Learning Moore Machines from Input-Output Traces

The problem of learning automata from example traces (but no equivalence or membership queries) is fundamental in automata learning theory and practice. In this paper we study this problem for finite state machines with inputs and outputs, and in particular for Moore machines. We develop three algorithms for solving this problem: (1) the PTAP algorithm, which transforms a set of input-output traces into an incomplete Moore machine and then completes the machine with self-loops; (2) the PRPNI algorithm, which uses the well-known RPNI algorithm for automata learning to learn a product of automata encoding a Moore machine; and (3) the MooreMI algorithm, which directly learns a Moore machine using PTAP extended with state merging. We prove that MooreMI has the fundamental identification in the limit property. We also compare the algorithms experimentally in terms of the size of the learned machine and several notions of accuracy, introduced in this paper. Finally, we compare with OSTIA, an algorithm that learns a more general class of transducers, and find that OSTIA generally does not learn a Moore machine, even when fed with a characteristic sample

The role of healthcare professionals in encouraging parents to see and hold their stillborn baby: a meta-synthesis of qualitative studies.

Background: Globally, during 2013 there were three million recorded stillbirths. Where clinical guidelines exist some recommend that professionals do not encourage parental contact. The guidance is based on quantitative evidence that seeing and holding the baby is not beneficial for everyone, but has been challenged by bereaved parents' organisations. We aim to inform future guideline development through a synthesis of qualitative studies reporting data relevant to the research question; how does the approach of healthcare professionals to seeing and holding the baby following stillbirth impact parents views and experiences? Methods/Findings: Using a predetermined search strategy of PubMed and PsychINFO we identified robust qualitative studies reporting bereaved parental views and/or experiences relating to seeing and holding their stillborn baby (final search 24 February, 2014). Eligible studies were English language, reporting parental views, with gestational loss >20weeks. Quality was independently assessed by three authors using a validated tool. We used meta-ethnographic techniques to identify key themes and a line of argument synthesis. We included 12 papers, representing the views of 333 parents (156 mothers, 150 fathers, and 27 couples) from six countries. The final themes were: "[Still]birth: Nature of care is paramount", "Real babies: Perfect beauties, monsters and spectres", and "Opportunity of a lifetime lost." Our line-of-argument synthesis highlights the contrast between all parents need to know their baby, with the time around birth being the only time memories can be made, and the variable ability that parents have to articulate their preferences at that time. Thus, we hypothesised that how health professionals approach contact between parents and their stillborn baby demands a degree of active management. An important limitation of this paper is all included studies originated from high income, westernised countries raising questions about the findings transferability to other cultural contexts. We do not offer new evidence to answer the question "Should parents see and hold their stillborn baby?", instead our findings advance understanding of how professionals can support parents to make appropriate decisions in a novel, highly charged and dynamic situation. Conclusions: Guidelines could be more specific in their recommendations regarding parental contact. The role of healthcare professionals in encouraging parents to see and hold their stillborn baby is paramount. Parental choice not to see their baby, apprehension, or uncertainty should be continuously revisited in the hours after birth as the opportunity for contact is fleeting and final

Challenges in conducting community-driven research created by differing ways of talking and thinking about science: a researcher’s perspective

Increasingly, health scientists are becoming aware that research collaborations that include community partnerships can be an effective way to broaden the scope and enhance the impact of research aimed at improving public health. Such collaborations extend the reach of academic scientists by integrating a variety of perspectives and thus strengthening the applicability of the research. Communication challenges can arise, however, when attempting to address specific research questions in these collaborations. In particular, inconsistencies can exist between scientists and community members in the use and interpretation of words and other language features, particularly when conducting research with a biomedical component. Additional challenges arise from differing perceptions of the investigative process. There may be divergent perceptions about how research questions should and can be answered, and in expectations about requirements of research institutions and research timelines. From these differences, misunderstandings can occur about how the results will ultimately impact the community. These communication issues are particularly challenging when scientists and community members are from different ethnic and linguistic backgrounds that may widen the gap between ways of talking and thinking about science, further complicating the interactions and exchanges that are essential for effective joint research efforts. Community-driven research that aims to describe the burden of disease associated with Helicobacter pylori infection is currently underway in northern Aboriginal communities located in the Yukon and Northwest Territories, Canada, with the goal of identifying effective public health strategies for reducing health risks from this infection. This research links community representatives, faculty from various disciplines at the University of Alberta, as well as territorial health care practitioners and officials. This highly collaborative work will be used to illustrate, from a researcher’s perspective, some of the challenges of conducting public health research in teams comprising members with varying backgrounds. The consequences of these challenges will be outlined, and potential solutions will be offered

Endosomal MR1 Trafficking Plays a Key Role in Presentation of Mycobacterium tuberculosis Ligands to MAIT Cells

Mucosal-Associated Invariant T (MAIT) cells, present in high frequency in airway and other mucosal tissues, have Th1 effector capacity positioning them to play a critical role in the early immune response to intracellular pathogens, including Mycobacterium tuberculosis (Mtb). MR1 is a highly conserved Class I-like molecule that presents vitamin B metabolites to MAIT cells. The mechanisms for loading these ubiquitous small molecules are likely to be tightly regulated to prevent inappropriate MAIT cell activation. To define the intracellular localization of MR1, we analyzed the distribution of an MR1-GFP fusion protein in antigen presenting cells. We found that MR1 localized to endosomes and was translocated to the cell surface upon addition of 6-formyl pterin (6-FP). To understand the mechanisms by which MR1 antigens are presented, we used a lentiviral shRNA screen to identify trafficking molecules that are required for the presentation of Mtb antigen to HLA-diverse T cells. We identified Stx18, VAMP4, and Rab6 as trafficking molecules regulating MR1-dependent MAIT cell recognition of Mtb-infected cells. Stx18 but not VAMP4 or Rab6 knockdown also resulted in decreased 6-FP-dependent surface translocation of MR1 suggesting distinct pathways for loading of exogenous ligands and intracellular mycobacterially-derived ligands. We postulate that endosome-mediated trafficking of MR1 allows for selective sampling of the intracellular environment.Career Development Award: (#IK2 CX000538); U.S. Department of Veterans Affairs Clinical Sciences Research and Development Program (MJH); U.S.Department of Veterans Affairs Biomedical Laboratory Research and Development Program (DML) Merit Award: (#I01 BX000533); American Lung Association: (RT-350058)

Effects of selective serotonin reuptake inhibitor treatment on plasma oxytocin and cortisol in major depressive disorder

Background: Oxytocin is known for its capacity to facilitate social bonding, reduce anxiety and for its actions on the stress hypothalamopituitary adrenal (HPA) axis. Since oxytocin can physiologically suppress activity of the HPA axis, clinical applications of this neuropeptide have been proposed in conditions where the function of the HPA axis is dysregulated. One such condition is major depressive disorder (MDD). Dysregulation of the HPA system is the most prominent endocrine change seen with MDD, and normalizing the HPA axis is one of the major targets of recent treatments. The potential clinical application of oxytocin in MDD requires improved understanding of its relationship to the symptoms and underlying pathophysiology of MDD. Previous research has investigated potential correlations between oxytocin and symptoms of MDD, including a link between oxytocin and treatment related symptom reduction. The outcomes of studies investigating whether antidepressive treatment (pharmacological and non-pharmacological) influences oxytocin concentrations in MDD, have produced conflicting outcomes. These outcomes suggest the need for an investigation of the influence of a single treatment class on oxytocin concentrations, to determine whether there is a relationship between oxytocin, the HPA axis (e.g., oxytocin and cortisol) and MDD. Our objective was to measure oxytocin and cortisol in patients with MDD before and following treatment with selective serotonin reuptake inhibitors, SSRI. Method: We sampled blood from arterial plasma. Patients with MDD were studied at the same time twice; pre- and post- 12 weeks treatment, in an unblinded sequential design (clinicaltrials.govNCT00168493). Results: Results did not reveal differences in oxytocin or cortisol concentrations before relative to following SSRI treatment, and there were no significant relationships between oxytocin and cortisol, or these two physiological variables and psychological symptom scores, before or after treatment. Conclusions: These outcomes demonstrate that symptoms of MDD were reduced following effective treatment with an SSRI, and further, stress physiology was unlikely to be a key factor in this outcome. Further research is required to discriminate potential differences in underlying stress physiology for individuals with MDD who respond to antidepressant treatment, relative to those who experience treatment resistance.Charlotte Keating, Tye Dawood, David A Barton, Gavin W Lambert and Alan J Tilbroo

Tracing the Flow of Perceptual Features in an Algorithmic Brain Network

The model of the brain as an information processing machine is a profound hypothesis in which neuroscience, psychology and theory of computation are now deeply rooted. Modern neuroscience aims to model the brain as a network of densely interconnected functional nodes. However, to model the dynamic information processing mechanisms of perception and cognition, it is imperative to understand brain networks at an algorithmic level–i.e. as the information flow that network nodes code and communicate. Here, using innovative methods (Directed Feature Information), we reconstructed examples of possible algorithmic brain networks that code and communicate the specific features underlying two distinct perceptions of the same ambiguous picture. In each observer, we identified a network architecture comprising one occipito-temporal hub where the features underlying both perceptual decisions dynamically converge. Our focus on detailed information flow represents an important step towards a new brain algorithmics to model the mechanisms of perception and cognition

Can improving working memory prevent academic difficulties? A school based randomised controlled trial.

BACKGROUND: Low academic achievement is common and is associated with adverse outcomes such as grade repetition, behavioural disorders and unemployment. The ability to accurately identify these children and intervene before they experience academic failure would be a major advance over the current 'wait to fail' model. Recent research suggests that a possible modifiable factor for low academic achievement is working memory, the ability to temporarily store and manipulate information in a 'mental workspace'. Children with working memory difficulties are at high risk of academic failure. It has recently been demonstrated that working memory can be improved with adaptive training tasks that encourage improvements in working memory capacity. Our trial will determine whether the intervention is efficacious as a selective prevention strategy for young children at risk of academic difficulties and is cost-effective. METHODS/DESIGN: This randomised controlled trial aims to recruit 440 children with low working memory after a school-based screening of 2880 children in Grade one. We will approach caregivers of all children from 48 participating primary schools in metropolitan Melbourne for consent. Children with low working memory will be randomised to usual care or the intervention. The intervention will consist of 25 computerised working memory training sessions, which take approximately 35 minutes each to complete. Follow-up of children will be conducted at 6, 12 and 24 months post-randomisation through child face-to-face assessment, parent and teacher surveys and data from government authorities. The primary outcome is academic achievement at 12 and 24 months, and other outcomes include child behaviour, attention, health-related quality of life, working memory, and health and educational service utilisation. DISCUSSION: A successful start to formal learning in school sets the stage for future academic, psychological and economic well-being. If this preventive intervention can be shown to be efficacious, then we will have the potential to prevent academic underachievement in large numbers of at-risk children, to offer a ready-to-use intervention to the Australian school system and to build international research partnerships along the health-education interface, in order to carry our further studies of effectiveness and generalisability.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Bdellovibrio bacteriovorus Inhibits Staphylococcus aureus Biofilm Formation and Invasion into Human Epithelial Cells

Bdellovibrio bacteriovorus HD100 is a predatory bacterium that attacks many Gram-negative human pathogens. A serious drawback of this strain, however, is its ineffectiveness against Gram-positive strains, such as the human pathogen Staphylococcus aureus. Here we demonstrate that the extracellular proteases produced by a host-independent B. bacteriovorus (HIB) effectively degrade/inhibit the formation of S. aureus biofilms and reduce its virulence. A 10% addition of HIB supernatant caused a 75% or greater reduction in S. aureus biofilm formation as well as 75% dispersal of pre-formed biofilms. LC-MS-MS analyses identified various B. bacteriovorus proteases within the supernatant, including the serine proteases Bd2269 and Bd2321. Tests with AEBSF confirmed that serine proteases were active in the supernatant and that they impacted S. aureus biofilm formation. The supernatant also possessed a slight DNAse activity. Furthermore, treatment of planktonic S. aureus with the supernatant diminished its ability to invade MCF-10a epithelial cells by 5-fold but did not affect the MCF-10a viability. In conclusion, this study illustrates the hitherto unknown ability of B. bacteriovorus to disperse Gram-positive pathogenic biofilms and mitigate their virulence.open6

MAIT cells launch a rapid, robust and distinct hyperinflammatory response to bacterial superantigens and quickly acquire an anergic phenotype that impedes their cognate antimicrobial function: Defining a novel mechanism of superantigen-induced immunopathology and immunosuppression

Superantigens (SAgs) are potent exotoxins secreted by Staphylococcus aureus and Streptococcus pyogenes. They target a large fraction of T cell pools to set in motion a "cytokine storm" with severe and sometimes life-threatening consequences typically encountered in toxic shock syndrome (TSS). Given the rapidity with which TSS develops, designing timely and truly targeted therapies for this syndrome requires identification of key mediators of the cytokine storm's initial wave. Equally important, early host responses to SAgs can be accompanied or followed by a state of immunosuppression, which in turn jeopardizes the host's ability to combat and clear infections. Unlike in mouse models, the mechanisms underlying SAg-associated immunosuppression in humans are ill-defined. In this work, we have identified a population of innate-like T cells, called mucosa-associated invariant T (MAIT) cells, as the most powerful source of pro-inflammatory cytokines after exposure to SAgs. We have utilized primary human peripheral blood and hepatic mononuclear cells, mouse MAIT hybridoma lines, HLA-DR4-transgenic mice, MAIThighHLA-DR4+ bone marrow chimeras, and humanized NOD-scid IL-2Rγnull mice to demonstrate for the first time that: i) mouse and human MAIT cells are hyperresponsive to SAgs, typified by staphylococcal enterotoxin B (SEB); ii) the human MAIT cell response to SEB is rapid and far greater in magnitude than that launched by unfractionated conventional T, invariant natural killer T (iNKT) or γδ T cells, and is characterized by production of interferon (IFN)-γ, tumor necrosis factor (TNF)-α and interleukin (IL)-2, but not IL-17A; iii) high-affinity MHC class II interaction with SAgs, but not MHC-related protein 1 (MR1) participation, is required for MAIT cell activation; iv) MAIT cell responses to SEB can occur in a T cell receptor (TCR) Vβ-specific manner but are largely contributed by IL-12 and IL-18; v) as MAIT cells are primed by SAgs, they also begin to develop a molecular signature consistent with exhaustion and failure to participate in antimicrobial defense. Accordingly, they upregulate lymphocyte-activation gene 3 (LAG-3), T cell immunoglobulin and mucin-3 (TIM-3), and/or programmed cell death-1 (PD-1), and acquire an anergic phenotype that interferes with their cognate function against Klebsiella pneumoniae and Escherichia coli; vi) MAIT cell hyperactivation and anergy co-utilize a signaling pathway that is governed by p38 and MEK1/2. Collectively, our findings demonstrate a pathogenic, rather than protective, role for MAIT cells during infection. Furthermore, we propose a novel mechanism of SAg-associated immunosuppression in humans. MAIT cells may therefore provide an attractive therapeutic target for the management of both early and late phases of severe SAg-mediated illnesses

Confidence and psychosis: a neuro-computational account of contingency learning disruption by NMDA blockade.

A state of pathological uncertainty about environmental regularities might represent a key step in the pathway to psychotic illness. Early psychosis can be investigated in healthy volunteers under ketamine, an NMDA receptor antagonist. Here, we explored the effects of ketamine on contingency learning using a placebo-controlled, double-blind, crossover design. During functional magnetic resonance imaging, participants performed an instrumental learning task, in which cue-outcome contingencies were probabilistic and reversed between blocks. Bayesian model comparison indicated that in such an unstable environment, reinforcement learning parameters are downregulated depending on confidence level, an adaptive mechanism that was specifically disrupted by ketamine administration. Drug effects were underpinned by altered neural activity in a fronto-parietal network, which reflected the confidence-based shift to exploitation of learned contingencies. Our findings suggest that an early characteristic of psychosis lies in a persistent doubt that undermines the stabilization of behavioral policy resulting in a failure to exploit regularities in the environment.FV was supported by the Groupe Pasteur Mutualité. RG was supported by the Fondation pour la Recherche Médicale and the Fondation Bettencourt Schueller. SP is supported by a Marie Curie Intra-European fellowship (FP7-PEOPLE-2012-IEF). AF was supported by National Health and Medical Research Council grants (IDs : 1050504 and 1066779) and an Australian Research Council Future Fellowship (ID: FT130100589). This work was supported by the Wellcome Trust and the Bernard Wolfe Health Neuroscience Fund.This is the final version of the article. It first appeared from the Nature Publishing Group via http://dx.doi.org/10.1038/mp.2015.7