GPER-induced signaling is essential for the survival of breast cancer stem cells.

G protein-coupled estrogen receptor-1 (GPER), a member of the G protein-coupled receptor (GPCR) superfamily, mediates estrogen-induced proliferation of normal and malignant breast epithelial cells. However, its role in breast cancer stem cells (BCSCs) remains unclear. Here we showed greater expression of GPER in BCSCs than non-BCSCs of three patient-derived xenografts of ER- /PR+ breast cancers. GPER silencing reduced stemness features of BCSCs as reflected by reduced mammosphere forming capacity in vitro, and tumor growth in vivo with decreased BCSC populations. Comparative phosphoproteomics revealed greater GPER-mediated PKA/BAD signaling in BCSCs. Activation of GPER by its ligands, including tamoxifen (TMX), induced phosphorylation of PKA and BAD-Ser118 to sustain BCSC characteristics. Transfection with a dominant-negative mutant BAD (Ser118Ala) led to reduced cell survival. Taken together, GPER and its downstream signaling play a key role in maintaining the stemness of BCSCs, suggesting that GPER is a potential therapeutic target for eradicating BCSCs

FAM129B, an antioxidative protein, reduces chemosensitivity by competing with Nrf2 for Keap1 binding.

BackgroundThe transcription factor Nrf2 is a master regulator of antioxidant response. While Nrf2 activation may counter increasing oxidative stress in aging, its activation in cancer can promote cancer progression and metastasis, and confer resistance to chemotherapy and radiotherapy. Thus, Nrf2 has been considered as a key pharmacological target. Unfortunately, there are no specific Nrf2 inhibitors for therapeutic application. Moreover, high Nrf2 activity in many tumors without Keap1 or Nrf2 mutations suggests that alternative mechanisms of Nrf2 regulation exist.MethodsInteraction of FAM129B with Keap1 is demonstrated by immunofluorescence, colocalization, co-immunoprecipitation and mammalian two-hybrid assay. Antioxidative function of FAM129B is analyzed by measuring ROS levels with DCF/flow cytometry, Nrf2 activation using luciferase reporter assay and determination of downstream gene expression by qPCR and wester blotting. Impact of FAM129B on in vivo chemosensitivity is examined in mice bearing breast and colon cancer xenografts. The clinical relevance of FAM129B is assessed by qPCR in breast cancer samples and data mining of publicly available databases.FindingsWe have demonstrated that FAM129B in cancer promotes Nrf2 activity by reducing its ubiquitination through competition with Nrf2 for Keap1 binding via its DLG and ETGE motifs. In addition, FAM129B reduces chemosensitivity by augmenting Nrf2 antioxidative signaling and confers poor prognosis in breast and lung cancer.InterpretationThese findings demonstrate the important role of FAM129B in Nrf2 activation and antioxidative response, and identify FMA129B as a potential therapeutic target. FUND: The Chang Gung Medical Foundation (Taiwan) and the Ministry of Science and Technology (Taiwan)

Learning Deep Latent Spaces for Multi-Label Classification

Multi-label classification is a practical yet challenging task in machine learning related fields, since it requires the prediction of more than one label category for each input instance. We propose a novel deep neural networks (DNN) based model, Canonical Correlated AutoEncoder (C2AE), for solving this task. Aiming at better relating feature and label domain data for improved classification, we uniquely perform joint feature and label embedding by deriving a deep latent space, followed by the introduction of label-correlation sensitive loss function for recovering the predicted label outputs. Our C2AE is achieved by integrating the DNN architectures of canonical correlation analysis and autoencoder, which allows end-to-end learning and prediction with the ability to exploit label dependency. Moreover, our C2AE can be easily extended to address the learning problem with missing labels. Our experiments on multiple datasets with different scales confirm the effectiveness and robustness of our proposed method, which is shown to perform favorably against state-of-the-art methods for multi-label classification.Comment: published in AAAI-201

Speech Dereverberation Based on Integrated Deep and Ensemble Learning Algorithm

Reverberation, which is generally caused by sound reflections from walls, ceilings, and floors, can result in severe performance degradation of acoustic applications. Due to a complicated combination of attenuation and time-delay effects, the reverberation property is difficult to characterize, and it remains a challenging task to effectively retrieve the anechoic speech signals from reverberation ones. In the present study, we proposed a novel integrated deep and ensemble learning algorithm (IDEA) for speech dereverberation. The IDEA consists of offline and online phases. In the offline phase, we train multiple dereverberation models, each aiming to precisely dereverb speech signals in a particular acoustic environment; then a unified fusion function is estimated that aims to integrate the information of multiple dereverberation models. In the online phase, an input utterance is first processed by each of the dereverberation models. The outputs of all models are integrated accordingly to generate the final anechoic signal. We evaluated the IDEA on designed acoustic environments, including both matched and mismatched conditions of the training and testing data. Experimental results confirm that the proposed IDEA outperforms single deep-neural-network-based dereverberation model with the same model architecture and training data

Structural insights into the gating of DNA passage by the topoisomerase II DNA-gate.

Type IIA topoisomerases (Top2s) manipulate the handedness of DNA crossovers by introducing a transient and protein-linked double-strand break in one DNA duplex, termed the DNA-gate, whose opening allows another DNA segment to be transported through to change the DNA topology. Despite the central importance of this gate-opening event to Top2 function, the DNA-gate in all reported structures of Top2-DNA complexes is in the closed state. Here we present the crystal structure of a human Top2 DNA-gate in an open conformation, which not only reveals structural characteristics of its DNA-conducting path, but also uncovers unexpected yet functionally significant conformational changes associated with gate-opening. This structure further implicates Top2's preference for a left-handed DNA braid and allows the construction of a model representing the initial entry of another DNA duplex into the DNA-gate. Steered molecular dynamics calculations suggests the Top2-catalyzed DNA passage may be achieved by a rocker-switch-type movement of the DNA-gate

Searching for Moving Objects in HSC-SSP: Pipeline and Preliminary Results

The Hyper Suprime-Cam Subaru Strategic Program (HSC-SSP) is currently the deepest wide- field survey in progress. The 8.2 m aperture of Subaru telescope is very powerful in detect- ing faint/small moving objects, including near-Earth objects, asteroids, centaurs and Tran- Neptunian objects (TNOs). However, the cadence and dithering pattern of the HSC-SSP are not designed for detecting moving objects, making it difficult to do so systematically. In this paper, we introduce a new pipeline for detecting moving objects (specifically TNOs) in a non-dedicated survey. The HSC-SSP catalogs are re-arranged into the HEALPix architecture. Then, the stationary detections and false positive are removed with a machine learning al- gorithm to produce a list of moving object candidates. An orbit linking algorithm and visual inspections are executed to generate the final list of detected TNOs. The preliminary results of a search for TNOs using this new pipeline on data from the first HSC-SSP data release (Mar 2014 to Nov 2015) are also presented.Comment: 32 pages, 10 figures, 2 tables, submitted to HSC special issue in PAS

Electromagnetic induced transparency and slow light in interacting quantum degenerate atomic gases

We systematically develop the full quantum theory for the electromagnetic induced transparency (EIT) and slow light properties in ultracold Bose and Fermi gases. It shows a very different property from the classical theory which assumes frozen atomic motion. For example, the speed of light inside the atomic gases can be changed dramatically near the Bose-Einstein condensation temperature, while the presence of the Fermi sea can destroy the EIT effect even at zero temperature. From experimental point of view, such quantum EIT property is mostly manifested in the counter-propagating excitation schemes in either the low-lying Rydberg transition with a narrow line width or in the D2 transitions with a very weak coupling field. We further investigate the interaction effects on the EIT for a weakly interacting Bose-Einstein condensate, showing an inhomogeneous broadening of the EIT profile and nontrivial change of the light speed due to the quantum many-body effects beyond mean field energy shifts.Comment: 7 figure