Automata guided hierarchical reinforcement learning for zero-shot skill composition

An obstacle that prevents the wide adoption of (deep) reinforcement learning (RL) in control systems is its need for a large amount of interactions with the environment in order to master a skill. The learned skill usually generalizes poorly across domains and re-training is often necessary when presented with a new task. We present a framework that combines methods in formal methods with hierarchical reinforcement learning (HRL). The set of techniques we provide allows for convenient specification of tasks with complex logic, learn hierarchical policies (meta-controller and low-level controllers) with well-defined intrinsic rewards using any RL methods and is able to construct new skills from existing ones without additional learning. We evaluate the proposed methods in a simple grid world simulation as well as simulation on a Baxter robot

MYC-microRNA-9-metastasis connection in breast cancer

[Excerpt] Metastasis accounts for more than 90% of cancer patients’ mortality. The metastatic process involves multiple steps [1]. Initially, cancer cells from the primary tumor invade adjacent stroma. To acquire this capacity, cells undergo a process called epithelial-mesenchymal transition (EMT), in which cells in re-sponse to signals from the surrounding stroma, undergo a switch between cell phenotypes and acquire mesenchymal properties and show reduced intercel-lular adhesion, allowing cells to be-come motile. Then cells enter systemic circulation, either through the blood or lymph, and finally extravasate into the parenchyma of distant tissues, where they form micrometastasis and prolifer-ate to form secondary tumors [2]. [...

Epidermal growth factor receptor-regulated miR-125a-5p – a metastatic inhibitor of lung cancer

Both the epidermal growth factor receptor signaling pathway and microRNA (miRNA) play an important role in lung cancer development and progression. To address the potential role of miRNA in epidermal growth factor receptor signaling, we identified miR-125a-5p as a downstream target, using an miRNA array. We further demonstrated that miR-125a-5p inhibited migration and invasion of lung cancer cells. Moreover, miR-125a-5p regulated the expression of several downstream genes of epidermal growth factor receptor signaling. Importantly, examination of lung cancer samples revealed a significant correlation of miR-125a-5p repression with lung carcinogenesis. Taken together, our results provide compelling evidence that miR-125a-5p, an epidermal growth factor-signaling-regulated miRNA, may function as a metastatic suppressor

NeuronBank: A Tool for Cataloging Neuronal Circuitry

The basic unit of any nervous system is the neuron. Therefore, understanding the operation of nervous systems ultimately requires an inventory of their constituent neurons and synaptic connectivity, which form neural circuits. The presence of uniquely identifiable neurons or classes of neurons in many invertebrates has facilitated the construction of cellular-level connectivity diagrams that can be generalized across individuals within a species. Homologous neurons can also be recognized across species. Here we describe NeuronBank.org, a web-based tool that we are developing for cataloging, searching, and analyzing neuronal circuitry within and across species. Information from a single species is represented in an individual branch of NeuronBank. Users can search within a branch or perform queries across branches to look for similarities in neuronal circuits across species. The branches allow for an extensible ontology so that additional characteristics can be added as knowledge grows. Each entry in NeuronBank generates a unique accession ID, allowing it to be easily cited. There is also an automatic link to a Wiki page allowing an encyclopedic explanation of the entry. All of the 44 previously published neurons plus one previously unpublished neuron from the mollusc, Tritonia diomedea, have been entered into a branch of NeuronBank as have 4 previously published neurons from the mollusc, Melibe leonina. The ability to organize information about neuronal circuits will make this information more accessible, ultimately aiding research on these important models

Profiling the circulating miRnome reveals a temporal regulation of the bone injury response

Bone injury healing is an orchestrated process that starts with an inflammatory phase followed by repair and remodelling of the bone defect. The initial inflammation is characterized by local changes in immune cell populations and molecular mediators, including microRNAs (miRNAs). However, the systemic response to bone injury remains largely uncharacterized. Thus, this study aimed to profile the changes in the plasma miRnome after bone injury and determine its biological implications. Methods: A rat model of femoral bone defect was used, and animals were evaluated at days 3 and 14 after injury. Non-operated (NO) and sham operated animals were used as controls. Blood and spleen were collected and peripheral blood mononuclear cells (PBMC) and plasma were separated. Plasma miRnome was determined by RT-qPCR array and bioinformatics Ingenuity pathway analysis (IPA) was performed. Proliferation of bone marrow mesenchymal stem/stromal cells (MSC) was evaluated by Ki67 staining and high-throughput cell imaging. Candidate miRNAs were evaluated in splenocytes by RT-qPCR, and proteins found in the IPA analysis were analysed in splenocytes and PBMC by Western blot. Results: Bone injury resulted in timely controlled changes to the miRNA expression profile in plasma. At day 3 there was a major down-regulation of miRNA levels, which was partially recovered by day 14 post-injury. Interestingly, bone injury led to a significant up-regulation of let-7a, let-7d and miR-21 in plasma and splenocytes at day 14 relative to day 3 after bone injury, but not in sham operated animals. IPA predicted that most miRNAs temporally affected were involved in cellular development, proliferation and movement. MSC proliferation was analysed and found significantly increased in response to plasma of animals days 3 and 14 post-injury, but not from NO animals. Moreover, IPA predicted that miRNA processing proteins Ago2 and Dicer were specifically inhibited at day 3 post-injury, with Ago2 becoming activated at day 14. Protein levels of Ago2 and Dicer in splenocytes were increased at day 14 relative to day 3 post-bone injury and NO animals, while in PBMC, levels were reduced at day 3 (albeit Dicer was not significant) and remained low at day 14. Ephrin receptor B6 followed the same tendency as Ago2 and Dicer, while Smad2/3 was significantly decreased in splenocytes from day 14 relative to NO and day 3 post-bone injury animals. Conclusion: Results show a systemic miRNA response to bone injury that is regulated in time and is related to inflammation resolution and the start of bone repair/regeneration, unravelling candidate miRNAs to be used as biomarkers in the monitoring of healthy bone healing and as therapeutic targets for the development of improved bone regeneration therapies.This work was funded by project NORTE-01-0145-FEDER-000012, supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF), and AO Foundation-Switzerland (project S-15-83S). AMS, MIA, CC and JHT were supported by FCT-Fundação para a Ciência e a Tecnologia, through fellowships SFRH/BD/ 85968/2012, SFRH/BPD/91011/2012, SFRH/BDP/ 87071/2012 and SFRH/BD/112832/2015, respecttively. Work in Dr. Calin's laboratory is supported by National Institutes of Health (NIH/NCATS) grant UH3TR00943-01 through the NIH Common Fund, Office of Strategic Coordination (OSC), the NIH/NCI grant 1R01CA182905-01, a U54 grant-UPR/MDACC Partnership for Excellence in Cancer Research 2016 Pilot Project, a Team DOD (CA160445P1) grant, a Ladies Leukemia League grant, a CLL Moonshot Flagship project, a SINF 2017 grant, and the Estate of C. G. Johnson, J

The information needs of people living with ankylosing spondylitis: a questionnaire survey

<p>BACKGROUND:Today, health care is patient-centred with patients more involved in medical decision making and taking an active role in managing their disease. It is important that patients are appropriately informed about their condition and that their health care needs are met. We examine the information utilisation, sources and needs of people with ankylosing spondylitis (AS).</p> <p>METHODS: Participants in an existing AS cohort study were asked to complete a postal or online questionnaire containing closed and open-ended questions, regarding their information access and needs. Participants were stratified by age and descriptive statistics were performed using STATA 11, while thematic analysis was performed on open-ended question narratives. Qualitative data was handled in Microsoft Access and explored for emerging themes and patterns of experiences.</p> <p>RESULTS: Despite 73% of respondents having internet access, only 49% used the internet to access information regarding AS. Even then, this was only infrequently. Only 50% of respondents reported accessing written information about AS, which was obtained mainly in specialist clinics. Women were more likely than men to access information (63% (women) 46% (men)) regardless of the source, while younger patients were more likely to use online sources. The main source of non-written information was the rheumatologist. Overall, the respondents felt there was sufficient information available, but there was a perception that the tone was often too negative. The majority (95%) of people would like to receive a regular newsletter about AS, containing positive practical and local information. Suggestions were also made for more information about AS to be made available to non-specialist medical professionals and the general public.</p> <p>CONCLUSIONS: There appears to be sufficient information available for people with AS in the UK and this is mostly accessed by younger AS patients. Many patients, particularly men, choose not to access AS information and concerns were raised about its negative tone. Patients still rely on written and verbal information from their specialists. Future initiatives should focus on the delivery of more positive information, targeting younger participants in particular and increasing the awareness in the general population and wider non-specialist medical community.</p&gt

PDGF induced microRNA alterations in cancer cells

Platelet derived growth factor (PDGF) regulates gene transcription by binding to specific receptors. PDGF plays a critical role in oncogenesis in brain and other tumors, regulates angiogenesis, and remodels the stroma in physiologic conditions. Here, we show by using microRNA (miR) arrays that PDGFs regulate the expression and function of miRs in glioblastoma and ovarian cancer cells. The two PDGF ligands AA and BB affect expression of several miRs in ligand-specific manner; the most robust changes consisting of let-7d repression by PDGF-AA and miR-146b induction by PDGF-BB. Induction of miR-146b by PDGF-BB is modulated via MAPK-dependent induction of c-fos. We demonstrate that PDGF regulates expression of some of its known targets (e.g. cyclin D1) through miR alterations and identify the epidermal growth factor receptor (EGFR) as a new PDGF-BB target. We show that its expression and function are repressed by PDGF-induced miR-146b and that mir-146b and EGFR correlate inversely in human glioblastomas. We propose that PDGF-regulated gene transcription involves alterations in non-coding RNAs and provide evidence for a miR-dependent feedback mechanism balancing growth factor receptor signaling in cancer cells

Biological and clinical significance of cancer stem cell plasticity

In the past decade, the traditional view of cancers as a homogeneous collection of malignant cells is being replaced by a model of ever increasing complexity suggesting that cancers are complex tissues composed of multiple cell types. This complex model of tumorigenesis has been well supported by a growing body of evidence indicating that most cancers including those derived from blood and solid tissues display a hierarchical organization of tumor cells with phenotypic and functional heterogeneity and at the apex of this hierarchy are cells capable of self-renewal. These “tumor imitating cells” or “cancer stem cells” drive tumorigenesis and contribute to metastasis, treatment resistance and tumor relapse. Although tumor stem cells themselves may display both genetic and phenotypic heterogeneity, recent studies have demonstrated that cancer stem cells maintain plasticity to transition between mesenchymal-like (EMT) and epithelial-like (MET) states, which may be regulated by the tumor microenvironment. These stem cell state transitions may play a fundamental role in tumor progression and treatment resistance. In this review, we discuss the emerging knowledge regarding the plasticity of cancer stem cells with an emphasis on the signaling pathways and noncoding RNAs including microRNAs (miRNA) and long non-coding RNAs (lncRNAs) in regulation of this plasticity during tumor growth and metastasis. Lastly, we point out the importance of targeting both the EMT and MET states of CSCs in order to eliminate these lethal seeds of cancers. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40169-014-0032-3) contains supplementary material, which is available to authorized users

Mechanisms and role of microRNA deregulation in cancer onset and progression

MicroRNAs are key regulators of various fundamental biological processes and, although representing only a small portion of the genome, they regulate a much larger population of target genes. Mature microRNAs (miRNAs) are single-stranded RNA molecules of 20–23 nucleotide (nt) length that control gene expression in many cellular processes. These molecules typically reduce the stability of mRNAs, including those of genes that mediate processes in tumorigenesis, such as inflammation, cell cycle regulation, stress response, differentiation, apoptosis and invasion. MicroRNA targeting is mostly achieved through specific base-pairing interactions between the 5′ end (‘seed’ region) of the miRNA and sites within coding and untranslated regions (UTRs) of mRNAs; target sites in the 3′ UTR diminish mRNA stability. Since miRNAs frequently target hundreds of mRNAs, miRNA regulatory pathways are complex. Calin and Croce were the first to demonstrate a connection between microRNAs and increased risk of developing cancer, and meanwhile the role of microRNAs in carcinogenesis has definitively been evidenced. It needs to be considered that the complex mechanism of gene regulation by microRNAs is profoundly influenced by variation in gene sequence (polymorphisms) of the target sites. Thus, individual variability could cause patients to present differential risks regarding several diseases. Aiming to provide a critical overview of miRNA dysregulation in cancer, this article reviews the growing number of studies that have shown the importance of these small molecules and how these microRNAs can affect or be affected by genetic and epigenetic mechanisms