Disseminated tumor cells (DTCs) in secondary organs often remain dormant for a long period of time before re-awakening and growing into overt metastases. We have previously identified NR2F1/COUP-TF1, an orphan nuclear receptor, as a master regulator of tumor cell dormancy in head and neck squamous cell carcinoma (HNSCC) and other cancer types. Here we describe the identification and function of a novel NR2F1 agonist herein referred to as compound 26 (C26). C26 was found to specifically activate NR2F1 in HNSCC cells, leading to increased NR2F1 transcription and nuclear protein accumulation. C26-mediated activation of NR2F1 induced growth arrest of HNSCC PDX line and cell lines in 3D cultures in vitro and on chicken embryo chorioallantoic membrane (CAM) in vivo. The effect of C26 on growth arrest was lost when NR2F1 was knocked out by CRISPR/Cas9. C26-induced growth arrest was mediated by activation of an NR2F1-regulated dormancy program, including upregulation of cyclin-dependent kinase (CDK) inhibitor p27 and the transcription factors retinoic acid receptor β (RARβ) and Sox9. In mice bearing HNSCC PDX tumors, combined adjuvant and neo-adjuvant treatment with C26 resulted in complete inhibition of lethal lung metastasis. Mechanistic analysis showed that lung DTCs in C26-treated mice displayed an NR2F1hi/p27hi/Ki-67lo phenotype, which kept them dormant in a single-cell state preventing their outgrowth into overt metastases. Our work reveales a novel NR2F1 agonist and provides a proof of principle strategy supporting that inducing DTC dormancy using NR2F1 agonists could be used as a therapeutic strategy to prevent metastasis.

Feature-based and location-based volitional covert attention 1 are mediated by different mechanisms and affect memory at 2 different timescales 3 Abstract 6Our ongoing subjective experiences, and our memories of those experiences, are shaped by our prior 7 experiences, goals, and situational understanding. These factors shape how we allocate our attentional 8 resources over different aspects of our ongoing experiences. These attentional shifts may happen overtly 9 (e.g., when we change where we are looking) or covertly (e.g., without any explicit physical manifestation). 10Additionally, we may attend to what is happening at a specific spatial location (e.g., because we think 11 something important is happening there) or we may attend to particular features irrespective of their 12 locations (e.g., when we search for a friend's face in a crowd). We ran two covert attention experiments that 13 differed in how long they asked participants to maintain the focus of the features or locations they were 14 attending. Later, the participants performed a recognition memory task for attended, unattended, and 15 novel stimuli. Participants were able to shift the location of their covert attentional focus more rapidly than 16 they were able to shift their focus of covert attention to stimulus features, and the effects of location-based 17 attention on memory were longer-lasting than the effects of feature-based attention.

Distinct means have been developed to answer an increasing demand and need for methods that can accurately predict and detect the fertile phase of the menstrual cycle and fit various indications and changing situations of women's reproductive life. Methods based on the detection of direct fertility markers, such as hormonal tests and ultrasound, are more objective and accurate than traditional markers based on indirect markers, but cost and dependence on supplies limit their application. Nevertheless, these methods could be used during a few cycles either as support in the teaching phase or in difficult cases and for specific indications. Likewise, some new devices designed to facilitate recording and calculation of fertility signals could be combined with clinical methods to improve prediction and detection of the fertile phase. Besides the search for new fertility markers and the development of new methods, the possibility of combining already existing methods would certainly improve use-effectiveness and acceptance.

18Ionic silver is known to be an effective antimicrobial agent widely used in the cleaning 19 and medical industries, however, there are several concerns regarding the release of silver 20 pollutants into the environment. Presented here are two engineered bacterial biosensors for the 21 detection and quantification of silver. The biosensors contain a silver resistance operon and a 22 GFP gene that is strictly regulated through silver activated regulatory regions that control 23 expression of the sil operons. The two biosensors are responsive to a wide range of silver ion 24 concentrations, and a correlation between silver and GFP signal is seen at select concentration 25 ranges. The biosensors were shown to detect silver ions released from silver nanoparticles, and 26 have the potential to become a method for monitoring ion release rates of different nanoparticles. 27Interestingly, the close homology of the silver resistance and copper resistance genes allowed for 28 the biosensor to also be responsive to copper ions, implying that copper ions activate silver 29 resistance. Further development of this biosensor could lead to commercial applications for 30 environmental monitoring. 31 Importance 32Ionic silver is known to have many harmful environmental effects. Silver pollutants have been 33 found in various environmental settings such as natural waterways and tailings from mining 34 operations, raising concern. In addition, persistent exposure to silver in medical and 35 environmental settings has led to the development of silver resistant bacteria, many of which are 36 also resistant to a wide range of antibiotics. Some of these have the potential to develop into 37 human pathogens. It then becomes important to have standardized methods for detecting and 38 3 monitoring silver concentrations in various environments so that appropriate measures can be 39 taken to prevent further silver ion release. This research shows that bacterial biosensors 40 engineered to detect and quantify silver ions can be developed as effective alternatives to 41 traditional analytical techniques. Further development of such biosensors could result in a 42 commercial system for short and long term environmental monitoring, which is important as 43 products containing silver and other heavy metals become increasingly popular. 44 131 media (LB and modified LB) is expected since sodium chloride is known to form a AgCl 132 precipitate which would decrease the availability of free silver ions. A lower amount of available 133 silver ions in the media could assist the biosensor cells survival at higher absolute silver 134 concentrations, resulting in a greater detection range, as was observed. 135 Correlation between GFP signal and silver ion concentration is detected with 136 the biosensor variants 137 A correlation between GFP signal and silver ion concentration is detected with the biosensor 138 variants. The correlation range varies depending on the media, and in specific segments of the 139 detection range. Both RADEK.1 and RADEK.2...