Sacubitril/valsartan reverses cardiac structure and function in experimental model of hypertension-induced hypertrophic cardiomyopathy.

This study evaluated the effect of sacubtril/valsartan on cardiac remodeling, molecular and cellular adaptations in experimental (rat) model of hypertension-induced hypertrophic cardiomyopathy. Thirty Wistar Kyoto rats, 10 healthy (control) and 20 rats with confirmed hypertension-induced hypertrophic cardiomyopathy (HpCM), were used for this study. The HpCM group was further subdivided into untreated and sacubitril/valsartan-treated groups. Myocardial structure and function were assessed using echocardiography, Langendorff's isolated heart experiment, blood sampling and qualitative polymerase chain reaction. Echocardiographic examinations revealed protective effects of sacubitril/valsartan by improving left ventricular internal diameter in systole and diastole and fractional shortening. Additionally, sacubitril/valsartan treatment decreased systolic and diastolic blood pressures in comparison with untreated hypertensive rats. Moreover, sacubitril/valsartan treatment reduced oxidative stress and apoptosis (reduced expression of Bax and Cas9 genes) compared to untreated rats. There was a regular histomorphology of cardiomyocytes, interstitium, and blood vessels in treated rats compared to untreated HpCM rats which expressed hypertrophic cardiomyocytes, with polymorphic nuclei, prominent nucleoli and moderately dilated interstitium. In experimental model of hypertension-induced hypertrophic cardiomyopathy, sacubitril/valsartan treatment led to improved cardiac structure, haemodynamic performance, and reduced oxidative stress and apoptosis. Sacubitril/valsartan thus presents as a potential therapeutic strategy resulted in hypertension-induced hypertrophic cardiomyopathy.

Fast deliberation is related to unconditional behaviour in iterated Prisoners' Dilemma experiments.

People have different preferences for what they allocate for themselves and what they allocate to others in social dilemmas. These differences result from contextual reasons, intrinsic values, and social expectations. What is still an area of debate is whether these differences can be estimated from differences in each individual's deliberation process. In this work, we analyse the participants' reaction times in three different experiments of the Iterated Prisoner's Dilemma with the Drift Diffusion Model, which links response times to the perceived difficulty of the decision task, the rate of accumulation of information (deliberation), and the intuitive attitudes towards the choices. The correlation between these results and the attitude of the participants towards the allocation of resources is then determined. We observe that individuals who allocated resources equally are correlated with more deliberation than highly cooperative or highly defective participants, who accumulate evidence more quickly to reach a decision. Also, the evidence collection is faster in fixed neighbour settings than in shuffled ones. Consequently, fast decisions do not distinguish cooperators from defectors in these experiments, but appear to separate those that are more reactive to the behaviour of others from those that act categorically.

Inferring strategies from observations in long iterated Prisoner's dilemma experiments.

While many theoretical studies have revealed the strategies that could lead to and maintain cooperation in the Iterated Prisoner's dilemma, less is known about what human participants actually do in this game and how strategies change when being confronted with anonymous partners in each round. Previous attempts used short experiments, made different assumptions of possible strategies, and led to very different conclusions. We present here two long treatments that differ in the partner matching strategy used, i.e. fixed or shuffled partners. Here we use unsupervised methods to cluster the players based on their actions and then Hidden Markov Model to infer what the memory-one strategies are in each cluster. Analysis of the inferred strategies reveals that fixed partner interaction leads to behavioral self-organization. Shuffled partners generate subgroups of memory-one strategies that remain entangled, apparently blocking the self-selection process that leads to fully cooperating participants in the fixed partner treatment. Analyzing the latter in more detail shows that AllC, AllD, TFT- and WSLS-like behavior can be observed. This study also reveals that long treatments are needed as experiments with less than 25 rounds capture mostly the learning phase participants go through in these kinds of experiments.

Delegation to artificial agents fosters prosocial behaviors in the collective risk dilemma.

Home assistant chat-bots, self-driving cars, drones or automated negotiation systems are some of the several examples of autonomous (artificial) agents that have pervaded our society. These agents enable the automation of multiple tasks, saving time and (human) effort. However, their presence in social settings raises the need for a better understanding of their effect on social interactions and how they may be used to enhance cooperation towards the public good, instead of hindering it. To this end, we present an experimental study of human delegation to autonomous agents and hybrid human-agent interactions centered on a non-linear public goods dilemma with uncertain returns in which participants face a collective risk. Our aim is to understand experimentally whether the presence of autonomous agents has a positive or negative impact on social behaviour, equality and cooperation in such a dilemma. Our results show that cooperation and group success increases when participants delegate their actions to an artificial agent that plays on their behalf. Yet, this positive effect is less pronounced when humans interact in hybrid human-agent groups, where we mostly observe that humans in successful hybrid groups make higher contributions earlier in the game. Also, we show that participants wrongly believe that artificial agents will contribute less to the collective effort. In general, our results suggest that delegation to autonomous agents has the potential to work as commitment devices, which prevent both the temptation to deviate to an alternate (less collectively good) course of action, as well as limiting responses based on betrayal aversion.

Pseudevernia furfuracea inhibits migration and invasion of colorectal carcinoma cell lines.

ETHNOPHARMACOLOGICAL RELEVANCE: Pseudevernia furfuracea (L.) Zopf is common lichen species, traditionally used worldwide in treating various medical conditions, among which are intestinal issues and cancer. Most studies are focused mainly on cytotoxic potential of lichens, whilst their antimigratory and antiinvasive properties are often disregarded. Migration and invasion of cancer cells are pivotal processes in cancer metastasis, wherein cancer cells are able to migrate individually or in form of a coherent mass. One of successful strategies in anticancer treatments is targeting Wnt/ß-catenin signal pathway, that is aberrantly activated in colorectal carcinoma, as well as lowering level of migratory/invasive markers. AIM OF THE STUDY: Present study aimed to show antimigratory/invasive potential of Pseudevernia furfuracea methanol extract on HCT-116 and SW-480 colorectal carcinoma cell lines and to elucidate possible mechanism of its action. MATERIALS AND METHODS: Collective cell migration was assessed by Wound healing assay and single cell migration in real time by RTCA method. Analysis of anti- and promigratory protein expression was performed using immunofluorescent staining. Additionally, gene expression of antimigratory/promigratory and invasive (E-cadherin, ß-catenin, N-cadherin, Vimentin, Snail and MMP-9) markers were investigated by qRT-PCR method. Concentration of MMP-9 was determined colorimetrically by ELISA test. RESULTS: P. furfuracea extract was able to suppress both collective and single cancer cell migration, by inhibiting expression of promigratory/invasive markers and possibly re-establishing cell-cell adhesions. The present study indicates at P. furfuracea as effective antimigratory treatment, and HCT-116 cells were proved to be a more sensitive cell line to applied treatment. CONCLUSIONS: This lichen species is a promising candidate for application in treatment of cancer in order to prevent metastasis.

The Beneficial Role of Filipendula ulmaria Extract in Prevention of Prodepressant Effect and Cognitive Impairment Induced by Nanoparticles of Calcium Phosphates in Rats.

Mineral components of dental composites are used in many medical and dental applications, including preventive, restorative, and regenerative dentistry. To evaluate the behavioural alterations induced by nanosized particles of novel dental composites, by means of depressive level and cognitive functions, experimental groups of rats were chronically administered with nanosized hydroxyapatite (HA), tricalcium phosphate (TCP), and amorphous calcium phosphate (ACP) with or without simultaneous application of Filipendula ulmaria L. (FU) methanolic extract. The significant prodepressant action was observed in groups solely treated with HA and ACP. Besides, prolonged treatment with ACP also resulted in a significant decline in cognitive functions estimated in the novel object recognition test. The adverse impact of calcium phosphates on estimated behavioural functions was accompanied by increased oxidative damage and apoptotic markers in the prefrontal cortex, as well as diminished specific neurotrophin (BDNF) and gabaergic expression. The results of our investigation showed that simultaneous antioxidant supplementation with FU extract prevented calcium phosphate-induced behavioural disturbances, as well as prooxidative and apoptotic actions, with the simultaneous restoration of BDNF and GABA-A receptors in the prefrontal cortex. These findings suggest that FU may be useful in the prevention of prodepressant impact and cognitive decline as early as the manifestation of calcium phosphate-induced neurotoxicity.

Timing Uncertainty in Collective Risk Dilemmas Encourages Group Reciprocation and Polarization.

Social dilemmas are often shaped by actions involving uncertain returns only achievable in the future, such as climate action or voluntary vaccination. In this context, uncertainty may produce non-trivial effects. Here, we assess experimentally - through a collective risk dilemma - the effect of timing uncertainty, i.e. how uncertainty about when a target needs to be reached affects the participants' behaviors. We show that timing uncertainty prompts not only early generosity but also polarized outcomes, where participants' total contributions are distributed unevenly. Furthermore, analyzing participants' behavior under timing uncertainty reveals an increase in reciprocal strategies. A data-driven game-theoretical model captures the self-organizing dynamics underpinning these behavioral patterns. Timing uncertainty thus casts a shadow on the future that leads participants to respond early, whereas reciprocal strategies appear to be important for group success. Yet, the same uncertainty also leads to inequity and polarization, requiring the inclusion of new incentives handling these societal issues.

Do people imitate when making decisions? Evidence from a spatial Prisoner's Dilemma experiment.

How do people decide which action to take? This question is best answered using Game Theory, which has proposed a series of decision-making mechanisms that people potentially use. In network simulations, wherein games are repeated and pay-off differences can be observed, those mechanisms often rely on imitation of successful behaviour. Surprisingly, little to no evidence has been provided about whether people actually imitate more successful opponents when altering their actions in that context. By comparing two experimental treatments wherein participants play the iterated Prisoner's Dilemma game in a lattice, we aim to answer whether more successful actions are imitated. While in the first treatment, participants have the possibility to use pay-off differences in making their decision, the second treatment hinders such imitation as no information about the gains is provided. If imitation of the more successful plays a role then there should be a difference in how players switch from cooperation to defection between both treatments. Although, cooperation and pay-off levels do not appear to be significantly different between both treatments, detailed analysis shows that there are behavioural differences: when confronted with a more successful co-player, the focal player will imitate her behaviour as the switching is related to the experienced pay-off inequality.

A quantitative description of the transition between intuitive altruism and rational deliberation in iterated Prisoner's Dilemma experiments.

What is intuitive: pro-social or anti-social behaviour? To answer this fundamental question, recent studies analyse decision times in game theory experiments under the assumption that intuitive decisions are fast and that deliberation is slow. These analyses keep track of the average time taken to make decisions under different conditions. Lacking any knowledge of the underlying dynamics, such simplistic approach might however lead to erroneous interpretations. Here we model the cognitive basis of strategic cooperative decision making using the Drift Diffusion Model to discern between deliberation and intuition and describe the evolution of the decision making in iterated Prisoner's Dilemma experiments. We find that, although initially people's intuitive decision is to cooperate, rational deliberation quickly becomes dominant over an initial intuitive bias towards cooperation, which is fostered by positive interactions as much as frustrated by a negative one. However, this initial pro-social tendency is resilient, as after a pause it resets to the same initial value. These results illustrate the new insight that can be achieved thanks to a quantitative modelling of human behavior.

Trends of the World Input and Output Network of Global Trade.

The international trade naturally maps onto a complex networks. Theoretical analysis of this network gives valuable insights about the global economic system. Although different economic data sets have been investigated from the network perspective, little attention has been paid to its dynamical behaviour. Here we take the World Input Output Data set, which has values of the annual transactions between 40 different countries of 35 different sectors for the period of 15 years, and infer the time interdependence between countries and sectors. As a measure of interdependence we use correlations between various time series of the network characteristics. First we form 15 primary networks for each year of the data we have, where nodes are countries and links are annual exports from one country to the other. Then we calculate the strengths (weighted degree) and PageRank of each country in each of the 15 networks for 15 different years. This leads to sets of time series and by calculating the correlations between these we form a secondary network where the links are the positive correlations between different countries or sectors. Furthermore, we also form a secondary network where the links are negative correlations in order to study the competition between countries and sectors. By analysing this secondary network we obtain a clearer picture of the mutual influences between countries. As one might expect, we find that political and geographical circumstances play an important role. However, the derived correlation network reveals surprising aspects which are hidden in the primary network. Sometimes countries which belong to the same community in the original network are found to be competitors in the secondary networks. E.g. Spain and Portugal are always in the same trade flow community, nevertheless secondary network analysis reveal that they exhibit contrary time evolution.

A comparative analysis of spatial Prisoner's Dilemma experiments: conditional cooperation and payoff irrelevance.

We have carried out a comparative analysis of data collected in three experiments on Prisoner's Dilemmas on lattices available in the literature. We focus on the different ways in which the behavior of human subjects can be interpreted, in order to empirically narrow down the possibilities for behavioral rules. Among the proposed update dynamics, we find that the experiments do not provide significant evidence for non-innovative game dynamics such as imitate-the-best or pairwise comparison rules, whereas moody conditional cooperation is supported by the data from all three experiments. This conclusion questions the applicability of many theoretical models that have been proposed to understand human behavior in spatial Prisoner's Dilemmas. A rule compatible with all our experiments, moody conditional cooperation, suggests that there is no detectable influence of interaction networks on the emergence of cooperation in behavioral experiments.

Consistent strategy updating in spatial and non-spatial behavioral experiments does not promote cooperation in social networks.

The presence of costly cooperation between otherwise selfish actors is not trivial. A prominent mechanism that promotes cooperation is spatial population structure. However, recent experiments with human subjects report substantially lower level of cooperation then predicted by theoretical models. We analyze the data of such an experiment in which a total of 400 players play a Prisoner's Dilemma on a 4×4 square lattice in two treatments, either interacting via a fixed square lattice (15 independent groups) or with a population structure changing after each interaction (10 independent groups). We analyze the statistics of individual decisions and infer in which way they can be matched with the typical models of evolutionary game theorists. We find no difference in the strategy updating between the two treatments. However, the strategy updates are distinct from the most popular models which lead to the promotion of cooperation as shown by computer simulations of the strategy updating. This suggests that the promotion of cooperation by population structure is not as straightforward in humans as often envisioned in theoretical models.

Three is a crowd in iterated prisoner's dilemmas: experimental evidence on reciprocal behavior.

Reciprocity or conditional cooperation is one of the most prominent mechanisms proposed to explain the emergence of cooperation in social dilemmas. Recent experimental findings on networked games suggest that conditional cooperation may also depend on the previous action of the player. We here report on experiments on iterated, multi-player Prisoner's dilemma, on groups of 2 to 5 people. We confirm the dependence on the previous step and that memory effects for earlier periods are not significant. We show that the behavior of subjects in pairwise dilemmas is qualitatively different from the cases with more players; After an initial decay, cooperation increases significantly reaching values above 80%. The strategy of the players is rather universal as far as their willingness to reciprocate cooperation is concerned, whereas there is much diversity in their initial propensity to cooperate. Our results indicate that, for cooperation to emerge and thrive, three is a crowd.

On the coexistence of cooperators,defectors and conditional cooperators in the multiplayer iterated Prisoner's Dilemma.

Recent experimental evidence [Grujic Fosco, Araujo, Cuesta, Sánchez, 2010. Social experiments in the mesoscale: humans playing a spatial Prisoner's dilemma. PLoS ONE 5, e13749] on the spatial Prisoner's Dilemma suggests that players choosing to cooperate or not on the basis of their previous action and the actions of their neighbors coexist with steady defectors and cooperators. We here study the coexistence of these three strategies in the multiplayer iterated Prisoner's Dilemma by means of the replicator dynamics. We consider groups with n=2, 3, 4 and 5 players and compute the payoffs to every type of player as the limit of a Markov chain where the transition probabilities between actions are found from the corresponding strategies. We show that for group sizes up to n=4 there exists an interior point in which the three strategies coexist, the corresponding basin of attraction decreasing with increasing number of players, whereas we have not been able to locate such a point for n=5. We analytically show that in the limit n --> ∞ no interior points can arise. We conclude by discussing the implications of this theoretical approach on the behavior observed in experiments.

Early mobilization out of bed after ischaemic stroke reduces severe complications but not cerebral blood flow: a randomized controlled pilot trial.

OBJECTIVE: To evaluate whether early mobilization after acute ischaemic stroke is better than delayed mobilization with regard to medical complications and if it is safe in relation to neurological function and cerebral blood flow. DESIGN: Randomized controlled pilot trial of early versus delayed mobilization out of bed with incidence of severe complications as the primary outcome. SETTING: Acute stroke unit in the neurology department of a University Hospital. PARTICIPANTS: Fifty patients after ischaemic stroke with a National Institutes of Health Stroke Scale (NIHSS) score >6 were recruited. INTERVENTION: All patients were treated with physiotherapy immediately after their admission. In the early protocol patients were mobilized out of bed after 52 hours, in the delayed protocol after seven days. RESULTS: Eight out of 50 randomized patients were excluded from the per-protocol analysis because of early transfer to other hospitals. There were 2 (8%) severe complications in the 25 early mobilization patients and 8 (47%) in the 17 delayed mobilization patients (P < 0.006). There were no differences in the total number of complications or in clinical outcome. In the 26 patients (62%) who underwent serial transcranial Doppler ultrasonography, no blood flow differences were found. CONCLUSION: We found an apparent reduction in severe complications and no increase in total complications with an early mobilization protocol after acute ischaemic stroke. No influence on neurological three-month outcomes or on cerebral blood flow was seen. These results justify larger trials comparing mobilization protocols with possibly even faster mobilization out of bed than explored here.

Vagus nerve stimulator treatment in adult-onset Rasmussen's encephalitis.

We describe a patient with adult-onset Rasmussen's encephalitis (RE) responsive to vagus nerve stimulation. This previously healthy woman developed RE in the right hemisphere at the age of 27. Despite antiepileptic drug polytherapy, she continued to experience subcontinuous, simple-partial left-sided motor seizures and slowly progressive cognitive impairment. Resective surgery was not considered owing to the preservation of left motor skills. She was implanted with a vagus nerve stimulator at the age of 41; after 6 months she experienced a greater than 50% reduction in seizure frequency, which persisted over 2 years together with improvement of her neurological and cognitive status.

Social experiments in the mesoscale: humans playing a spatial prisoner's dilemma.

BACKGROUND: The evolutionary origin of cooperation among unrelated individuals remains a key unsolved issue across several disciplines. Prominent among the several mechanisms proposed to explain how cooperation can emerge is the existence of a population structure that determines the interactions among individuals. Many models have explored analytically and by simulation the effects of such a structure, particularly in the framework of the Prisoner's Dilemma, but the results of these models largely depend on details such as the type of spatial structure or the evolutionary dynamics. Therefore, experimental work suitably designed to address this question is needed to probe these issues. METHODS AND FINDINGS: We have designed an experiment to test the emergence of cooperation when humans play Prisoner's Dilemma on a network whose size is comparable to that of simulations. We find that the cooperation level declines to an asymptotic state with low but nonzero cooperation. Regarding players' behavior, we observe that the population is heterogeneous, consisting of a high percentage of defectors, a smaller one of cooperators, and a large group that shares features of the conditional cooperators of public goods games. We propose an agent-based model based on the coexistence of these different strategies that is in good agreement with all the experimental observations. CONCLUSIONS: In our large experimental setup, cooperation was not promoted by the existence of a lattice beyond a residual level (around 20%) typical of public goods experiments. Our findings also indicate that both heterogeneity and a "moody" conditional cooperation strategy, in which the probability of cooperating also depends on the player's previous action, are required to understand the outcome of the experiment. These results could impact the way game theory on graphs is used to model human interactions in structured groups.

[Amyotrophic lateral sclerosis also threatens the octogenarian]. / La sclérose latérale amyotrophique atteint aussi te quatrième age.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease, incurable, mostly declared near the age of sixty-seventy, but more rarely for the older individuals. Because presenting symptoms are non specific (muscle weakness, functional decline, loss of ambulation, dyspnea, dysphagia), diagnosis in early stages may be difficult and delayed, particularly on polymorbid older patients. Symptomatic management is the mainstay of treatment for ALS; care in multidisciplinary team, with maximal psychologic support, is associated with enhanced quality of life. In this article we remind markings aspects of ALS of the older subject, in the light of the follow-up of five patients in our geriatric service.

Emergent EEG in clinical practice.

OBJECTIVE: Emergency situations require a rapid and precise diagnostic approach. However, the exact role and value of the electroencephalogram (EEG) in emergent conditions have yet to be clearly defined. Our objective was to determine why clinicians order an emergency EEG, to assess to what extent it helps establish a correct diagnosis and to evaluate the result it has on subsequent patient management. METHODS: We studied all successive emergency EEGs ordered during a 3-month period in our institution. We analyzed the reasons why each EEG was ordered and interviewed the prescribing clinicians in order to determine the impact the result of the EEG had on the diagnosis and subsequent therapeutic management. RESULTS: We prospectively studied a total of 111 consecutive recordings. The main reasons for ordering an emergent EEG were: suspected cerebral death (21%), non-convulsive status epilepticus (19.7%), subtle status epilepticus (14%) and follow-up of convulsive status epilepticus (11.2%). In 77.5% of the cases the clinicians considered that the EEG contributed to making the diagnosis and that it helped confirm a clinically-suspected diagnosis in 36% of the cases. When subtle status epilepticus (SSE) or non-convulsive status epilepticus (NCSE) was suspected, the diagnosis was confirmed in 45% and 43.3% of the cases, respectively. In 22.2% of the requests involving follow-up of convulsive status epilepticus after initial treatment, the EEG demonstrated persistent status epilepticus. It resulted in a change in patient treatment in 37.8% of all the cases. When the EEG helped establish the diagnosis, patient treatment was subsequently modified in 46.6% of the cases. CONCLUSIONS: This prospective study confirms the value of an emergent EEG in certain specific clinical contexts: the management of convulsive status epilepticus following initial treatment or to rule out subtle status epilepticus. An emergent EEG can also be ordered if one suspects the existence of non-convulsive status epilepticus when a patient presents with mental confusion or altered wakefulness after first looking for the specific signs suggesting this diagnostic hypothesis. SIGNIFICANCE: After 50 years of development and use in daily practice, the EEG remains a dependable, inexpensive and useful diagnostic tool in a number of clearly-defined emergency situations.