Postinhibitory excitation in motoneurons can be facilitated by hyperpolarization-activated inward currents: A simulation study.

Postinhibitory excitation is a transient overshoot of a neuron's baseline firing rate following an inhibitory stimulus and can be observed in vivo in human motoneurons. However, the biophysical origin of this phenomenon is still unknown and both reflex pathways and intrinsic motoneuron properties have been proposed. We hypothesized that postinhibitory excitation in motoneurons can be facilitated by hyperpolarization-activated inward currents (h-currents). Using an electrical circuit model, we investigated how h-currents can modulate the postinhibitory response of motoneurons. Further, we analyzed the spike trains of human motor units from the tibialis anterior muscle during reciprocal inhibition. The simulations revealed that the activation of h-currents by an inhibitory postsynaptic potential can cause a short-term increase in a motoneuron's firing probability. This result suggests that the neuron can be excited by an inhibitory stimulus. In detail, the modulation of the firing probability depends on the time delay between the inhibitory stimulus and the previous action potential. Further, the postinhibitory excitation's strength correlates with the inhibitory stimulus's amplitude and is negatively correlated with the baseline firing rate as well as the level of input noise. Hallmarks of h-current activity, as identified from the modeling study, were found in 50% of the human motor units that showed postinhibitory excitation. This study suggests that h-currents can facilitate postinhibitory excitation and act as a modulatory system to increase motoneuron excitability after a strong inhibition.

Direct reciprocity between individuals that use different strategy spaces.

In repeated interactions, players can use strategies that respond to the outcome of previous rounds. Much of the existing literature on direct reciprocity assumes that all competing individuals use the same strategy space. Here, we study both learning and evolutionary dynamics of players that differ in the strategy space they explore. We focus on the infinitely repeated donation game and compare three natural strategy spaces: memory-1 strategies, which consider the last moves of both players, reactive strategies, which respond to the last move of the co-player, and unconditional strategies. These three strategy spaces differ in the memory capacity that is needed. We compute the long term average payoff that is achieved in a pairwise learning process. We find that smaller strategy spaces can dominate larger ones. For weak selection, unconditional players dominate both reactive and memory-1 players. For intermediate selection, reactive players dominate memory-1 players. Only for strong selection and low cost-to-benefit ratio, memory-1 players dominate the others. We observe that the supergame between strategy spaces can be a social dilemma: maximum payoff is achieved if both players explore a larger strategy space, but smaller strategy spaces dominate.

Indirect reciprocity with private, noisy, and incomplete information.

Indirect reciprocity is a mechanism for cooperation based on shared moral systems and individual reputations. It assumes that members of a community routinely observe and assess each other and that they use this information to decide who is good or bad, and who deserves cooperation. When information is transmitted publicly, such that all community members agree on each other's reputation, previous research has highlighted eight crucial moral systems. These "leading-eight" strategies can maintain cooperation and resist invasion by defectors. However, in real populations individuals often hold their own private views of others. Once two individuals disagree about their opinion of some third party, they may also see its subsequent actions in a different light. Their opinions may further diverge over time. Herein, we explore indirect reciprocity when information transmission is private and noisy. We find that in the presence of perception errors, most leading-eight strategies cease to be stable. Even if a leading-eight strategy evolves, cooperation rates may drop considerably when errors are common. Our research highlights the role of reliable information and synchronized reputations to maintain stable moral systems.

Quantitative assessment can stabilize indirect reciprocity under imperfect information.

The field of indirect reciprocity investigates how social norms can foster cooperation when individuals continuously monitor and assess each other's social interactions. By adhering to certain social norms, cooperating individuals can improve their reputation and, in turn, receive benefits from others. Eight social norms, known as the "leading eight," have been shown to effectively promote the evolution of cooperation as long as information is public and reliable. These norms categorize group members as either 'good' or 'bad'. In this study, we examine a scenario where individuals instead assign nuanced reputation scores to each other, and only cooperate with those whose reputation exceeds a certain threshold. We find both analytically and through simulations that such quantitative assessments are error-correcting, thus facilitating cooperation in situations where information is private and unreliable. Moreover, our results identify four specific norms that are robust to such conditions, and may be relevant for helping to sustain cooperation in natural populations.

Linking cortex and contraction-Integrating models along the corticomuscular pathway.

Computational models of the neuromusculoskeletal system provide a deterministic approach to investigate input-output relationships in the human motor system. Neuromusculoskeletal models are typically used to estimate muscle activations and forces that are consistent with observed motion under healthy and pathological conditions. However, many movement pathologies originate in the brain, including stroke, cerebral palsy, and Parkinson's disease, while most neuromusculoskeletal models deal exclusively with the peripheral nervous system and do not incorporate models of the motor cortex, cerebellum, or spinal cord. An integrated understanding of motor control is necessary to reveal underlying neural-input and motor-output relationships. To facilitate the development of integrated corticomuscular motor pathway models, we provide an overview of the neuromusculoskeletal modelling landscape with a focus on integrating computational models of the motor cortex, spinal cord circuitry, α-motoneurons and skeletal muscle in regard to their role in generating voluntary muscle contraction. Further, we highlight the challenges and opportunities associated with an integrated corticomuscular pathway model, such as challenges in defining neuron connectivities, modelling standardisation, and opportunities in applying models to study emergent behaviour. Integrated corticomuscular pathway models have applications in brain-machine-interaction, education, and our understanding of neurological disease.

The evolution of indirect reciprocity under action and assessment generosity.

Indirect reciprocity is a mechanism for the evolution of cooperation based on social norms. This mechanism requires that individuals in a population observe and judge each other's behaviors. Individuals with a good reputation are more likely to receive help from others. Previous work suggests that indirect reciprocity is only effective when all relevant information is reliable and publicly available. Otherwise, individuals may disagree on how to assess others, even if they all apply the same social norm. Such disagreements can lead to a breakdown of cooperation. Here we explore whether the predominantly studied 'leading eight' social norms of indirect reciprocity can be made more robust by equipping them with an element of generosity. To this end, we distinguish between two kinds of generosity. According to assessment generosity, individuals occasionally assign a good reputation to group members who would usually be regarded as bad. According to action generosity, individuals occasionally cooperate with group members with whom they would usually defect. Using individual-based simulations, we show that the two kinds of generosity have a very different effect on the resulting reputation dynamics. Assessment generosity tends to add to the overall noise and allows defectors to invade. In contrast, a limited amount of action generosity can be beneficial in a few cases. However, even when action generosity is beneficial, the respective simulations do not result in full cooperation. Our results suggest that while generosity can favor cooperation when individuals use the most simple strategies of reciprocity, it is disadvantageous when individuals use more complex social norms.

Ypd1 Is an Essential Protein of the Major Fungal Pathogen Aspergillus fumigatus and a Key Element in the Phosphorelay That Is Targeted by the Antifungal Drug Fludioxonil.

Aspergillus fumigatus is a major fungal pathogen causing life threatening infections in immunocompromised humans and certain animals. The HOG pathway is for two reasons interesting in this context: firstly, it is a stress signaling pathway that contributes to the ability of this pathogen to adapt to various stress conditions and secondly, it is the target of antifungal agents, such as fludioxonil or pyrrolnitrin. In this study, we demonstrate that Ypd1 is an essential protein in A. fumigatus. As the central component of the multistep phosphorelay it represents the functional link between the sensor histidine kinases and the downstream response regulators SskA and Skn7. A GFP-Ypd1 fusion was found to reside in both, the cytoplasm and the nucleus and this pattern was only slightly affected by fludioxonil. A strain in which the ypd1 gene is expressed from a tet-on promoter construct is unable to grow under non-inducing conditions and shows the characteristic features of A. fumigatus wild type hyphae treated with fludioxonil. Expression of wild type Ypd1 prevents this lethal phenotype, but expression of an Ypd1 mutant protein lacking the conserved histidine at position 89 was unable to do so, which confirms that A. fumigatus Ypd1 is a phosphotransfer protein. Generation of ypd1tet-on variants of several mutant strains revealed that the lethal phenotype associated with low amounts of Ypd1 depends on SskA, but not on TcsC or Skn7. The ΔsskA ypd1tet-on, but not the ΔsskAΔskn7 ypd1tet-on mutant, was sensitive to fludioxonil, which underlines the importance of Skn7 in this context. We finally succeeded to delete ypd1, but only if sskA and skn7 were both inactivated, not in a ΔsskA single mutant. Hence, a deletion of ypd1 and an inactivation of Ypd1 by fludioxonil result in similar phenotypes and the two response regulators SskA and Skn7 are involved in both processes albeit with a different relative importance.

A unified framework of direct and indirect reciprocity.

Direct and indirect reciprocity are key mechanisms for the evolution of cooperation. Direct reciprocity means that individuals use their own experience to decide whether to cooperate with another person. Indirect reciprocity means that they also consider the experiences of others. Although these two mechanisms are intertwined, they are typically studied in isolation. Here, we introduce a mathematical framework that allows us to explore both kinds of reciprocity simultaneously. We show that the well-known 'generous tit-for-tat' strategy of direct reciprocity has a natural analogue in indirect reciprocity, which we call 'generous scoring'. Using an equilibrium analysis, we characterize under which conditions either of the two strategies can maintain cooperation. With simulations, we additionally explore which kind of reciprocity evolves when members of a population engage in social learning to adapt to their environment. Our results draw unexpected connections between direct and indirect reciprocity while highlighting important differences regarding their evolvability.

Changes in Loss Sensitivity During Treatment in Concurrent Disorders Inpatients: A Computational Model Approach to Assessing Risky Decision-Making.

BACKGROUND: Recent studies have employed computational modeling to characterize deficits in aspects of decision-making not otherwise detected using traditional behavioral task outcomes. While prospect utility-based modeling has shown to differentiate decision-making patterns between users of different drugs, its relevance in the context of treatment has yet to be examined. This study investigated model-based decision-making as it relates to treatment outcome in inpatients with co-occurring mental health and substance use disorders. METHODS: 50 patients (Mage = 38.5, SD = 11.4; 16F) completed the Cambridge Gambling Task (CGT) within 2 weeks of admission (baseline) and 6 months into treatment (follow-up), and 50 controls (Mage = 31.9, SD = 10.0; 25F) completed CGT under a single outpatient session. We evaluated 4 traditional CGT outputs and 5 decisional processes derived from the Cumulative Model. Psychiatric diagnoses and discharge data were retrieved from patient health records. RESULTS: Groups were similar in age, sex, and premorbid IQ. Differences in years of education were included as covariates across all group comparisons. All patients had ≥1 mental health diagnosis, with 80% having >1 substance use disorder. On the CGT, patients showed greater Deliberation Time and Delay Aversion than controls. Estimated model parameters revealed higher Delayed Reward Discounting, and lower Probability Distortion and Loss Sensitivity in patients relative to controls. From baseline to follow-up, patients (n = 24) showed a decrease in model-derived Loss Sensitivity and Color Choice Bias. Lastly, poorer Quality of Decision-Making and Choice Consistency, and greater Color Choice Bias independently predicted higher likelihood of treatment dropout, while none were significant in relation to treatment length of stay. CONCLUSION: This is the first study to assess a computational model of decision-making in the context of treatment for concurrent disorders. Patients were more impulsive and slower to deliberate choice than controls. While both traditional and computational outcomes predicted treatment adherence in patients, findings suggest computational methods are able to capture treatment-sensitive aspects of decision-making not accessible via traditional methods. Further research is needed to confirm findings as well as investigate the relationship between model-based decision-making and post-treatment outcomes.

Characterization of Electromechanical Delay Based on a Biophysical Multi-Scale Skeletal Muscle Model.

Skeletal muscles can be voluntary controlled by the somatic nervous system yielding an active contractile stress response. Thereby, the active muscle stresses are transmitted to the skeleton by a cascade of connective tissue and thus enable motion. In the context of joint perturbations as well as the assessment of the complexity of neural control, the initial phase of the muscle-tendon system's stress response has a particular importance and is analyzed by means of electromechanical delay (EMD). EMD is defined as the time lag between the stimulation of a muscle and a measurable change in force output. While EMD is believed to depend on multiple structures / phenomena, it is hard to separate their contributions experimentally. We employ a physiologically detailed, three-dimensional, multi-scale model of an idealized muscle-tendon system to analyze the influence of (i) muscle and tendon length, (ii) the material behavior of skeletal muscle and tendon tissue, (iii) the chemo-electro-mechanical behavior of the muscle fibers and (iv) neural control on EMD. Comparisons with experimental data show that simulated EMD values are within the physiological range, i.e., between 6.1 and 68.6 ms, and that the model is able to reproduce the characteristic EMD-stretch curve, yielding the minimum EMD at optimal length. Simulating consecutive recruitment of motor units increases EMD by more than 20 ms, indicating that during voluntary contractions neural control is the dominant factor determining EMD. In contrast, the muscle fiber action potential conduction velocity is found to influence EMD even of a 27 cm long muscle by not more than 3.7 ms. We further demonstrate that in conditions where only little pre-stretch is applied to a muscle-tendon system, the mechanical behavior of both muscle and tendon tissue considerably impacts EMD. Predicting EMD for different muscle and tendon lengths indicates that the anatomy of a specific muscle-tendon system is optimized for its function, i.e., shorter tendon lengths are beneficial to minimize the neural control effort for muscles primary acting as motor in concentric contractions.

Relapse following discontinuation of imatinib mesylate therapy for FIP1L1/PDGFRA-positive chronic eosinophilic leukemia: implications for optimal dosing.

Although imatinib is clearly the treatment of choice for FIP1L1/PDGFRA-positive chronic eosinophilic leukemia (CEL), little is known about optimal dosing, duration of treatment, and the possibility of cure in this disorder. To address these questions, 5 patients with FIP1L1/PDGFRA-positive CEL with documented clinical, hematologic, and molecular remission on imatinib (400 mg daily) and without evidence of cardiac involvement were enrolled in a dose de-escalation trial. The imatinib dose was tapered slowly with close follow-up for evidence of clinical, hematologic, and molecular relapse. Two patients with endomyocardial fibrosis were maintained on imatinib 300 to 400 mg daily and served as controls. All 5 patients who underwent dose de-escalation, but neither of the control patients, experienced molecular relapse (P < .05). None developed recurrent symptoms, and eosinophil counts, serum B12, and tryptase levels remained suppressed. Reinitiation of therapy at the prior effective dose led to molecular remission in all 5 patients, although 2 patients subsequently required increased dosing to maintain remission. These data are consistent with suppression rather than elimination of the clonal population in FIP1L1/PDGFRA-positive CEL and suggest that molecular monitoring may be the most useful method in determining optimal dosing without the risk of disease exacerbation. This trial was registered at http://www.clinicaltrials.gov as no. NCT00044304.