Tissue specific induction of p62/sqstm1 by farnesoid X receptor

Background: Farnesoid X Receptor (FXR) is a member of the nuclear receptor superfamily and is a ligand-activated transcription factor essential for maintaining liver and intestinal homeostasis. FXR is protective against carcinogenesis and inflammation in liver and intestine as demonstrated by the development of inflammation and tumors in the liver and intestine of FXR knock-out mice. However, mechanisms for the protective effects of FXR are not completely understood. This study reports a novel role of FXR in regulating expression of Sqstm1, which encodes for p62 protein. p62 plays an important role in maintaining cellular homeostasis through selective autophagy and activating signal transduction pathways, such as NF-κB to support cell survival and caspase-8 to initiate apoptosis. FXR regulation of Sqstm1 may serve as a protective mechanism. Methods and Results: This study showed that FXR bound to the Sqstm1 gene in both mouse livers and ileums as determined by chromatin immunoprecipitation. In addition, FXR activation enhanced transcriptional activation of Sqstm1 in vitro. However, wild-type mice treated with GW4064, a synthetic FXR ligand, showed that FXR activation induced mRNA and protein expression of Sqstm1/p62 in ileum, but not in liver. Interestingly, FXR-transgenic mice showed induced mRNA expression of Sqstm1 in both liver and ileum compared to wild-type mice. Conclusions: Our current study has identified a novel role of FXR in regulating the expression of p62, a key factor in protein degradation and cell signaling. Regulation of p62 by FXR indicates tissue-specific and gene-dosage effects. Furthermore, FXR-mediated induction of p62 may implicate a protective mechanism of FXR. © 2012 Williams et al

Entanglement, subsystem particle numbers and topology in free fermion systems

We study the relationship between bipartite entanglement, subsystem particle number and topology in a half-filled free fermion system. It is proposed that the spin-projected particle numbers can distinguish the quantum spin Hall state from other states, and can be used to establish a new topological index for the system. Furthermore, we apply the new topological invariant to a disordered system and show that a topological phase transition occurs when the disorder strength is increased beyond a critical value. It is also shown that the subsystem particle number fluctuation displays behavior very similar to that of the entanglement entropy. This provides a lower-bound estimation for the entanglement entropy, which can be utilized to obtain an estimate of the entanglement entropy experimentally.Comment: 14 pages, 6 figure

Extraordinary quasiparticle scattering and bandwidth-control by dopants in iron-based superconductors

The diversities in crystal structures and ways of doping result in extremely diversified phase diagrams for iron-based superconductors. With angle-resolved photoemission spectroscopy (ARPES), we have systematically studied the effects of chemical substitution on the electronic structure of various series of iron-based superconductors. In addition to the control of Fermi surface topology by heterovalent doping, we found two more extraordinary effects of doping: 1. the site and band dependencies of quasiparticle scattering; and more importantly 2. the ubiquitous and significant bandwidth-control by both isovalent and heterovalent dopants in the iron-anion layer. Moreover, we found that the bandwidth-control could be achieved by either applying the chemical pressure or doping electrons, but not by doping holes. Together with other findings provided here, these results complete the microscopic picture of the electronic effects of dopants, which facilitates a unified understanding of the diversified phase diagrams and resolutions to many open issues of various iron-based superconductors.Comment: 12 pages, 9 figure

Full one-loop QCD and electroweak corrections to sfermion pair production in γγ\gamma \gamma collisions

We have calculated the full one-loop electroweak (EW) and QCD corrections to the third generation scalar-fermion pair production processes $e^+e^- \to \gamma \gamma \to \tilde{f_i}\bar{\tilde{f_i}} (f=t,b,\tau)$ at an electron-positron linear collider(LC) in the minimal supersymmetric standard model (MSSM). We analyze the dependence of the radiative corrections on the parameters such as the colliding energy $\sqrt{\hat s}$ and the SUSY fundamental parameters $A_f$, $\tan \beta$, $\mu$, $M_{SUSY}$ and so forth. The numerical results show that the EW corrections to the squark-, stau-pair production processes and QCD corrections to the squark-pair production processes give substantial contributions in some parameter space. The EW relative corrections to squark-pair production processes can be comparable with QCD corrections at high energies. Therefore, these EW and QCD corrections cannot be neglected in precise measurement of sfermion pair productions via $\gamma\gamma$ collision at future linear colliders.Comment: to be appeared in Phys. Rev.

Offline Pre-trained Multi-agent Decision Transformer

Offline reinforcement learning leverages previously collected offline datasets to learn optimal policies with no necessity to access the real environment. Such a paradigm is also desirable for multi-agent reinforcement learning (MARL) tasks, given the combinatorially increased interactions among agents and with the environment. However, in MARL, the paradigm of offline pre-training with online fine-tuning has not been studied, nor even datasets or benchmarks for offline MARL research are available. In this paper, we facilitate the research by providing large-scale datasets and using them to examine the usage of the decision transformer in the context of MARL. We investigate the generalization of MARL offline pre-training in the following three aspects: 1) between single agents and multiple agents, 2) from offline pretraining to online fine tuning, and 3) to that of multiple downstream tasks with few-shot and zero-shot capabilities. We start by introducing the first offline MARL dataset with diverse quality levels based on the StarCraftII environment, and then propose the novel architecture of multi-agent decision transformer (MADT) for effective offline learning. MADT leverages the transformer’s modelling ability for sequence modelling and integrates it seamlessly with both offline and online MARL tasks. A significant benefit of MADT is that it learns generalizable policies that can transfer between different types of agents under different task scenarios. On the StarCraft II offline dataset, MADT outperforms the state-of-the-art offline reinforcement learning (RL) baselines, including BCQ and CQL. When applied to online tasks, the pre-trained MADT significantly improves sample efficiency and enjoys strong performance in both few-short and zero-shot cases. To the best of our knowledge, this is the first work that studies and demonstrates the effectiveness of offline pre-trained models in terms of sample efficiency and generalizability enhancements for MARL

Integral equation method for the electromagnetic wave propagation in stratified anisotropic dielectric-magnetic materials

We investigate the propagation of electromagnetic waves in stratified anisotropic dielectric-magnetic materials using the integral equation method (IEM). Based on the superposition principle, we use Hertz vector formulations of radiated fields to study the interaction of wave with matter. We derive in a new way the dispersion relation, Snell's law and reflection/transmission coefficients by self-consistent analyses. Moreover, we find two new forms of the generalized extinction theorem. Applying the IEM, we investigate the wave propagation through a slab and disclose the underlying physics which are further verified by numerical simulations. The results lead to a unified framework of the IEM for the propagation of wave incident either from a medium or vacuum in stratified dielectric-magnetic materials.Comment: 14pages, 3figure

Superconductivity up to 30 K in the vicinity of quantum critical point in BaFe2_{2}(As1−x_{1-x}Px_{x})2_{2}

We report bulk superconductivity induced by an isovalent doping of phosphorus in BaFe$_{2}$(As$_{1-x}$P$_{x}$)$_{2}$. The P-for-As substitution results in shrinkage of lattice, especially for the FeAs block layers. The resistivity anomaly associated with the spin-density-wave (SDW) transition in the undoped compound is gradually suppressed by the P doping. Superconductivity with the maximum $T_c$ of 30 K emerges at $x$=0.32, coinciding with a magnetic quantum critical point (QCP) which is evidenced by the disappearance of SDW order and the linear temperature-dependent resistivity in the normal state. The $T_c$ values were found to decrease with further P doping, and no superconductivity was observed down to 2 K for $x\geq$ 0.77. The appearance of superconductivity in the vicinity of QCP hints to the superconductivity mechanism in iron-based arsenides.Comment: 9 pages, 4 figures; more data; to appear in Journal of Physics: Condensed Matte

TGLI1 transcription factor mediates breast cancer brain metastasis via activating metastasis-initiating cancer stem cells and astrocytes in the tumor microenvironment

Mechanisms for breast cancer metastasis remain unclear. Whether truncated glioma-associated oncogene homolog 1 (TGLI1), a transcription factor known to promote angiogenesis, migration and invasion, plays any role in metastasis of any tumor type has never been investigated. In this study, results of two mouse models of breast cancer metastasis showed that ectopic expression of TGLI1, but not GLI1, promoted preferential metastasis to the brain. Conversely, selective TGLI1 knockdown using antisense oligonucleotides led to decreased breast cancer brain metastasis (BCBM) in vivo. Immunohistochemical staining showed that TGLI1, but not GLI1, was increased in lymph node metastases compared to matched primary tumors, and that TGLI1 was expressed at higher levels in BCBM specimens compared to primary tumors. TGLI1 activation is associated with a shortened time to develop BCBM and enriched in HER2-enriched and triple-negative breast cancers. Radioresistant BCBM cell lines and specimens expressed higher levels of TGLI1, but not GLI1, than radiosensitive counterparts. Since cancer stem cells (CSCs) are radioresistant and metastasis-initiating cells, we examined TGLI1 for its involvement in breast CSCs and found TGLI1 to transcriptionally activate stemness genes CD44, Nanog, Sox2, and OCT4 leading to CSC renewal, and TGLI1 outcompetes with GLI1 for binding to target promoters. We next examined whether astrocyte-priming underlies TGLI1-mediated brain tropism and found that TGLI1-positive CSCs strongly activated and interacted with astrocytes in vitro and in vivo. These findings demonstrate, for the first time, that TGLI1 mediates breast cancer metastasis to the brain, in part, through promoting metastasis-initiating CSCs and activating astrocytes in BCBM microenvironment

Adipocytes Activate Mitochondrial Fatty Acid Oxidation and Autophagy to Promote Tumor Growth in Colon Cancer

Obesity has been associated with increased incidence and mortality of a wide variety of human cancers including colorectal cancer. However, the molecular mechanism by which adipocytes regulate the metabolism of colon cancer cells remains elusive. In this study, we showed that adipocytes isolated from adipose tissues of colon cancer patients have an important role in modulating cellular metabolism to support tumor growth and survival. Abundant adipocytes were found in close association with invasive tumor cells in colon cancer patients. Co-culture of adipocytes with colon cancer cells led to a transfer of free fatty acids that released from the adipocytes to the cancer cells. Uptake of fatty acids allowed the cancer cells to survive nutrient deprivation conditions by upregulating mitochondrial fatty acid β-oxidation. Mechanistically, co-culture of adipocytes or treating cells with fatty acids induced autophagy in colon cancer cells as a result of AMPK activation. Inhibition of autophagy attenuated the ability of cancer cells to utilize fatty acids and blocked the growth-promoting effect of adipocytes. In addition, we found that adipocytes stimulated the expression of genes associated with cancer stem cells and downregulated genes associated with intestinal epithelial cell differentiation in primary colon cancer cells and mouse tumor organoids. Importantly, the presence of adipocytes promoted the growth of xenograft tumors in vivo. Taken together, our results show that adipocytes in the tumor microenvironment serve as an energy provider and a metabolic regulator to promote the growth and survival of colon cancer cells

The Scurfy mutation of FoxP3 in the thymus stroma leads to defective thymopoiesis

The Scurfy mutation of the FoxP3 gene (FoxP3sf) in the mouse and analogous mutations in human result in lethal autoimmunity. The mutation of FoxP3 in the hematopoietic cells impairs the development of regulatory T cells. In addition, development of the Scurfy disease also may require mutation of the gene in nonhematopoietic cells. The T cell–extrinsic function of FoxP3 has not been characterized. Here we show that the FoxP3sf mutation leads to defective thymopoiesis, which is caused by inactivation of FoxP3 in the thymic stromal cells. FoxP3 mutation also results in overexpression of ErbB2 in the thymic stroma, which may be involved in defective thymopoiesis. Our data reveal a novel T cell–extrinsic function of FoxP3. In combination, the T cell–intrinsic and –extrinsic defects provide plausible explanation for the severity of the autoimmune diseases in the scurfy mice and in patients who have immunodysregulation, polyendocrinopathy, enteropathy, and X-linked syndrome