Learning to play against any mixture of opponents.

Intuitively, experience playing against one mixture of opponents in a given domain should be relevant for a different mixture in the same domain. If the mixture changes, ideally we would not have to train from scratch, but rather could transfer what we have learned to construct a policy to play against the new mixture. We propose a transfer learning method, Q-Mixing, that starts by learning Q-values against each pure-strategy opponent. Then a Q-value for any distribution of opponent strategies is approximated by appropriately averaging the separately learned Q-values. From these components, we construct policies against all opponent mixtures without any further training. We empirically validate Q-Mixing in two environments: a simple grid-world soccer environment, and a social dilemma game. Our experiments find that Q-Mixing can successfully transfer knowledge across any mixture of opponents. Next, we consider the use of observations during play to update the believed distribution of opponents. We introduce an opponent policy classifier-trained reusing Q-learning data-and use the classifier results to refine the mixing of Q-values. Q-Mixing augmented with the opponent policy classifier performs better, with higher variance, than training directly against a mixed-strategy opponent.

Greener Operations: a James Lind Alliance Priority Setting Partnership to define research priorities in environmentally sustainable perioperative practice through a structured consensus approach.

OBJECTIVES: To agree on the 'top 10' research priorities for environmentally sustainable perioperative practice. DESIGN: Surveys and literature review; final consensus workshop using a nominal group technique. SETTING: UK-based setting. PARTICIPANTS: Healthcare professionals, patients, carers and the public. OUTCOME MEASURES: Initial survey-suggested research questions; interim survey-shortlist of 'indicative' questions (the 20 most frequently nominated by patients, carers and the public, and healthcare professionals); final workshop-ranked research priorities. RESULTS: Initial survey-1926 suggestions by 296 respondents, refined into 60 indicative questions. Interim survey-325 respondents. Final workshop-21 participants agreed the 'top 10': (1) How can more sustainable reusable equipment safely be used during and around the time of an operation? (2) How can healthcare organisations more sustainably procure (obtain) medicines, equipment and items used during and around the time of an operation? (3) How can healthcare professionals who deliver care during and around the time of an operation be encouraged to adopt sustainable actions in practice? (4) Can more efficient use of operating theatres and associated practices reduce the environmental impact of operations? (5) How can the amount of waste generated during and around the time of an operation be minimised? (6) How do we measure and compare the short-term and long-term environmental impacts of surgical and non-surgical treatments for the same condition? (7) What is the environmental impact of different anaesthetic techniques (eg, different types of general, regional and local anaesthesia) used for the same operation? (8) How should the environmental impact of an operation be weighed against its clinical outcomes and financial costs? (9) How can environmental sustainability be incorporated into the organisational management of operating theatres? (10) What are the most sustainable forms of effective infection prevention and control used around the time of an operation (eg, personal protective equipment, drapes, clean air ventilation)? CONCLUSIONS: A broad range of 'end-users' have identified research priorities for sustainable perioperative care.

CBRNE3 medicine in the austere environment: the challenges.

Chemical, Biological, Radiological, Nuclear and Explosive/Environmental/Endemic Disease (CBRNE3) incidents encompass a wide spectrum of events from natural events/disasters to industrial accidents through to deliberate military release and nuclear war. The UK military operates globally and in environments that are often austere. The very nature of these environments means that CBRNE3 incidents are a very real risk, and a CBRNE3 incident in a well-developed society could ultimately create an austere environment. Responding to such an event in an austere environment poses challenges.The very nature of the environment may be problematic. It may be very remote with limited or no access by road and/or air. It may have limited resources such as water and infrastructure required to manage the event. Extremes of temperature and weather may pose a risk to casualties and responders alike. Specialist teams and equipment may be required, but the host or partner nations may not have suitable capability and these resources may take time to mobilise from the home base. The volume of equipment and material needed in the response may overwhelm logistical chains which may not be robust enough to withstand the initial incident.Proper planning and preparedness is crucial to operating in and managing a CBRNE3 incident in an austere environment. Recognition of the potential threat by intelligence gathering and recognition by personnel on the ground are essential. This requires an appropriate awareness at all levels of command and appropriate prior training, including interoperability training with partner forces. Ultimately, robust planning and training is key to managing CBRNE3 incidents in an austere environment.

Exogenous Orientation of Attention to the Center of Mass in a Visual Search Task.

Anne Treisman's scientific career included broad-ranging contributions that advanced our understanding of the attentional mechanisms that people rely on to make sense of the world. In this paper, we describe results from a visual-search paradigm first developed by Grabowecky and Treisman (Grabowecky, 1992). Their design exploited known feature-search asymmetries (Treisman & Gormican, 1988) to investigate the role of a center of mass (CoM) mechanism in determining the initial locus of visual-spatial attention in visual search. The original experiment supported the hypothesis that CoM influences initial orienting of visual-spatial attention, as targets near the CoM of a multi-element array were detected more quickly than targets distant from the CoM. These findings were replicated in a follow-up experiment using a different feature-search asymmetry, with eye-tracking added to verify central fixation. We also investigated whether CoM had any influence on pop-out search, and found no evidence that it does. Surprisingly, the effect of position of the search array on the CoM suggested that CoM may be computed independently for elements contained within each visual hemifield. Whereas our work on CoM with Treisman was initiated within an earlier theoretical context, the present results are also compatible with contemporary theoretical advances; both the early results and the new results can be integrated within current ways of thinking about attention and pre-attentive mechanisms.

Optimization of a nicotine degrading enzyme for potential use in treatment of nicotine addiction.

BACKGROUND: Smoking and tobacco use continue to be the largest preventable causes of death globally. A novel therapeutic approach has recently been proposed: administration of an enzyme that degrades nicotine, the main addictive component of tobacco, minimizing brain exposure and reducing its reinforcing effects. Pre-clinical proof of concept has been previously established through dosing the amine oxidase NicA2 from Pseudomonas putida in rat nicotine self-administration models of addiction. RESULTS: This paper describes efforts towards optimizing NicA2 for potential therapeutic use: enhancing potency, improving its pharmacokinetic profile, and attenuating immunogenicity. Libraries randomizing residues located in all 22 active site positions of NicA2 were screened. 58 single mutations with 2- to 19-fold enhanced catalytic activity compared to wt at 10 µM nicotine were identified. A novel nicotine biosensor assay allowed efficient screening of the many primary hits for activity at nicotine concentrations typically found in smokers. 10 mutants with improved activity in rat serum at or below 250 nM were identified. These catalytic improvements translated to increased potency in vivo in the form of further lowering of nicotine blood levels and nicotine accumulation in the brains of Sprague-Dawley rats. Examination of the X-ray crystal structure suggests that these mutants may accelerate the rate limiting re-oxidation of the flavin adenine dinucleotide cofactor by enhancing molecular oxygen's access. PEGylation of NicA2 led to prolonged serum half-life and lowered immunogenicity observed in a human HLA DR4 transgenic mouse model, without impacting nicotine degrading activity. CONCLUSIONS: Systematic mutational analysis of the active site of the nicotine-degrading enzyme NicA2 has yielded 10 variants that increase the catalytic activity and its effects on nicotine distribution in vivo at nicotine plasma concentrations found in smokers. In addition, PEGylation substantially increases circulating half-life and reduces the enzyme's immunogenic potential. Taken together, these results provide a viable path towards generation of a drug candidate suitable for human therapeutic use in treating nicotine addiction.

Auditory Brainstem Implant Array Position Varies Widely Among Adult and Pediatric Patients and Is Associated With Perception.

OBJECTIVES: The auditory brainstem implant (ABI) provides sound awareness to patients who are ineligible for cochlear implantation. Auditory performance varies widely among similar ABI cohorts. We hypothesize that differences in electrode array position contribute to this variance. Herein, we classify ABI array position based on postoperative imaging and investigate the relationship between position and perception. DESIGN: Retrospective review of pediatric and adult ABI users with postoperative computed tomography. To standardize views across subjects, true axial reformatted series of scans were created using the McRae line. Using multiplanar reconstructions, basion and electrode array tip coordinates and array angles from vertical were measured. From a lateral view, array angles (V) were classified into types I to IV, and from posterior view, array angles (T) were classified into types A to D. Array position was further categorized by measuring distance vertical from basion (D1) and lateral from midline (D2). Differences between array classifications were compared with audiometric thresholds, number of active electrodes, and pitch ranking. RESULTS: Pediatric (n = 4, 2 with revisions) and adult (n = 7) ABI subjects were included in this study. Subjects had a wide variety of ABI array angles, but most were aimed superiorly and posteriorly (type II, n = 7) from lateral view and upright or medially tilted from posterior view (type A, n = 6). Mean pediatric distances were 8 to 42% smaller than adults for D1 and D2. In subjects with perceptual data, electrical thresholds and the number of active electrodes differed among classification types. CONCLUSIONS: In this first study to classify ABI electrode array orientation, array position varied widely. This variability may explain differences in auditory performance.

Identification of an ATP-controlled allosteric switch that controls actin filament nucleation by Arp2/3 complex.

Nucleation of branched actin filaments by Arp2/3 complex is tightly regulated to control actin assembly in cells. Arp2/3 complex activation involves conformational changes brought about by ATP, Nucleation Promoting Factor (NPF) proteins, actin filaments and NPF-recruited actin monomers. To understand how these factors promote activation, we must first understand how the complex is held inactive in their absence. Here we demonstrate that the Arp3 C-terminal tail is a structural switch that prevents Arp2/3 complex from adopting an active conformation. The interaction between the tail and a hydrophobic groove in Arp3 blocks movement of Arp2 and Arp3 into an activated filament-like (short pitch) conformation. Our data indicate ATP binding destabilizes this interaction via an allosteric link between the Arp3 nucleotide cleft and the hydrophobic groove, thereby promoting the short-pitch conformation. Our results help explain how Arp2/3 complex is locked in an inactive state without activators and how autoinhibition is relieved.

Role and structural mechanism of WASP-triggered conformational changes in branched actin filament nucleation by Arp2/3 complex.

The Arp2/3 (Actin-related proteins 2/3) complex is activated by WASP (Wiskott-Aldrich syndrome protein) family proteins to nucleate branched actin filaments that are important for cellular motility. WASP recruits actin monomers to the complex and stimulates movement of Arp2 and Arp3 into a "short-pitch" conformation that mimics the arrangement of actin subunits within filaments. The relative contribution of these functions in Arp2/3 complex activation and the mechanism by which WASP stimulates the conformational change have been unknown. We purified budding yeast Arp2/3 complex held in or near the short-pitch conformation by an engineered covalent cross-link to determine if the WASP-induced conformational change is sufficient for activity. Remarkably, cross-linked Arp2/3 complex bypasses the need for WASP in activation and is more active than WASP-activated Arp2/3 complex. These data indicate that stimulation of the short-pitch conformation is the critical activating function of WASP and that monomer delivery is not a fundamental requirement for nucleation but is a specific requirement for WASP-mediated activation. During activation, WASP limits nucleation rates by releasing slowly from nascent branches. The cross-linked complex is inhibited by WASP's CA region, even though CA potently stimulates cross-linking, suggesting that slow WASP detachment masks the activating potential of the short-pitch conformational switch. We use structure-based mutations and WASP-Arp fusion chimeras to determine how WASP stimulates movement toward the short-pitch conformation. Our data indicate that WASP displaces the autoinhibitory Arp3 C-terminal tail from a hydrophobic groove at Arp3's barbed end to destabilize the inactive state, providing a mechanism by which WASP stimulates the short-pitch conformation and activates Arp2/3 complex.

A unified framework for automatic wound segmentation and analysis with deep convolutional neural networks.

Wound surface area changes over multiple weeks are highly predictive of the wound healing process. Furthermore, the quality and quantity of the tissue in the wound bed also offer important prognostic information. Unfortunately, accurate measurements of wound surface area changes are out of reach in the busy wound practice setting. Currently, clinicians estimate wound size by estimating wound width and length using a scalpel after wound treatment, which is highly inaccurate. To address this problem, we propose an integrated system to automatically segment wound regions and analyze wound conditions in wound images. Different from previous segmentation techniques which rely on handcrafted features or unsupervised approaches, our proposed deep learning method jointly learns task-relevant visual features and performs wound segmentation. Moreover, learned features are applied to further analysis of wounds in two ways: infection detection and healing progress prediction. To the best of our knowledge, this is the first attempt to automate long-term predictions of general wound healing progress. Our method is computationally efficient and takes less than 5 seconds per wound image (480 by 640 pixels) on a typical laptop computer. Our evaluations on a large-scale wound database demonstrate the effectiveness and reliability of the proposed system.

Interactions with actin monomers, actin filaments, and Arp2/3 complex define the roles of WASP family proteins and cortactin in coordinately regulating branched actin networks.

Arp2/3 complex is an important actin filament nucleator that creates branched actin filament networks required for formation of lamellipodia and endocytic actin structures. Cellular assembly of branched actin networks frequently requires multiple Arp2/3 complex activators, called nucleation promoting factors (NPFs). We recently presented a mechanism by which cortactin, a weak NPF, can displace a more potent NPF, N-WASP, from nascent branch junctions to synergistically accelerate nucleation. The distinct roles of these NPFs in branching nucleation are surprising given their similarities. We biochemically dissected these two classes of NPFs to determine how their Arp2/3 complex and actin interacting segments modulate their influences on branched actin networks. We find that the Arp2/3 complex-interacting N-terminal acidic sequence (NtA) of cortactin has structural features distinct from WASP acidic regions (A) that are required for synergy between the two NPFs. Our mutational analysis shows that differences between NtA and A do not explain the weak intrinsic NPF activity of cortactin, but instead that cortactin is a weak NPF because it cannot recruit actin monomers to Arp2/3 complex. We use TIRF microscopy to show that cortactin bundles branched actin filaments using actin filament binding repeats within a single cortactin molecule, but that N-WASP antagonizes cortactin-mediated bundling. Finally, we demonstrate that multiple WASP family proteins synergistically activate Arp2/3 complex and determine the biochemical requirements in WASP proteins for synergy. Our data indicate that synergy between WASP proteins and cortactin may play a general role in assembling diverse actin-based structures, including lamellipodia, podosomes, and endocytic actin networks.

Stromal cell-derived factor and granulocyte-monocyte colony-stimulating factor form a combined neovasculogenic therapy for ischemic cardiomyopathy.

OBJECTIVE: Ischemic heart failure is an increasingly prevalent global health concern with major morbidity and mortality. Currently, therapies are limited, and novel revascularization methods might have a role. This study examined enhancing endogenous myocardial revascularization by expanding bone marrow-derived endothelial progenitor cells with the marrow stimulant granulocyte-monocyte colony-stimulating factor and recruiting the endothelial progenitor cells with intramyocardial administration of the potent endothelial progenitor cell chemokine stromal cell-derived factor. METHODS: Ischemic cardiomyopathy was induced in Lewis rats (n = 40) through left anterior descending coronary artery ligation. After 3 weeks, animals were randomized into 4 groups: saline control, granulocyte-monocyte colony-stimulating factor only (GM-CSF only), stromal cell-derived factor only (SDF only), and combined stromal cell-derived factor/granulocyte-monocyte colony-stimulating factor (SDF/GM-CSF) (n = 10 each). After another 3 weeks, hearts were analyzed for endothelial progenitor cell density by endothelial progenitor cell marker colocalization immunohistochemistry, vasculogenesis by von Willebrand immunohistochemistry, ventricular geometry by hematoxylin-and-eosin microscopy, and in vivo myocardial function with an intracavitary pressure-volume conductance microcatheter. RESULTS: The saline control, GM-CSF only, and SDF only groups were equivalent. Compared with the saline control group, animals in the SDF/GM-CSF group exhibited increased endothelial progenitor cell density (21.7 +/- 3.2 vs 9.6 +/- 3.1 CD34 + /vascular endothelial growth factor receptor 2-positive cells per high-power field, P = .01). There was enhanced vascularity (44.1 +/- 5.5 versus 23.8 +/- 2.2 von Willebrand factor-positive vessels per high-power field, P = .007). SDF/GM-CSF group animals experienced less adverse ventricular remodeling, as manifested by less cavitary dilatation (9.8 +/- 0.1 mm vs 10.1 +/- 0.1 mm [control], P = .04) and increased border-zone wall thickness (1.78 +/- 0.19 vs 1.41 +/- 0.16 mm [control], P = .03). (SDF/GM-CSF group animals had improved cardiac function compared with animals in the saline control group (maximum pressure: 93.9 +/- 3.2 vs 71.7 +/- 3.1 mm Hg, P < .001; maximum dP/dt: 3513 +/- 303 vs 2602 +/- 201 mm Hg/s, P < .05; cardiac output: 21.3 +/- 2.7 vs 13.3 +/- 1.3 mL/min, P < .01; end-systolic pressure-volume relationship slope: 1.7 +/- 0.4 vs 0.5 +/- 0.2 mm Hg/microL, P < .01.) CONCLUSION: This novel revascularization strategy of bone marrow stimulation and intramyocardial delivery of the endothelial progenitor cell chemokine stromal cell-derived factor yielded significantly enhanced myocardial endothelial progenitor cell density, vasculogenesis, geometric preservation, and contractility in a model of ischemic cardiomyopathy.