We describe a stream-based analysis pipeline to detect gravitational waves from the merger of binary neutron stars, binary black holes, and neutron-star–black-hole binaries within ∼1 min of the ...arrival of the merger signal at Earth. Such low-latency detection is crucial for the prompt response by electromagnetic facilities in order to observe any fading electromagnetic counterparts that might be produced by mergers involving at least one neutron star. Even for systems expected not to produce counterparts, low-latency analysis of the data is useful for deciding when not to point telescopes, and as feedback to observatory operations. Analysts using this pipeline were the first to identify GW151226, the second gravitational-wave event ever detected. The pipeline also operates in an offline mode, in which it incorporates more refined information about data quality and employs acausal methods that are inapplicable to the online mode. The pipeline’s offline mode was used in the detection of the first two gravitational-wave events, GW150914 and GW151226, as well as the identification of a third candidate, LVT151012.
We describe a search underway for periodic gravitational waves from the central compact object in the supernova remnant Cassiopeia A. The object is the youngest likely neutron star in the Galaxy. Its ...position is well known, but the object does not pulse in any electromagnetic radiation band and thus presents a challenge in searching the parameter space of frequency and frequency derivatives. We estimate that a fully coherent search can, with a reasonable amount of time on a computing cluster, achieve a sensitivity at which it is theoretically possible (though not likely) to observe a signal even with the initial LIGO noise spectrum. Cassiopeia A is only the second object after the Crab pulsar for which this is true. The search method described here can also obtain interesting results for similar objects with current LIGO sensitivity.
Osteosarcoma (OS) is the most frequent pediatric malignant bone tumor that has a high propensity for metastases. Through osteoblast-specific alteration of p53 status, we developed a genetically ...engineered mouse model of localized and metastatic OS to gain an understanding into the molecular pathogenesis of OS. Microarray analysis of both localized tumors and metastatic tumors identified the downregulation of the naked cuticle homolog 2 (NKD2) gene, a negative regulator of Wnt signaling. Overexpression of NKD2 in metastatic human and mouse OS cells significantly decreases cell proliferation, migration and invasion ability in vitro and drastically diminishes OS tumor growth and metastasis in vivo, whereas downregulation enhances migratory and invasive potential. Evaluation of NKD2-overexpressing tumors revealed upregulation of tumor-suppressor genes and downregulation of molecules involved in blood vessel formation and cell migration. Furthermore, assessment of primary human OS revealed downregulation of NKD2 in metastatic and recurrent OS. Finally, we provide biological evidence that use of small-molecule inhibitors targeting the Wnt pathway can have therapeutic efficacy in decreasing metastatic properties in OS. Our studies provide compelling evidence that downregulation of NKD2 expression and alterations in associated regulated pathways have a significant role in driving OS tumor growth and metastasis.
We evaluate the cost‐of‐reproduction hypothesis in the burying beetleNicrophorus orbicollisand examine how the importance of this trade‐off changes as females age (i.e., the terminal‐investment ...hypothesis). These beetles breed on small vertebrate carcasses, which serve as a food resource for them and their offspring. Consistent with the cost‐of‐reproduction hypothesis, females manipulated to overproduce offspring suffered a reduction in fecundity and life span when compared to controls, although all reproducing females had reduced life spans compared to nonbreeding females. Older females produced larger broods and allocated less of the carcass to their own body mass and a greater proportion to offspring than did younger females. Resource allocation to offspring increased with age. Females given larger carcasses invested more in current reproduction and less in future reproduction than did females given smaller carcasses. Our results provide unconfounded support for both the cost‐of‐reproduction hypothesis (i.e., current reproduction constrains future reproductive output) and the terminal‐investment hypothesis (i.e., the importance of the trade‐off between current and future reproduction declines with age such that allocation to current reproduction should increase as females age).
Vascular endothelial growth factor-A (VEGF), a potent angiogenic factor, is also implicated in self-renewal in several normal tissue types. VEGF has been shown to drive malignant stem cells but ...mechanisms thereof and tumor types affected are not fully characterized. Here, we show VEGF promotes breast and lung cancer stem cell (CSC) self-renewal via VEGF receptor-2 (VEGFR-2)/STAT3-mediated upregulation of Myc and Sox2. VEGF increased tumor spheres and aldehyde dehydrogenase activity, both proxies for stem cell function in vitro, in triple-negative breast cancer (TNBC) lines and dissociated primary cancers, and in lung cancer lines. VEGF exposure before injection increased breast cancer-initiating cell abundance in vivo yielding increased orthotopic tumors, and increased metastasis from orthotopic primaries and following tail vein injection without further VEGF treatment. VEGF rapidly stimulated VEGFR-2/JAK2/STAT3 binding and activated STAT3 to bind MYC and SOX2 promoters and induce their expression. VEGFR-2 knockdown or inhibition abrogated VEGF-mediated STAT3 activation, MYC and SOX2 induction and sphere formation. Notably, knockdown of either STAT3, MYC or SOX2 impaired VEGF-upregulation of pSTAT3, MYC and SOX2 expression and sphere formation. Each transcription factor, once upregulated, appears to promote sustained activation of the others, creating a feed-forward loop to drive self-renewal. Thus, in addition to angiogenic effects, VEGF promotes tumor-initiating cell self-renewal through VEGFR-2/STAT3 signaling. Analysis of primary breast and lung cancers (>1300 each) showed high VEGF expression, was prognostic of poor outcome and strongly associated with STAT3 and MYC expression, supporting the link between VEGF and CSC self-renewal. High-VEGF tumors may be most likely to escape anti-angiogenics by upregulating VEGF, driving CSC self-renewal to re-populate post-treatment. Our work highlights the need to better define VEGF-driven cancer subsets and supports further investigation of combined therapeutic blockade of VEGF or VEGFR-2 and JAK2/STAT3.
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