Four-state rock-paper-scissors games on constrained Newman-Watts networks

We study the cyclic dominance of three species in two-dimensional constrained Newman-Watts networks with a four-state variant of the rock-paper-scissors game. By limiting the maximal connection distance $R_{max}$ in Newman-Watts networks with the long-rang connection probability $p$, we depict more realistically the stochastic interactions among species within ecosystems. When we fix mobility and vary the value of $p$ or $R_{max}$, the Monte Carlo simulations show that the spiral waves grow in size, and the system becomes unstable and biodiversity is lost with increasing $p$ or $R_{max}$. These results are similar to recent results of Reichenbach \textit{et al.} [Nature (London) \textbf{448}, 1046 (2007)], in which they increase the mobility only without including long-range interactions. We compared extinctions with or without long-range connections and computed spatial correlation functions and correlation length. We conclude that long-range connections could improve the mobility of species, drastically changing their crossover to extinction and making the system more unstable.Comment: 6 pages, 7 figure

Spontaneously induced general relativity with holographic interior and general exterior

We study the spontaneously induced general relativity (GR) from the scalar-tensor gravity. We demonstrate by numerical methods that a novel inner core can be connected to the Schwarzschild exterior with cosmological constants and any sectional curvature. Deriving an analytic core metric for a general exterior, we show that all the nontrivial features of the core, including the locally holographic entropy packing, are universal for the general exterior in static spacetimes. We also investigate whether the f(R) gravity can accommodate the nontrivial core.Comment: 16 pages, 5 figures; v3: clarification improved, revised version accepted by PL

HIF-1α Contributes to Hypoxia-induced Invasion and Metastasis of Esophageal Carcinoma via Inhibiting E-cadherin and Promoting MMP-2 Expression

Hypoxia-inducible factor-1α (HIF-1α) has been found to enhance tumor invasion and metastasis, but no study has reported its action in esophageal carcinoma. The goal of this study was to explore the probable mechanism of HIF-1α in the invasion and metastasis of esophageal carcinoma Eca109 cells in vitro and in vivo. mRNA and protein expression of HIF-1α, E-cadherin and matrix metalloproteinase-2 (MMP-2) under hypoxia were detected by RT-PCR and Western blotting. The effects of silencing HIF-1α on E-cadherin, MMP-2 mRNA and protein expression under hypoxia or normoxia were detected by RT-PCR and Western blotting, respectively. The invasive ability of Eca109 cells was tested using a transwell chambers. We established an Eca109-implanted tumor model and observed tumor growth and lymph node metastasis. The expression of HIF-1α, E-cadherin and MMP-2 in xenograft tumors was detected by Western blotting. After exposure to hypoxia, HIF-1α protein was up-regulated, both mRNA and protein levels of E-cadherin were down-regulated and MMP-2 was up-regulated, while HIF-1α mRNA showed no significant change. SiRNA could block HIF-1α effectively, increase E-cadherin expression and inhibit MMP-2 expression. The number of invading cells decreased after HIF-1α was silenced. Meanwhile, the tumor volume was much smaller, and the metastatic rate of lymph nodes and the positive rate were lower in vivo. Our observations suggest that HIF-1α inhibition might be an effective strategy to weaken invasion and metastasis in the esophageal carcinoma Eca109 cell line

INK4 Tumor Suppressor Proteins Mediate Resistance to CDK4/6 Kinase Inhibitors

Proteïnes supressores de tumors; Inhibidors de la quinasaProteínas supresoras de tumores; Inhibidores de la quinasaTumor suppressor proteins; Kinase inhibitorsCyclin-dependent kinases 4 and 6 (CDK4/6) represent a major therapeutic vulnerability for breast cancer. The kinases are clinically targeted via ATP competitive inhibitors (CDK4/6i); however, drug resistance commonly emerges over time. To understand CDK4/6i resistance, we surveyed over 1,300 breast cancers and identified several genetic alterations (e.g., FAT1, PTEN, or ARID1A loss) converging on upregulation of CDK6. Mechanistically, we demonstrate CDK6 causes resistance by inducing and binding CDK inhibitor INK4 proteins (e.g., p18INK4C). In vitro binding and kinase assays together with physical modeling reveal that the p18INK4C–cyclin D–CDK6 complex occludes CDK4/6i binding while only weakly suppressing ATP binding. Suppression of INK4 expression or its binding to CDK6 restores CDK4/6i sensitivity. To overcome this constraint, we developed bifunctional degraders conjugating palbociclib with E3 ligands. Two resulting lead compounds potently degraded CDK4/6, leading to substantial antitumor effects in vivo, demonstrating the promising therapeutic potential for retargeting CDK4/6 despite CDK4/6i resistance. Significance: CDK4/6 kinase activation represents a common mechanism by which oncogenic signaling induces proliferation and is potentially targetable by ATP competitive inhibitors. We identify a CDK6–INK4 complex that is resilient to current-generation inhibitors and develop a new strategy for more effective inhibition of CDK4/6 kinases.The Chandarlapaty lab has received generous funding support for this research from the Cancer Couch Foundation, the Shen Family Fund, the Smith Fund for Cancer Research, the Breast Cancer Research Foundation, an NIH Cancer Center Support Grant (P30 CA008748), and NIH R01234361. Q. Li has received support from Translational Research Oncology Training Fellowship (MSKCC) made possible by the generous contribution of First Eagle Investment Management. V. Serra reports grants from the Susan G. Komen Foundation (CCR15330331) and Instituto de Salud Carlos III (CPII19/00033) during the conduct of the study and grants from Novartis, Genentech, and AstraZeneca outside the submitted work. The Chodera laboratory receives or has received funding from multiple sources, including the NIH and an NIH Cancer Center Support Grant (P30 CA008748), the National Science Foundation, the Parker Institute for Cancer Immunotherapy, Relay Therapeutics, Entasis Therapeutics, Silicon Therapeutics, EMD Serono (Merck KGaA), AstraZeneca, Vir Biotechnology, Bayer, XtalPi, Foresite Laboratories, the Molecular Sciences Software Institute, the Starr Cancer Consortium, the Open Force Field Consortium, Cycle for Survival, a Louis V. Gerstner Young Investigator Award, and the Sloan Kettering Institute. J. Guo acknowledges support from NIH grant R01 GM121505. J.D. Chodera acknowledges support from NIH grant P30 CA008748, NIH grant R01 GM121505, and NIH grant R01 GM132386. A complete funding history for the Chodera lab can be found at http://choderalab.org/funding, including complete funding information and grant numbers. The authors thank Dr. Marie Will and Madeline Dorso for helpful comments on the manuscript and Dr. Zhan Yao for helpful advice on the kinase assays

A younger Universe implied by satellite pair correlations from SDSS observations of massive galaxy groups

Many of the satellites of galactic-mass systems such as the Miky Way, Andromeda and Centaurus A show evidence of coherent motions to a larger extent than most of the systems predicted by the standard cosmological model. It is an open question if correlations in satellite orbits are present in systems of different masses. Here , we report an analysis of the kinematics of satellite galaxies around massive galaxy groups. Unlike what is seen in Milky Way analogues, we find an excess of diametrically opposed pairs of satellites that have line-of-sight velocity offsets from the central galaxy of the same sign. This corresponds to a $\pmb{6.0\sigma}$ ($\pmb{p}$-value $\pmb{=\ 9.9\times10^{-10}}$) detection of non-random satellite motions. Such excess is predicted by up-to-date cosmological simulations but the magnitude of the effect is considerably lower than in observations. The observational data is discrepant at the$\pmb{4.1\sigma}$and$\pmb{3.6\sigma}$ level with the expectations of the Millennium and the Illustris TNG300 cosmological simulations, potentially indicating that massive galaxy groups assembled later in the real Universe. The detection of velocity correlations of satellite galaxies and tension with theoretical predictions is robust against changes in sample selection. Using the largest sample to date, our findings demonstrate that the motions of satellite galaxies represent a challenge to the current cosmological model.Comment: 28 pages, 9 figures, accepted for publication in Nature Astronom

Flow Cytometry and K-mer Analysis Estimates of the Genome Sizes of \u3cem\u3eBemisia tabaci\u3c/em\u3e B and Q (Hemiptera: Aleyrodidae)

The genome sizes of the B- and Q-types of the whitefly Bemisia tabaci (Gennnadius) were estimated using flow cytometry (Drosophila melanogaster as the DNA reference standard and propidium iodide (PI) as the fluorochrome) and k-mer analysis. For flow cytometry, the mean nuclear DNA content was 0.686 pg for B-type males, 1.392 pg for B-type females, 0.680 pg for Q-type males, and 1.306 pg for Q-type females. Based on the relationship between DNA content and genome size (1 pg DNA = 980 Mbp), the haploid genome size of B. tabaci ranged from 640 to 682 Mbp. For k-mer analysis, genome size of B-type by two methods were consistent highly, but the k-mer depth distribution graph of Q-type was not enough perfect and the genome size was estimated about 60 M larger than its flow cytometry result. These results corroborate previous reports of genome size based on karyotype analysis and chromosome counting. However, these estimates differ from previous flow cytometry estimates, probably because of differences in the DNA reference standard and dyeing time, which were superior in the current study. For Q-type genome size difference by two method, some discussion were also stated, and all these results represent a useful foundation for B. tabaci genomics research