Diet, Microbiota and Epigenetics as target for innovative strategies against food allergy: deciphering the protective mechanism of butyrate as crucial human milk effector

Objectives and study: The dramatic increase in food allergy prevalence and severity globally requires effective strategies. Food allergy derives from a defect in immune tolerance mechanisms. Immune tolerance is modulated by gut microbiota function and structure , and alterations in the gut microbiome composition (dysbiosis) early in the life have a pivotal role in the development of food allergy. Many environmental factors, including a low-fibre/high-fat diet, caesarean delivery, antiseptic agents, lack of breastfeeding, and drugs can induce gut microbiome dysbiosis, and have been associated with food allergy. New technologies and experimental tools have provided information regarding the importance of metabolites generated from dietary nutrients and selected probiotic strains that could act on immune tolerance mechanisms. The mechanisms are multiple and still not completely defined. Increasing evidence has provided useful information on optimal bacterial species/strains, dosage and timing for intervention. The increased knowledge of the crucial role played by nutrients and gut microbiota-derived metabolites is opening the way to a post-biotic approach in the stimulation of immune tolerance through epigenetic regulation. The mechanisms of the preventive effect of breast milk (BM) against food allergy (FA) are still largely undefined. The short chain fatty acid butyrate has a pivotal role in immune tolerance. We aimed to see whether BM butyrate concentrations are able to exert immune and non-immune tolerogenic effects in human enterocytes, peripheral blood mononuclear cells (PBMCs) from children affected by FA, and in FA animal model. Methods: Mature BM butyrate concentrations from 98 healthy women (aged 21-42 yrs) were assessed by gas-chromatography. Dose-dependent effects of butyrate in human enterocytes (Caco-2 cells) on immune (beta-defensin-3, HBD-3) and non-immune (mucus production; mucin 2, MUC2; tight-junction proteins, zonulin and occludin) were analyzed. PBMCs from 6 children with challenge-proven FA (2 cow milk allergy, 2 peanut allergy, 2 egg allergy; age range 1-5 yrs) were stimulated with b-lactoglobulin (BLG;100μg/ml), peanut extract (PE;200μg/ml) or ovalbumin (OVA;200μg/ml) in the presence or absence of butyrate. Expression and DNA methylation rate of IL4, IL5, IL-10, IFN-γ and Treg-specific-demethylated region (TSDR) Forkhead box Protein 3 (FoxP3) were assessed. Four-weeks-old female C3H/HeJ mice were used in FA animal model. Two weeks before first sensitization, oral gavage with 30 mg/kg/d of butyrate was started and continued during the whole study. Mice were sensitized orally on day 0, 7, 14, 21, 28 with 20 mg of BLG or 1 mg of OVA or 12 mg of PE mixed with 10 µg cholera toxin (CT) as adjuvant. Control mice receive CT only. On day 35 mice were challenged by gavage with BLG (50mg) or OVA (5mg) or PE (36mg). Anaphylaxis score and rectal temperature were assessed for 1 h after challenge and blood samples were collected to measure MCPT-1 and sIgE. After 24h, mice were sacrificed, colon, ileum and spleen were collected. Results: Mean butyrate concentration in BM was 0.75 mM (SD±0.15). Butyrate stimulates HBD-3, mucus production and MUC2, zonulin and occludin expression with maximal effective doses between 0.75 and 1 mM in human enterocytes. PBMCs stimulation with BLG, PE, OVA resulted in a significant increase in IL-4 and IL-5 production. A significant inhibition of IL-4 and IL-5 production was observed with 0.75 mM butyrate. Butyrate stimulated, in a dose-dependent manner (maximal effective dose 0.75 mM), IL-10 and IFN-γ production through a demethylation of respective genes and TSDR FoxP3 demethylation. Pre-treatment with butyrate significantly reduced anaphylactic score, body temperature decrease, serum MCPT-1 and sIgE levels. Butyrate stimulated mucus and IL-10 and IFN-γ production and inhibited IL-4, IL-5 and IL-13 production. Conclusion: Our data support the role of butyrate as effective human milk component able to prevent food allergy through a wide range of immune and non-immune tolerogenic mechanisms. Understanding how nutrients and metabolites, or probiotics could influence gut bacteria communities and the immune system will contribute to building up a precision medicine approach for food allergy care

Quantum Google in a Complex Network

We investigate the behavior of the recently proposed quantum Google algorithm, or quantum PageRank, in large complex networks. Applying the quantum algorithm to a part of the real World Wide Web, we find that the algorithm is able to univocally reveal the underlying scale-free topology of the network and to clearly identify and order the most relevant nodes (hubs) of the graph according to their importance in the network structure. Moreover, our results show that the quantum PageRank algorithm generically leads to changes in the hierarchy of nodes. In addition, as compared to its classical counterpart, the quantum algorithm is capable to clearly highlight the structure of secondary hubs of the network, and to partially resolve the degeneracy in importance of the low lying part of the list of rankings, which represents a typical shortcoming of the classical PageRank algorithm. Complementary to this study, our analysis shows that the algorithm is able to clearly distinguish scale-free networks from other widespread and important classes of complex networks, such as Erd\H{o}s-R\'enyi networks and hierarchical graphs. We show that the ranking capabilities of the quantum PageRank algorithm are related to an increased stability with respect to a variation of the damping parameter $\alpha$ that appears in the Google algorithm, and to a more clearly pronounced power-law behavior in the distribution of importance among the nodes, as compared to the classical algorithm. Finally, we study to which extent the increased sensitivity of the quantum algorithm persists under coordinated attacks of the most important nodes in scale-free and Erd\H{o}s-R\'enyi random graphs

Ultrafast Modification of the Polarity at LaAlO3_3/SrTiO3_3 Interfaces

Oxide growth with semiconductor-like accuracy has led to atomically precise thin films and interfaces that exhibit a plethora of phases and functionalities not found in the oxide bulk material. This yielded spectacular discoveries such as the conducting, magnetic or even superconducting LaAlO$_3$/SrTiO$_3$ interfaces separating two prototypical insulating perovskite materials. All these investigations, however, consider the static state at the interface, although studies on fast oxide interface dynamics would introduce a powerful degree of freedom to understanding the nature of the LaAlO$_3$/SrTiO$_3$ interface state. Here we show that the polarization state at the LaAlO$_3$/SrTiO$_3$ interface can be optically enhanced or attenuated within picoseconds. Our observations are explained by a model based on charge propagation effects in the interfacial vicinity and transient polarization buildup at the interface

Quantum speedup for active learning agents

Can quantum mechanics help us in building intelligent robots and agents? One of the defining characteristics of intelligent behavior is the capacity to learn from experience. However, a major bottleneck for agents to learn in any real-life situation is the size and complexity of the corresponding task environment. Owing to, e.g., a large space of possible strategies, learning is typically slow. Even for a moderate task environment, it may simply take too long to rationally respond to a given situation. If the environment is impatient, allowing only a certain time for a response, an agent may then be unable to cope with the situation and to learn at all. Here we show that quantum physics can help and provide a significant speed-up for active learning as a genuine problem of artificial intelligence. We introduce a large class of quantum learning agents for which we show a quadratic boost in their active learning efficiency over their classical analogues. This result will be particularly relevant for applications involving complex task environments.Comment: Minor updates, 14 pages, 3 figure

Treatment barriers, preferences and histories of individuals with symptoms of body dysmorphic disorder.

BackgroundIndividuals with mental health concerns face many barriers when accessing psychological treatment. Even when patients overcome these barriers, they often do not receive an evidence-based treatment. Although the current literature highlights these issues clearly across psychological disorders, the research is limited in relation to body dysmorphic disorder (BDD).AimThe aim of this study was to examine psychological treatment barriers, treatment delivery preferences and treatment histories of individuals with symptoms of BDD.MethodA total of 122 participants with clinically significant BDD symptoms (94% female; mean age = 34.19 years, SD = 10.86) completed the cross-sectional study.ResultsThe most frequently reported barriers to accessing psychological treatment for individuals with BDD symptoms were the cost of treatment (41%) and the belief that the symptoms did not warrant treatment (36%). Although 69% of treatment-seeking participants reported previously receiving cognitive behavioural therapy (CBT) for BDD, only 13% of participants appeared to receive best-practice CBT. The preferred modality of future psychological treatment delivery was face-to-face treatment with a therapist once a week (63%), rather than accelerated or remote treatment approaches.ConclusionsThe study suggests that there are significant barriers to accessing CBT for BDD. Reducing these barriers, as well as increasing consumer mental health literacy, is required to improve treatment access and treatment outcomes for individuals with BDD