression of GJA4 or CDKN1B, or chemical cell cycle inhibition, restores endothelial growth control and arterial gene expression. Thus, we elucidate a mechanochemical pathway in which arterial shear activates a NOTCH-GJA4-CDKN1B axis that promotes endothelial cell cycle arrest to enable arterial gene expression. These insights will guide vascular regeneration and engineering
Combining radiation and the ATR inhibitor berzosertib activates STING signaling and enhances immunotherapy via inhibiting SHP1 function in colorectal cancer
Abstract Background Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PDâ1) and programmed deathâligand 1 (PDâL1) have shown a moderate response in colorectal cancer (CRC) with deficient mismatch repair (dMMR) functions and poor response in patients with proficient MMR (pMMR). pMMR tumors are generally immunogenically âcoldâ, emphasizing combination strategies to turn the âcoldâ tumor âhotâ to enhance the efficacy of ICIs. ATR inhibitors (ATRi) have been proven to cooperate with radiation to promote antitumor immunity, but it is unclear whether ATRi could facilitate the efficacy of IR and ICI combinations in CRCs. This study aimed to investigate the efficacy of combining ATRi, irradiation (IR), and antiâPDâL1 antibodies in CRC mouse models with different microsatellite statuses. Methods The efficacy of combining ATRi, IR, and antiâPDâL1 antibodies was evaluated in CRC tumors. The tumor microenvironment and transcriptome signatures were investigated under different treatment regimens. The mechanisms were explored via cell viability assay, flow cytometry, immunofluorescence, immunoblotting, coâimmunoprecipitation, and realâtime quantitative PCR in multiple murine and human CRC cell lines. Results Combining ATRi berzosertib and IR enhanced CD8+T cell infiltration and enhanced the efficacy of antiâPDâL1 therapy in mouse CRC models with different microsatellite statuses. The mechanistic study demonstrated that IR + ATRi could activate both the canonical cGASâSTINGâpTBK1/pIRF3 axis by increasing cytosolic doubleâstranded DNA levels and the nonâcanonical STING signaling by attenuating SHP1âmediated inhibition of the TRAF6âSTINGâp65 axis, via promoting SUMOylation of SHP1 at lysine 127. By boosting the STING signaling, IR + ATRi induced type I interferonârelated gene expression and strong innate immune activation and reinvigorated the cold tumor microenvironment, thus facilitating immunotherapy. Conclusions The combination of ATRi and IR could facilitate antiâPDâL1 therapy by promoting STING signaling in CRC models with different microsatellite statuses. The new combination strategy raised by our study is worth investigating in the management of CRC
Endothelial nitric oxide synthase is not necessary for the early phase of ischemic preconditioning in the mouse
Pharmacological inhibition of LSD1 suppresses growth of hepatocellular carcinoma by inducing GADD45B
Abstract Lysineâspecific histone demethylase 1 (LSD1) is an attractive target for malignancies therapy. Nevertheless, its role in hepatocellular carcinoma (HCC) progression and the potential of its inhibitor in HCC therapy remains unclear. Here, we show that LSD1 overexpression in human HCC tissues is associated with HCC progression and poor patient survival. ZY0511, a highly selective and potent inhibitor of LSD1, suppressed human HCC cell proliferation in vitro and tumor growth in cellâderived and patientâderived HCC xenograft models in vivo. Mechanistically, ZY0511 induced mRNA expression of growth arrest and DNA damageâinducible gene 45beta (GADD45B) by inducing histone H3 at lysine 4 (H3K4) methylation at the promoter of GADD45B, a novel target gene of LSD1. In human HCC tissues, LSD1 level was correlated with a decreased level of GADD45B, which was associated with HCC progression and predicted poor patient survival. Moreover, coâadministration of ZY0511 and DTP3, which specifically enhanced the proâapoptotic effect of GADD45B, effectively inhibited HCC cell proliferation both in vitro and in vivo. Collectively, our study revealed the potential value of LSD1 as a promising target of HCC therapy. ZY0511 is a promising candidate for HCC therapy through upregulating GADD45B, thereby providing a novel combinatorial strategy for treating HCC
High-fat diet-induced upregulation of exosomal phosphatidylcholine contributes to insulin resistance
High-fat diet plays a role in development of insulin resistance. Here, the authors report a mechanism that underlies the development of diet induced insulin resistance through the activation of an aryl hydrocarbon receptor mediated signalling pathway in the liver by faecal exosomes derived from intestinal cells