Interplay between positive and negative activities that influence the role of Bicoid in transcription

The Drosophila mophogenetic protein Bicoid (Bcd) can activate transcription in a concentration-dependent manner in embryos. It contains a self-inhibitory domain that can interact with the co-repressor Sin3A. In this report, we study a Bcd mutant, Bcd(A57–61), which has a strengthened self-inhibitory function and is unable to activate the hb-CAT reporter in Drosophila cells, to analyze the role of co-factors in regulating Bcd function. We show that increased concentrations of the co-activator dCBP in cells can switch this protein from its inactive state to an active state on the hb-CAT reporter. The C-terminal portion of Bcd(A57–61) is required to mediate such activity-rescuing function of dCBP. Although capable of binding to DNA in vitro, Bcd(A57–61) is unable to access the hb enhancer element in cells, suggesting that its DNA binding defect is only manifested in a cellular context. Increased concentrations of dCBP restore not only the ability of Bcd(A57–61) to access the hb enhancer element in cells but also the occupancy of the general transcription factors TBP and TFIIB at the reporter promoter. These and other results suggest that an activator can undergo switches between its active and inactive states through sensing the opposing actions of positive and negative co-factors

MicroRNA-300 inhibits the metastasis of prostate cancer through the regulation of TRIM63

Purpose: To investigate the role of microRNA-300 in the tumorigenesis of prostate cancer (PCa), and the relationship between microRNA-300 level and clinical data of PCa patients.Methods: MicroRNA-300 levels in 63 matched PCa and adjacent tissues were determined via quantitative real-time polymerase chain reaction (qRT-PCR). The relationship between microRNA-300 level and the clinical profile of PCa patients was assessed. PCa cell phenotypes influenced by microRNA-300 were evaluated by a series of functional experiments, including CCK-8, colony formation, Transwell and wound healing assays. The role of microRNA-300/TRIM63 axis in the development of PCa was also examined.Results: MicroRNA-300 was more lowly expressed in PCa tissues than in adjacent normal tissues. PCa patients expressing lower levels of microRNA-300 had a higher Gleason score, higher rates of lymphatic metastasis and distant metastasis, and lower survival. Overexpression of microRNA-300 suppressed its proliferative and metastatic potential. Dual-luciferase reporter assay data confirmed that microRNA-300 specifically binds Tripartite Motif-containing Protein 63 (TRIM63). TRIM63 level was downregulated in PCa cells overexpressing microRNA-300.  Moreover, overexpression of TRIM63 abolished the role of microRNA-300 in influencing PCa cell phenotypes.Conclusion: MicroRNA-300 is downregulated in PCa. Its level is related to Gleason score, lymphatic metastasis, distant metastasis and poor prognosis of PCa patients. MicroRNA-300 stimulates proliferative and metastatic abilities in PCa cells by targeting TRIM63. This study may provide new targets for the development of new therapeutics for of PCa as well as its diagnosis

Robust Visual Question Answering: Datasets, Methods, and Future Challenges

Visual question answering requires a system to provide an accurate natural language answer given an image and a natural language question. However, it is widely recognized that previous generic VQA methods often exhibit a tendency to memorize biases present in the training data rather than learning proper behaviors, such as grounding images before predicting answers. Therefore, these methods usually achieve high in-distribution but poor out-of-distribution performance. In recent years, various datasets and debiasing methods have been proposed to evaluate and enhance the VQA robustness, respectively. This paper provides the first comprehensive survey focused on this emerging fashion. Specifically, we first provide an overview of the development process of datasets from in-distribution and out-of-distribution perspectives. Then, we examine the evaluation metrics employed by these datasets. Thirdly, we propose a typology that presents the development process, similarities and differences, robustness comparison, and technical features of existing debiasing methods. Furthermore, we analyze and discuss the robustness of representative vision-and-language pre-training models on VQA. Finally, through a thorough review of the available literature and experimental analysis, we discuss the key areas for future research from various viewpoints.Comment: IEEE TPAMI (Under Review

Adaptive loose optimization for robust question answering

Question answering methods are well-known for leveraging data bias, such as the language prior in visual question answering and the position bias in machine reading comprehension (extractive question answering). Current debiasing methods often come at the cost of significant in-distribution performance to achieve favorable out-of-distribution generalizability, while non-debiasing methods sacrifice a considerable amount of out-of-distribution performance in order to obtain high in-distribution performance. Therefore, it is challenging for them to deal with the complicated changing real-world situations. In this paper, we propose a simple yet effective novel loss function with adaptive loose optimization, which seeks to make the best of both worlds for question answering. Our main technical contribution is to reduce the loss adaptively according to the ratio between the previous and current optimization state on mini-batch training data. This loose optimization can be used to prevent non-debiasing methods from overlearning data bias while enabling debiasing methods to maintain slight bias learning. Experiments on the visual question answering datasets, including VQA v2, VQA-CP v1, VQA-CP v2, GQA-OOD, and the extractive question answering dataset SQuAD demonstrate that our approach enables QA methods to obtain state-of-the-art in- and out-of-distribution performance in most cases. The source code has been released publicly in \url{https://github.com/reml-group/ALO}.Comment: 13 pages,8 figure

Estrogen regulation of TRPM8 expression in breast cancer cells

<p>Abstract</p> <p>Background</p> <p>The calcium-permeable cation channel TRPM8 (melastatin-related transient receptor potential member 8) is over-expressed in several cancers. The present study aimed at investigating the expression, function and potential regulation of TRPM8 channels by ER alpha (estrogen receptor alpha) in breast cancer.</p> <p>Methods</p> <p>RT-PCR, Western blot, immuno-histochemical, and siRNA techniques were used to investigate TRPM8 expression, its regulation by estrogen receptors, and its expression in breast tissue. To investigate the channel activity in MCF-7 cells, we used the whole cell patch clamp and the calcium imaging techniques.</p> <p>Results</p> <p>TRPM8 channels are expressed at both mRNA and protein levels in the breast cancer cell line MCF-7. Bath application of the potent TRPM8 agonist Icilin (20 μM) induced a strong outwardly rectifying current at depolarizing potentials, which is associated with an elevation of cytosolic calcium concentration, consistent with established TRPM8 channel properties. RT-PCR experiments revealed a decrease in TRPM8 mRNA expression following steroid deprivation for 48 and 72 hours. In steroid deprived medium, addition of 17-beta-estradiol (E₂, 10 nM) increased both TRPM8 mRNA expression and the number of cells which respond to Icilin, but failed to affect the Ca²⁺entry amplitude. Moreover, silencing ERα mRNA expression with small interfering RNA reduced the expression of TRPM8. Immuno-histochemical examination of the expression of TRPM8 channels in human breast tissues revealed an over-expression of TRPM8 in breast adenocarcinomas, which is correlated with estrogen receptor positive (ER⁺) status of the tumours.</p> <p>Conclusion</p> <p>Taken together, these results show that TRPM8 channels are expressed and functional in breast cancer and that their expression is regulated by ER alpha.</p

Enhancer Sequences Influence the Role of the Amino-Terminal Domain of Bicoid in Transcription

Bicoid (Bcd) is a Drosophila melanogaster morphogenetic gradient that controls embryonic patterning by activating target gene expression in a concentration-dependent manner. In this study we describe experiments to determine how different enhancers respond to Bcd distinctively, focusing on two natural Bcd-responsive enhancer elements, hunchback (hb) and knirps (kni). Our results show that, on the hb enhancer element, the amino-terminal domain of Bcd (residues 1 to 91) plays primarily an inhibitory role, whereas on the kni enhancer element this same Bcd domain plays a positive role at low protein concentrations. We further demonstrate that while the amino-terminal domain is largely dispensable for cooperative binding to the hb enhancer element, it is preferentially required for cooperative binding to the kni enhancer element. Alteration of the arrangement of Bcd binding sites in the kni enhancer element reduces the role of the amino-terminal domain in cooperative DNA binding but increases the effectiveness of the self-inhibitory function. In addition, elimination of symmetric pairs of Bcd binding sites in the kni enhancer element reduces both DNA binding and activation by Bcd. We propose that the amino-terminal domain of Bcd is an enhancer-specific switch that contributes to the protein's ability to activate different target genes in distinct manners

COMPACT DUAL-BAND BANDPASS FILTER USING FOLDED SIR WITH TWO STUBS FOR WLAN

Abstract—A novel compact dual-band bandpass filter using tri-section stepped impedance resonators (SIRs) is presented for Wireless Local Area Network (WLAN). SIRs and one stub between parallel couple line are employed to realize two satisfactory passbands. Meanwhile, one transmission zero is generated between the two passbands to achieve a high out-of-band rejection. Simulated results show that two central frequencies are located at desired 2.4 and 5.2GHz with 3 dB fractional bandwidths of 6.3 % and 3.4 % respectively. The measured results are in good agreement with the simulated ones. 1

Self-Enhanced Electrochemiluminescence Imaging System Based on the Accelerated Generation of ROS under Ultrasound

Electrochemiluminescence (ECL) imaging, as an optical technology, has been developed at full tilt in the field of life science and nanomaterials. However, the relatively low ECL intensity or the high co-reactant concentration needed in the electrochemical reaction blocks its practical application. Here, we developed an ECL imaging system based on the rGO-TiO2–x composite material, where the co-reactant, reactive oxygen species (ROS), is generated in situ under the synergetic effect of of ultrasound (US) and electric irradiation. The rGO-TiO2–x composites facilitate the separation of electron (e–) and hole (h+) pairs and inhibit recombination triggered by external US irradiation due to the high electroconductivity of rGO and oxygen-deficient structures of TiO2, thus significantly boosting ROS generation. Furthermore, the increased defects on rGO accelerate the electron transfer rate, improving the electrocatalytic performance of the composite and forming more ROS. This high ultrasonic–electric synergistic efficacy is demonstrated through the enhancement of photon emission. Compared with the luminescence intensity triggered by US irradiation and electric field, an enhancement of ∼20-fold and 10-fold of the US combined with electric field-triggered emission is observed from this composite. Under the optimized conditions, using dopamine (DA) as a model target, the sensitivity of the US combined ECL strategy for detection of DA is two orders of magnitude higher than that of the ECL method. The successful detection of DA at low concentrations makes us believe that this strategy provides the possibility of applying ECL imaging for cellular single-molecule analysis and cancer therapy