Identification of Important Regulators of Colon Cancer Tumorigenesis By Functional Screening

TGFβ signaling is an important regulator in colon cancer. miRNAs regulate TGFβ signaling at multiple levels. In this study, through a functional screening, we identified miR-487b-3p and miR-656-3p, which modulate TGFβ effect in colon cancer cells. Further studies revealed that GRM3 and VGLUT3 are their respective targets. GRM3, a Metabotropic glutamate receptor in glutamatergic pathway is significantly upregulated in majority of human colonic adenocarcinomas tested and colon cancer cell lines. Knockdown of GRM3 expression or inhibition of GRM3 activation in colon cancer cells reduces cell survival and anchorage-independent growth in vitro and inhibits tumor growth in vivo. Mechanistically, GRM3 antagonizes TGFβ-mediated activation of protein kinase A and inhibition of AKT. In addition, TGFβ signaling increases GRM3 protein stability and knockdown of GRM3 enhances TGFβ-mediated tumor suppressor function. Since miR-487b-3p directly targets GRM3, overexpression of miR-487b-3p mimics the effects of GRM3 knockdown in vitro and in vivo. Expression of miR-487b-3p is decreased in colon adenocarcinomas and inversely correlates with GRM3 expression. VGLUT3, a vesicular glutamate transporter, is also markedly upregulated in human colonic adenocarcinomas and colon cancer cell lines. Knockdown of VGLUT3 expression in colon cancer cells reduces cell survival and anchorage-independent growth in vitro and inhibits tumor growth in vivo. Mechanistically, VGLUT3 antagonizes TGFβ-mediated suppression of cell survival and clonogenicity by maintaining AKT activation. MiR-656-3p represses VGLUT3 expression and mimics the effects of VGLUT3 knockdown in vitro and in vivo. Moreover, expression of miR-656-3p is decreased in colon cancer specimens and inversely correlates with VGLUT3 expression. This is particularly interesting and important from a therapeutic standpoint because numerous glutamatergic signaling inhibitor, many of which have been found unsuitable for treatment of neuropsychiatric disorders for reasons such as inability to readily penetrate blood brain barriers. Since GRM3 and VGLUT3 are upregulated in colon cancer, but rarely expressed in normal peripheral tissues, targeting GRM3 and VGLUT3 with such agents would not likely cause adverse neurological or peripheral side effects, making them attractive and specific molecular targets for colon cancer treatment

Non-Hermitian skin effect in a spin-orbit-coupled Bose-Einstein condensate

We study a Bose-Einstein condensate of ultracold atoms subject to a non-Hermitian spin-orbit coupling, where the system acquires non-Hermitian skin effect under the interplay of spin-orbit coupling and laser-induced atom loss. The presence of the non-Hermitian skin effect is confirmed through its key signatures in term of the spectral winding under the periodic boundary condition, the accumulation of eigen wavefunctions at boundaries under an open boundary condition, as well as bulk dynamics signaled by a directional flow. We show that the bulk dynamics in particular serves as a convenient signal for experimental detection. The impact of interaction and trapping potentials are also discussed based on non-Hermitian Gross-Pitaevskii equations. Our work demonstrates that the non-Hermitian skin effect and its rich implications in topology, dynamics and beyond are well within reach of current cold-atom experiments.Comment: 6 pages, 4 figure

Many-body non-Hermitian skin effect under dynamic gauge coupling

We study an atom-cavity hybrid system where fermionic atoms in a one-dimensional lattice are subject to a cavity-induced dynamic gauge potential. The gauge coupling leads to highly-degenerate steady states in which the fermions accumulate to one edge of the lattice under an open boundary condition. Such a phenomenon originates from the many-body Liouvillian superoperator of the system, which, being intrinsically non-Hermitian, is unstable against boundary perturbations and manifests the non-Hermitian skin effect. Contrary to the single-body case, the steady state of a multi-atom system is approached much slower under the open boundary condition, as the long-time damping of the cavity mode exhibits distinct rates at different times. This stage-wise slowdown is attributed to the competition between light-assisted hopping and the dynamic gauge coupling, which significantly reduces the steady-state degeneracy under the open boundary condition, as distinct hosts of quasi-steady states dominate the dynamics at different time scales.Comment: 13 pages, 7 figure

Engineering Non-Hermitian Skin Effect with Band Topology in Ultracold Gases

Non-Hermitian skin effect(NHSE) describes a unique non-Hermitian phenomenon that all eigen-modes are localized near the boundary, and has profound impact on a wide range of bulk properties. In particular, topological systems with NHSE have stimulated extensive research interests recently, given the fresh theoretical and experimental challenges therein. Here we propose a readily implementable scheme for achieving NHSE with band topology in ultracold gases. Specifically, the scheme realizes the one-dimensional optical Raman lattice with two types of spin-orbit coupling (SOC) and an additional laser-induced dissipation. By tuning the dissipation and the SOC strengths, NHSE and band topology can be individually controlled such that they can coexist in a considerable parameter regime. To identify the topological phase in the presence of NHSE, we have restored the bulk-boundary correspondence by invoking the non-Bloch band theory, and discussed the dynamic signals for detection. Our work serves as a guideline for engineering topological lattices with NHSE in the highly tunable environment of cold atoms, paving the way for future studies of exotic non-Hermitian physics in a genuine quantum many-body setting.Comment: 9+4 pages, 5+6 figure

Adaptive Safety Evaluation for Connected and Automated Vehicles with Sparse Control Variates

Safety performance evaluation is critical for developing and deploying connected and automated vehicles (CAVs). One prevailing way is to design testing scenarios using prior knowledge of CAVs, test CAVs in these scenarios, and then evaluate their safety performances. However, significant differences between CAVs and prior knowledge could severely reduce the evaluation efficiency. Towards addressing this issue, most existing studies focus on the adaptive design of testing scenarios during the CAV testing process, but so far they cannot be applied to high-dimensional scenarios. In this paper, we focus on the adaptive safety performance evaluation by leveraging the testing results, after the CAV testing process. It can significantly improve the evaluation efficiency and be applied to high-dimensional scenarios. Specifically, instead of directly evaluating the unknown quantity (e.g., crash rates) of CAV safety performances, we evaluate the differences between the unknown quantity and known quantity (i.e., control variates). By leveraging the testing results, the control variates could be well designed and optimized such that the differences are close to zero, so the evaluation variance could be dramatically reduced for different CAVs. To handle the high-dimensional scenarios, we propose the sparse control variates method, where the control variates are designed only for the sparse and critical variables of scenarios. According to the number of critical variables in each scenario, the control variates are stratified into strata and optimized within each stratum using multiple linear regression techniques. We justify the proposed method's effectiveness by rigorous theoretical analysis and empirical study of high-dimensional overtaking scenarios

Irreversible proliferation of magnetic moments at cleaved surfaces of the topological Kondo insulator SmB6

The compound SmB$_6$ is the best established realization of a topological Kondo insulator, in which a topological insulator state is obtained through Kondo coherence. Recent studies have found evidence that the surface of SmB$_6$ hosts ferromagnetic domains, creating an intrinsic platform for unidirectional ballistic transport at the domain boundaries. Here, surface-sensitive X-ray absorption (XAS) and bulk-sensitive resonant inelastic X-ray scattering (RIXS) spectra are measured at the Sm N$_{4,5}$-edge, and used to evaluate electronic symmetries, excitations and temperature dependence near the surface of cleaved samples. The XAS data show that the density of large-moment atomic multiplet states on a cleaved surface grows irreversibly over time, to a degree that likely exceeds a related change that has recently been observed in the surface 4f orbital occupation