Mycobacterial toxin induces analgesia in buruli ulcer by targeting the angiotensin pathways.

Mycobacterium ulcerans, the etiological agent of Buruli ulcer, causes extensive skin lesions, which despite their severity are not accompanied by pain. It was previously thought that this remarkable analgesia is ensured by direct nerve cell destruction. We demonstrate here that M. ulcerans-induced hypoesthesia is instead achieved through a specific neurological pathway triggered by the secreted mycobacterial polyketide mycolactone. We decipher this pathway at the molecular level, showing that mycolactone elicits signaling through type 2 angiotensin II receptors (AT2Rs), leading to potassium-dependent hyperpolarization of neurons. We further validate the physiological relevance of this mechanism with in vivo studies of pain sensitivity in mice infected with M. ulcerans, following the disruption of the identified pathway. Our findings shed new light on molecular mechanisms evolved by natural systems for the induction of very effective analgesia, opening up the prospect of new families of analgesics derived from such systems.

Human-environment feedback and the consistency of proenvironmental behavior.

Addressing global environmental crises such as anthropogenic climate change requires the consistent adoption of proenvironmental behavior by a large part of a population. Here, we develop a mathematical model of a simple behavior-environment feedback loop to ask how the individual assessment of the environmental state combines with social interactions to influence the consistent adoption of proenvironmental behavior, and how this feeds back to the perceived environmental state. In this stochastic individual-based model, individuals can switch between two behaviors, 'active' (or actively proenvironmental) and 'baseline', differing in their perceived cost (higher for the active behavior) and environmental impact (lower for the active behavior). We show that the deterministic dynamics and the stochastic fluctuations of the system can be approximated by ordinary differential equations and a Ornstein-Uhlenbeck type process. By definition, the proenvironmental behavior is adopted consistently when, at population stationary state, its frequency is high and random fluctuations in frequency are small. We find that the combination of social and environmental feedbacks can promote the spread of costly proenvironmental behavior when neither, operating in isolation, would. To be adopted consistently, strong social pressure for proenvironmental action is necessary but not sufficient-social interactions must occur on a faster timescale compared to individual assessment, and the difference in environmental impact must be small. This simple model suggests a scenario to achieve large reductions in environmental impact, which involves incrementally more active and potentially more costly behavior being consistently adopted under increasing social pressure for proenvironmentalism.

Prophylactic Proton Pump Inhibitors in Upper Gastrointestinal Bleeding: Impact and Underprescription in a French Multicentric Cohort.

BACKGROUND: Appropriate prescription of Proton pump inhibitors (PPIs) remains an important concern amid the rising overuse. A gap exists in the literature regarding the benefit of PPI prophylaxis and the consequences of underprescription in patients at risk for upper gastrointestinal bleeding (UGIB). AIMS: This study aims to describe the characteristics of hemorrhage in relation to PPI use in patients experiencing UGIB, with a focus on high-risk individuals requiring gastroprotection. METHODS: Data from a French multicentric cohort of patients experiencing UGIB were analyzed. Patients using PPI were compared to those without PPI considering bleeding etiologies and outcomes of peptic ulcer disease (PUD)-related hemorrhage. The rate of PPI use and its effect on bleeding characteristics in high-risk populations, defined based on international guidelines, were also assessed. RESULTS: Among 2497 included patients, 31.1% were on PPI at bleeding onset. PPI users exhibited a significantly lower rate of PUD-related bleeding in comparison with those without PPI (24.7 vs 40.8%, respectively, p < 0.0001). Similar difference was observed in high-risk populations, of whom, only 40.3% had gastroprotection with PPI before bleeding onset. PPI prophylaxis, however, did not influence the severity of bleeding in the general study population or in high-risk groups. Multivariate analysis identified age, comorbidities, and having more than two anti-thrombotic agents as predictors of severe bleeding. CONCLUSIONS: PPI users appear to have a lower rate of bleeding ulcers compared to non-users. However, underprescription in high-risk groups raises the need for standardized care to ensure appropriate PPI use.

Evaluation of Different Types of Stimuli in an Event-Related Potential-Based Brain-Computer Interface Speller under Rapid Serial Visual Presentation.

Rapid serial visual presentation (RSVP) is currently a suitable gaze-independent paradigm for controlling visual brain-computer interfaces (BCIs) based on event-related potentials (ERPs), especially for users with limited eye movement control. However, unlike gaze-dependent paradigms, gaze-independent ones have received less attention concerning the specific choice of visual stimuli that are used. In gaze-dependent BCIs, images of faces-particularly those tinted red-have been shown to be effective stimuli. This study aims to evaluate whether the colour of faces used as visual stimuli influences ERP-BCI performance under RSVP. Fifteen participants tested four conditions that varied only in the visual stimulus used: grey letters (GL), red famous faces with letters (RFF), green famous faces with letters (GFF), and blue famous faces with letters (BFF). The results indicated significant accuracy differences only between the GL and GFF conditions, unlike prior gaze-dependent studies. Additionally, GL achieved higher comfort ratings compared with other face-related conditions. This study highlights that the choice of stimulus type impacts both performance and user comfort, suggesting implications for future ERP-BCI designs for users requiring gaze-independent systems.

Peace is a form of cooperation, and so are the cultural technologies which make peace possible.

While necessary parts of the puzzle, cultural technologies are insufficient to explain peace. They are a form of second-order cooperation - a cooperative interaction designed to incentivize first-order cooperation. We propose an explanation for peacemaking cultural technologies, and therefore peace, based on the reputational incentives for second-order cooperation.

Comparison of Two Paradigms Based on Stimulation with Images in a Spelling Brain-Computer Interface.

A P300-based speller can be used to control a home automation system via brain activity. Evaluation of the visual stimuli used in a P300-based speller is a common topic in the field of brain-computer interfaces (BCIs). The aim of the present work is to compare, using the usability approach, two types of stimuli that have provided high performance in previous studies. Twelve participants controlled a BCI under two conditions, which varied in terms of the type of stimulus employed: a red famous face surrounded by a white rectangle (RFW) and a range of neutral pictures (NPs). The usability approach included variables related to effectiveness (accuracy and information transfer rate), efficiency (stress and fatigue), and satisfaction (pleasantness and System Usability Scale and Affect Grid questionnaires). The results indicated that there were no significant differences in effectiveness, but the system that used NPs was reported as significantly more pleasant. Hence, since satisfaction variables should also be considered in systems that potential users are likely to employ regularly, the use of different NPs may be a more suitable option than the use of a single RFW for the development of a home automation system based on a visual P300-based speller.

Reciprocal contracts - not competitive acquisition - explain the moral psychology of ownership.

We applaud Boyer's attempt to ground the psychology of ownership partly in a cooperative logic. In this commentary, we propose to go further and ground the psychology of ownership solely in a cooperative logic. The predictions of bargaining theory, we argue, completely contradict the actual features of ownership intuitions. Ownership is only about the calculation of mutually beneficial, reciprocal contracts.

The puritanical moral contract: Purity, cooperation, and the architecture of the moral mind.

Commentators raise fundamental questions about the notion of purity (sect. R1), the architecture of moral cognition (sect. R2), the functional relationship between morality and cooperation (sect. R3), the role of folk-theories of self-control in moral judgment (sect. R4), and the cultural variation of morality (sect. R5). In our response, we address all these issues by clarifying our theory of puritanism, responding to counter-arguments, and incorporating welcome corrections and extensions.

Cooperation as a signal of time preferences.

Many evolutionary models explain why we cooperate with non-kin, but few explain why cooperative behaviour and trust vary. Here, we introduce a model of cooperation as a signal of time preferences, which addresses this variability. At equilibrium in our model (i) future-oriented individuals are more motivated to cooperate, (ii) future-oriented populations have access to a wider range of cooperative opportunities, and (iii) spontaneous and inconspicuous cooperation reveal stronger preference for the future, and therefore inspire more trust. Our theory sheds light on the variability of cooperative behaviour and trust. Since affluence tends to align with time preferences, results (i) and (ii) explain why cooperation is often associated with affluence, in surveys and field studies. Time preferences also explain why we trust others based on proxies for impulsivity, and, following result (iii), why uncalculating, subtle and one-shot cooperators are deemed particularly trustworthy. Time preferences provide a powerful and parsimonious explanatory lens, through which we can better understand the variability of trust and cooperation.

Moral disciplining: The cognitive and evolutionary foundations of puritanical morality.

Why do many societies moralize apparently harmless pleasures, such as lust, gluttony, alcohol, drugs, and even music and dance? Why do they erect temperance, asceticism, sobriety, modesty, and piety as cardinal moral virtues? According to existing theories, this puritanical morality cannot be reduced to concerns for harm and fairness: It must emerge from cognitive systems that did not evolve for cooperation (e.g., disgust-based "purity" concerns). Here, we argue that, despite appearances, puritanical morality is no exception to the cooperative function of moral cognition. It emerges in response to a key feature of cooperation, namely that cooperation is (ultimately) a long-term strategy, requiring (proximately) the self-control of appetites for immediate gratification. Puritanical moralizations condemn behaviors which, although inherently harmless, are perceived as indirectly facilitating uncooperative behaviors, by impairing the self-control required to refrain from cheating. Drinking, drugs, immodest clothing, and unruly music and dance are condemned as stimulating short-term impulses, thus facilitating uncooperative behaviors (e.g., violence, adultery, free-riding). Overindulgence in harmless bodily pleasures (e.g., masturbation, gluttony) is perceived as making people slave to their urges, thus altering abilities to resist future antisocial temptations. Daily self-discipline, ascetic temperance, and pious ritual observance are perceived as cultivating the self-control required to honor prosocial obligations. We review psychological, historical, and ethnographic evidence supporting this account. We use this theory to explain the fall of puritanism in western, educated, industrialized, rich, and democratic (WEIRD) societies, and discuss the cultural evolution of puritanical norms. Explaining puritanical norms does not require adding mechanisms unrelated to cooperation in our models of the moral mind.

Ketogenic Diet Impairment of Mycobacterium ulcerans Growth and Toxin Production and Enhancement of Host Response to Infection in an Experimental Mouse Model.

Ketogenic diets have been used to treat diverse conditions, and there is growing evidence of their benefits for tissue repair and in inflammatory disease treatment. However, their role in infectious diseases has been little studied. Buruli ulcer (Mycobacterium ulcerans infection) is a chronic infectious disease characterized by large skin ulcerations caused by mycolactone, the major virulence factor of the bacillus. In the current study, we investigated the impact of ketogenic diet on this cutaneous disease in an experimental mouse model. This diet prevented ulceration, by modulating bacterial growth and host inflammatory response. ß-hydroxybutyrate, the major ketone body produced during ketogenic diet and diffusing in tissues, impeded M. ulcerans growth and mycolactone production in vitro underlying its potential key role in infection. These results pave the way for the development of new patient management strategies involving shorter courses of treatment and improving wound healing, in line with the major objectives of the World Health Organization.

The emergence of cooperation by evolutionary generalization.

In principle, any cooperative behaviour can be evolutionarily stable as long as it is incentivized by a reward from the beneficiary, a mechanism that has been called reciprocal cooperation. However, what makes this mechanism so powerful also has an evolutionary downside. Reciprocal cooperation faces a chicken-and-egg problem of the same kind as communication: it requires two functions to evolve at the same time-cooperation and response to cooperation. As a result, it can only emerge if one side first evolves for another reason, and is then recycled into a reciprocal function. Developing an evolutionary model in which we make use of machine learning techniques, we show that this occurs if the fact to cooperate and reward others' cooperation become general abilities that extend beyond the set of contexts for which they have initially been selected. Drawing on an evolutionary analogy with the concept of generalization, we identify the conditions necessary for this to happen. This allows us to understand the peculiar distribution of reciprocal cooperation in the wild, virtually absent in most species-or limited to situations where individuals have partially overlapping interests, but pervasive in the human species.

3D printing of silica glass through a multiphoton polymerization process.

We introduce a laser-based process relying on multiphoton-induced polymerization to produce complex three-dimensional (3D) glass parts. A focused, intense laser beam is used to polymerize a transparent resin, loaded with additives and silica nanoparticles, at the wavelength of the laser beam through nonlinear absorption processes. The object is created directly in the volume, overcoming the limitation of the layer-by-layer process. The process enables the production of silica parts with consecutive debinding and sintering processes. With bulk silica density and a resolution that depends on the laser spot size, 3D objects of centimetric dimensions are obtained.

Nothing better to do? Environment quality and the evolution of cooperation by partner choice.

The effects of partner choice have been documented in a large number of biological systems such as sexual markets, interspecific mutualisms, or human cooperation. There are, however, a number of situations in which one would expect this mechanism to play a role, but where no such effect has ever been demonstrated. This is the case in particular in many intraspecific interactions, such as collective hunts, in non-human animals. Here we use individual-based simulations to solve this apparent paradox. We show that the conditions for partner choice to operate are in fact restrictive. They entail that individuals can compare social opportunities and choose the best. The challenge is that social opportunities are often rare because they necessitate the co-occurrence of (i) at least one available partner, and (ii) a resource to exploit together with this partner. This has three consequences. First, partner choice cannot lead to the evolution of cooperation when resources are scarce, which explains that this mechanism could never be observed in many cases of intraspecific cooperation in animals. Second, partner choice can operate when partners constitute in themselves a resource, which is the case in sexual interactions and interspecific mutualisms. Third, partner choice can lead to the evolution of cooperation when individuals live in a rich environment, and/or when they are highly efficient at extracting resources from their environment.

Evolution of Hepatitis C Virus Treatment During the Era of Sofosbuvir-Based Therapies: A Real-World Experience in France.

BACKGROUND: Treatment of hepatitis C virus (HCV) has been dramatically improved with the introduction of direct-acting antiviral agents (DAAs). Universal access to pangenotypic DAAs was provided in France from 2017, expanding the type of patients treated. Real-world studies are important to confirm effectiveness and safety in clinical practice, particularly in vulnerable populations. AIMS: To assess real-world effectiveness and safety of sofosbuvir-based therapy in adults with chronic HCV infection before and after universal access to DAAs in France. METHODS: This multicenter, non-interventional, prospective study assessed the effectiveness, safety, patient-reported outcomes and adherence with sofosbuvir-based regimens from October 2015 to July 2016 (Period 1: sofosbuvir-based therapy excluding sofosbuvir/velpatasvir) and from October 2017 to July 2018 (Period 2: pangenotypic sofosbuvir/velpatasvir-based therapy). RESULTS: Baseline data were documented for 1029 patients. Overall, 797 (77%) had sustained virologic response data available ≥ 9 weeks after treatment completion. Per protocol response was high (97%) irrespective of age, alcohol consumption, recreational drug use, or HIV/HCV coinfection. Adverse events occurred in approximately 25% of patients with the majority experiencing Grade 1 or 2 events. Sofosbuvir-based regimens improved health-related quality of life from baseline to end of treatment in patients with data at all timepoints. Overall, 99% of patients reported total or almost total adherence to therapy. CONCLUSIONS: Sofosbuvir-based therapy, including pangenotypic sofosbuvir/velpatasvir, is effective for the treatment of HCV in real-world clinical practice. This is an important step towards HCV elimination.

The evolution of music: One trait, many ultimate-level explanations.

We propose an approach reconciling the ultimate-level explanations proposed by Savage et al. and Mehr et al. as to why music evolved. We also question the current adaptationist view of culture, which too often fails to disentangle distinct fitness benefits.

σ-Conjugation and H-Bond-Directed Supramolecular Self-Assembly: Key Features for Efficient Long-Lived Room Temperature Phosphorescent Organic Molecular Crystals.

Long-lived room temperature phosphorescence from organic molecular crystals attracts great attention. Persistent luminescence depends on the electronic properties of the molecular components, mainly π-conjugated donor-acceptor (D-A) chromophores, and their molecular packing. Here, a strategy is developed by designing two isomeric molecular phosphors incorporating and combining a bridge for σ-conjugation between the D and A units and a structure-directing unit for H-bond-directed supramolecular self-assembly. Calculations highlight the critical role played by the two degrees of freedom of the σ-conjugated bridge on the chromophore optical properties. The molecular crystals exhibit RTP quantum yields up to 20 % and lifetimes up to 520 ms. The crystal structures of the efficient phosphorescent materials establish the existence of an unprecedented well-organization of the emitters into 2D rectangular columnar-like supramolecular structure stabilized by intermolecular H-bonding.

Why cooperation is not running away.

A growing number of experimental and theoretical studies show the importance of partner choice as a mechanism to promote the evolution of cooperation, especially in humans. In this paper, we focus on the question of the precise quantitative level of cooperation that should evolve under this mechanism. When individuals compete to be chosen by others, their level of investment in cooperation evolves towards higher values, a process called competitive altruism, or runaway cooperation. Using a classic adaptive dynamics model, we first show that when the cost of changing partner is low, this runaway process can lead to a profitless escalation of cooperation. In the extreme, when partner choice is entirely frictionless, cooperation even increases up to a level where its cost entirely cancels out its benefit. That is, at evolutionary equilibrium, individuals gain the same payoff than if they had not cooperated at all. Second, importing models from matching theory in economics we, however, show that when individuals can plastically modulate their choosiness in function of their own cooperation level, partner choice stops being a runaway competition to outbid others and becomes a competition to form the most optimal partnerships. In this case, when the cost of changing partner tends towards zero, partner choice leads to the evolution of the socially optimum level of cooperation. This last result could explain the observation that human cooperation seems to be often constrained by considerations of social efficiency.

Kossel Effect in Periodic Multilayers.

The Kossel effect is the diffraction by a periodically structured medium, of the characteristic X-ray radiation emitted by the atoms of the medium. We show that multilayers designed for X-ray optics applications are convenient periodic systems to use in order to produce the Kossel effect, modulating the intensity emitted by the sample in a narrow angular range defined by the Bragg angle. We also show that excitation can be done by using photons (X-rays), electrons or protons (or charged particles), under near normal or grazing incident geometries, which makes the method relatively easy to implement. The main constraint comes from the angular resolution necessary for the detection of the emitted radiation. This leads to small solid angles of detection and long acquisition times to collect data with sufficient statistical significance. Provided this difficulty is overcome, the comparison or fit of the experimental Kossel curves, i.e., the angular distributions of the intensity of an emitted radiation of one of the element of the periodic stack, with the simulated curves enables getting information on the depth distribution of the elements throughout the multilayer. Thus the same kind of information obtained from the more widespread method of X-ray standing wave induced fluorescence used to characterize stacks of nanometer period, can be obtained using the Kossel effect.

Effects of Age on Treatment of Chronic Hepatitis C with Direct Acting Antivirals.

INTRODUCTION AND AIM: Data on the efficacy and tolerance of interferon-free treatment in chronic hepatitis C (CHC) in elderly patients are limited in phase II-III trials. MATERIAL AND METHODS: A prospective cohort of adult patients with CHC treated in French general hospitals. RESULTS: Data from 1,123 patients, distributed into four age groups, were analyzed. Of these, 278 were > 64 years old (fourth quartile) and 133 were > 73 years old (tenth decile). Elderly patients weighed less, were more frequently treatment-experienced women infected with genotype 1b or 2, while they less frequently had genotype 3 or HIV coinfection, but had more frequent comorbidities and drug consumption. Half of the patients had cirrhosis, whatever their ages. The main treatment regimens were sofosbuvir/ledipasvir (37.8%), sofosbuvir/daclatasvir (31.8%), sofosbuvir/simeprevir (16.9%), sofosbuvir/ribavirin (7.8%); ribavirin was given to 24% of patients. The overall sustained virological response (SVR) rate was 91.0 % (95% CI: 89.292.5%) with no difference according to age. Logistic regression of the independent predictors of SVR were albumin, hepatocellular carcinoma and treatment regimen, but not age. The rate of severe adverse events (66 in 59/1062 [5.6%] patients) tended to be greater in patients older than 64 years of age (21/261,8.1%), but the only independent predictors of SAE by logistic regression were cirrhosis and baseline hemoglobin. Patient-reported overall tolerance was excellent in all age groups, and patient-reported fatigue decreased during and after treatment, independent of age. CONCLUSIONS: The high efficacy and tolerance of interferon-free regimens is confirmed in elderly patients in real-life conditions.