Game theory of mind

This paper introduces a model of ‘theory of mind’, namely, how we represent the intentions and goals of others to optimise our mutual interactions. We draw on ideas from optimum control and game theory to provide a ‘game theory of mind’. First, we consider the representations of goals in terms of value functions that are prescribed by utility or rewards. Critically, the joint value functions and ensuing behaviour are optimised recursively, under the assumption that I represent your value function, your representation of mine, your representation of my representation of yours, and so on ad infinitum. However, if we assume that the degree of recursion is bounded, then players need to estimate the opponent's degree of recursion (i.e., sophistication) to respond optimally. This induces a problem of inferring the opponent's sophistication, given behavioural exchanges. We show it is possible to deduce whether players make inferences about each other and quantify their sophistication on the basis of choices in sequential games. This rests on comparing generative models of choices with, and without, inference. Model comparison is demonstrated using simulated and real data from a ‘stag-hunt’. Finally, we note that exactly the same sophisticated behaviour can be achieved by optimising the utility function itself (through prosocial utility), producing unsophisticated but apparently altruistic agents. This may be relevant ethologically in hierarchal game theory and coevolution

Selective serotonin reuptake inhibitors in the treatment of generalized anxiety disorder

Selective serotonin reuptake inhibitors have proven efficacy in the treatment of panic disorder, obsessive–compulsive disorder, post-traumatic stress disorder and social anxiety disorder. Accumulating data shows that selective serotonin reuptake inhibitor treatment can also be efficacious in patients with generalized anxiety disorder. This review summarizes the findings of randomized controlled trials of selective serotonin reuptake inhibitor treatment for generalized anxiety disorder, examines the strengths and weaknesses of other therapeutic approaches and considers potential new treatments for patients with this chronic and disabling anxiety disorder

Bargaining with Optimism

Excessive optimism is a prominent explanation for bargaining delays. Recent results demonstrate that optimism plays a subtle role in bargaining, and its careful analysis may shed valuable insights into negotiation behavior. This article reviews some of these results, focusing on the following findings. First, when there is a nearby deadline, optimistic players delay the agreement to the last period before the deadline, replicating a broad empirical regularity known as the deadline effect. Second, there cannot be a substantial delay under persistent optimism; i.e., excessive optimism alone cannot explain delays. Third, when optimistic players are expected to learn during the negotiation, they delay the agreement in order to persuade their opponents. The delays in these results can be quite costly, Pareto inefficient, and common knowledge at the beginning of the game

Early and Middle Holocene Hunter-Gatherer Occupations in Western Amazonia: The Hidden Shell Middens

We report on previously unknown early archaeological sites in the Bolivian lowlands, demonstrating for the first time early and middle Holocene human presence in western Amazonia. Multidisciplinary research in forest islands situated in seasonally-inundated savannahs has revealed stratified shell middens produced by human foragers as early as 10,000 years ago, making them the oldest archaeological sites in the region. The absence of stone resources and partial burial by recent alluvial sediments has meant that these kinds of deposits have, until now, remained unidentified. We conducted core sampling, archaeological excavations and an interdisciplinary study of the stratigraphy and recovered materials from three shell midden mounds. Based on multiple lines of evidence, including radiocarbon dating, sedimentary proxies (elements, steroids and black carbon), micromorphology and faunal analysis, we demonstrate the anthropogenic origin and antiquity of these sites. In a tropical and geomorphologically active landscape often considered challenging both for early human occupation and for the preservation of hunter-gatherer sites, the newly discovered shell middens provide evidence for early to middle Holocene occupation and illustrate the potential for identifying and interpreting early open-air archaeological sites in western Amazonia. The existence of early hunter-gatherer sites in the Bolivian lowlands sheds new light on the region's past and offers a new context within which the late Holocene "Earthmovers" of the Llanos de Moxos could have emerged. © 2013 Lombardo et al

Reducing Self-harm in Adolescents. An individual participant data meta-analysis (RISA-IPD): systematic review protocol

Introduction Up to 10% of adolescents report self-harm in the previous year. Non-fatal repetition is common (18% in 1 year), death from any cause shows a fourfold and suicide a 10-fold excess. Despite the scale of the problem, there is insufficient evidence for effective interventions for self-harm. Those who self-harm do so for a variety of different reasons. Different treatments may be more effective for subgroups of adolescents; however, little is known about which subgroups are appropriate for further study. This protocol outlines a systematic review and individual participant data meta-analysis (IPD-MA) to identify subgroups of adolescents for which therapeutic interventions for self-harm show some evidence of benefit. Methods and analysis A systematic literature search was conducted in August 2019 (including Cochrane Library, Embase, trial registers and other databases). An update search is planned. Study selection will identify randomised controlled trials examining interventions to reduce self-harm in adolescents who have self-harmed and presented to services. Identified research teams will be invited to contribute data and form a collaborative group. Two-stage IPD-MA will be used to evaluate effectiveness of different therapeutic interventions compared with any active or non-active control on repetition of self-harm, general psychopathology, depression, suicidal ideation, quality of life and death. Subgroup analyses will identify adolescent subgroups in whom different therapeutic interventions may be more effective. Meta-regression will explore moderating study and intervention effects. Sensitivity analyses will incorporate aggregate data from studies lacking IPD and test the robustness of results to methods for handling missing data, within-study clustering, non-adherence and study quality. Ethics and dissemination Ethical approval is provided by the University of Leeds, Faculty of Medicine and Health Ethics Committee (18-098). Outcomes will inform research recommendations and will be disseminated internationally through the collaborative group, a service user advisory group, open-access peer-reviewed publication and conference presentations. PROSPERO registration number CRD42019152119

Passive Prophylactic Administration with a Single Dose of Anti-Fel d 1 Monoclonal Antibodies REGN1908-1909 in Cat Allergen-Induced Allergic Rhinitis: A Randomized, Double-blind, Placebo Controlled Trial

RATIONALE: Sensitization to Felis domesticus allergen 1 (Fel d 1) contributes to persistent allergic rhinitis and asthma. Existing treatment options for cat allergy, including allergen immunotherapy (AIT) are only moderately effective, and AIT has limited use due to safety concerns. OBJECTIVES: To explore the relationship among the pharmaokinteic, clinical, and immunological effects of REGN1908-1909 (anti-Fel d 1 monoclonal antibodies) in patients after treatment. METHODS: Patients received REGN1908-1909 (n=36) or placebo (n=37) in a phase 1b study. Fel d 1-induced basophil and IgE-facilitated allergen binding responses were evaluated at baseline and days 8, 29 and 85. Cytokine and chemokine levels in nasal fluids were measured. REGN1908-1909 inhibition of allergen-IgE binding in patient serum was evaluated. MEASUREMENTS AND MAIN RESULTS: Peak serum drug concentrations were concordant with maximal observed clinical response. The anti-Fel d 1 IgE/cat-dander IgE ratio in pretreatment serum correlated with Total Nasal Symptom Score improvement. The allergen neutralizing capacity of REGN1908-1909 was observed in serum and nasal fluid, and was detected in an inhibition assay. Type-2 cytokines (IL-4, IL-5 and IL-13) and chemokines (CCL17/TARC, CCL5/RANTES) in nasal fluid were inhibited in REGN1908-1909-treated patients compared to placebo (all P < 0.05); IL-13 and IL-5 levels correlated with TNSS improvement. Ex vivo assays demonstrated that REGN1908 and REGN1909 combined was more potent than each alone for inhibiting FcεRI- and FcεRII (CD23)-mediated allergic responses and subsequent T-cell activation. CONCLUSION: Single passive dose administration of Fel d 1-neutralizing IgG antibodies improved nasal symptoms in cat-allergic patients, and was underscored by suppression of FcεRI-, FcεRII- and Th2-mediated allergic responses. Clinical trial registration available at www.clinicaltrials.gov, ID: NCT02127801

Identification of the Neogenin-Binding Site on the Repulsive Guidance Molecule A

Repulsive guidance molecule (RGM) is a membrane-bound protein that was originally identified as an axon guidance molecule in the chick retinotectal system. RGMa, one of the 3 isoforms found in mammals, is involved in laminar patterning, cephalic neural tube closure, axon guidance, and inhibition of axonal regeneration. In addition to its roles in the nervous system, RGMa plays a role in enhancing helper T-cell activation. Binding of RGM to its receptor, neogenin, is considered necessary to transduce these signals; however, information on the binding of RGM to neogenin is limited. Using co-immunoprecipitation studies, we have identified that the RGMa region required for binding to neogenin contains amino acids (aa) 259–295. Synthesized peptide consisting of aa 284–293 directly binds to the extracellular domain (ECD) of recombinant neogenin, and addition of this peptide inhibits RGMa-induced growth cone collapse in mouse cortical neurons. Thus, we propose that this peptide is a promising lead in finding reagents capable of inhibiting RGMa signaling

Anchoring of proteins to lactic acid bacteria

The anchoring of proteins to the cell surface of lactic acid bacteria (LAB) using genetic techniques is an exciting and emerging research area that holds great promise for a wide variety of biotechnological applications. This paper reviews five different types of anchoring domains that have been explored for their efficiency in attaching hybrid proteins to the cell membrane or cell wall of LAB. The most exploited anchoring regions are those with the LPXTG box that bind the proteins in a covalent way to the cell wall. In recent years, two new modes of cell wall protein anchoring have been studied and these may provide new approaches in surface display. The important progress that is being made with cell surface display of chimaeric proteins in the areas of vaccine development and enzyme- or whole-cell immobilisation is highlighted.

Adding 5-hydroxytryptamine receptor type 3 antagonists may reduce drug-induced nausea in poor insight obsessive-compulsive patients taking off-label doses of selective serotonin reuptake inhibitors: a 52-week follow-up case report

Poor-insight obsessive-compulsive disorder (PI-OCD) is a severe form of OCD where the 'typically obsessive' features of intrusive, 'egodystonic' feelings and thoughts are absent. PI-OCD is difficult to treat, often requiring very high doses of serotonergic drugs as well as antipsychotic augmentation. When this occurs, unpleasant side effects as nausea are common, eventually further reducing compliance to medication and increasing the need for pharmacological alternatives. We present the case of a PI-OCD patient who developed severe nausea after response to off-label doses of the selective serotonin reuptake inhibitor (SSRI), fluoxetine. Drug choices are discussed, providing pharmacodynamic rationales and hypotheses along with reports of rating scale scores, administered within a follow-up period of 52 weeks. A slight reduction of fluoxetine dose, augmentation with mirtazapine and a switch from amisulpride to olanzapine led to resolution of nausea while preserving the anti-OCD therapeutic effect. Mirtazapine and olanzapine have already been suggested for OCD treatment, although a lack of evidence exists about their role in the course of PI-OCD. Both mirtazapine and olanzapine also act as 5-hydroxytryptamine receptor type 3 (5-HT3) blockers, making them preferred choices especially in cases of drug-induced nausea

Regulation of mammary gland branching morphogenesis by the extracellular matrix and its remodeling enzymes.

A considerable body of research indicates that mammary gland branching morphogenesis is dependent, in part, on the extracellular matrix (ECM), ECM-receptors, such as integrins and other ECM receptors, and ECM-degrading enzymes, including matrix metalloproteinases (MMPs) and their inhibitors, tissue inhibitors of metalloproteinases (TIMPs). There is some evidence that these ECM cues affect one or more of the following processes: cell survival, polarity, proliferation, differentiation, adhesion, and migration. Both three-dimensional culture models and genetic manipulations of the mouse mammary gland have been used to study the signaling pathways that affect these processes. However, the precise mechanisms of ECM-directed mammary morphogenesis are not well understood. Mammary morphogenesis involves epithelial 'invasion' of adipose tissue, a process akin to invasion by breast cancer cells, although the former is a highly regulated developmental process. How these morphogenic pathways are integrated in the normal gland and how they become dysregulated and subverted in the progression of breast cancer also remain largely unanswered questions