Attenuation of pattern recognition receptor signaling is mediated by a MAP kinase kinase kinase

Pattern recognition receptors (PRRs) play a key role in plant and animal innate immunity. PRR binding of their cognate ligand triggers a signaling network and activates an immune response. Activation of PRR signaling must be controlled prior to ligand binding to prevent spurious signaling and immune activation. Flagellin perception in Arabidopsis through FLAGELLIN‐SENSITIVE 2 (FLS2) induces the activation of mitogen‐activated protein kinases (MAPKs) and immunity. However, the precise molecular mechanism that connects activated FLS2 to downstream MAPK cascades remains unknown. Here, we report the identification of a differentially phosphorylated MAP kinase kinase kinase that also interacts with FLS2. Using targeted proteomics and functional analysis, we show that MKKK7 negatively regulates flagellin‐triggered signaling and basal immunity and this requires phosphorylation of MKKK7 on specific serine residues. MKKK7 attenuates MPK6 activity and defense gene expression. Moreover, MKKK7 suppresses the reactive oxygen species burst downstream of FLS2, suggesting that MKKK7‐mediated attenuation of FLS2 signaling occurs through direct modulation of the FLS2 complex.     

Models of coral growth: spontaneous branching,compactification and the Laplacian growth assumption

In stony corals it is often observed that specimens collected from a sheltered growth site have more open and more thinly branched growth forms than specimens of the same species from more exposed growth sites, where stronger water currents are found. This observation was explained using an abiotic computational model inspired by coral growth, in which the growth velocity depended locally on the absorption of a resource dispersed by advection and diffusion (Kaandorp and Sloot, J. Theor. Biol 209 (2001) 257). In that model a morphological range was found; as the Péclet-number (indicating the relative importance of advective and diffusive nutrient transport) was increased, more compact and spherical growth forms were found. Two unsatisfactory items have remained in this model, which we address in the present paper. First, an explicit curvature rule was responsible for branching. In this work we show that the curvature rule is not needed: the model exhibits spontaneous branching, provided that the resource field is computed with enough precision. Second, previously no explanation was given for the morphological range found in the simulations. Here we show that such an explanation is given by the conditions under which spontaneous branching occurs in our model, in which the compactness of the growth forms depends on the ratio of the rates of growth and nutrient transport. We did not find an effect of flow. This suggests that the computational evidence that hydrodynamics influences the compactness of corals in laminar flows may not be conclusive. The applicability of the Laplacian growth paradigm to understand coral growth is discussed.     

Can Treadmill Perturbations Evoke Stretch Reflexes in the Calf Muscles?

Disinhibition of reflexes is a problem amongst spastic patients, for it limits a smooth and efficient execution of motor functions during gait. Treadmill belt accelerations may potentially be used to measure reflexes during walking, i.e. by dorsal flexing the ankle and stretching the calf muscles, while decelerations show the modulation of reflexes during a reduction of sensory feedback. The aim of the current study was to examine if belt accelerations and decelerations of different intensities applied during the stance phase of treadmill walking can evoke reflexes in the gastrocnemius, soleus and tibialis anterior in healthy subjects. Muscle electromyography and joint kinematics were measured in 10 subjects. To determine whether stretch reflexes occurred, we assessed modelled musculo-tendon length and stretch velocity, the amount of muscle activity, as well as the incidence of bursts or depressions in muscle activity with their time delays, and co-contraction between agonist and antagonist muscle. Although the effect on the ankle angle was small with 2.8±1.0°, the perturbations caused clear changes in muscle length and stretch velocity relative to unperturbed walking. Stretched muscles showed an increasing incidence of bursts in muscle activity, which occurred after a reasonable electrophysiological time delay (163–191 ms). Their amplitude was related to the muscle stretch velocity and not related to co-contraction of the antagonist muscle. These effects increased with perturbation intensity. Shortened muscles showed opposite effects, with a depression in muscle activity of the calf muscles. The perturbations only slightly affected the spatio-temporal parameters, indicating that normal walking was retained. Thus, our findings showed that treadmill perturbations can evoke reflexes in the calf muscles and tibialis anterior. This comprehensive study could form the basis for clinical implementation of treadmill perturbations to functionally measure reflexes during treadmill-based clinical gait analysis.     

Ternary representation of trivariate data

A new fast trivariate display technique based on the ratio of three measured variables and of relative cell number, obtained from flow cytometric measurements, is described.     

Mesoscopic simulations of systolic flow in the human abdominal aorta

The complex nature of blood flow in the human arterial system is still gaining more attention, as it has become clear that cardiovascular diseases localize in regions of complex geometry and complex flow fields. In this article, we demonstrate that the lattice Boltzmann method can serve as a mesoscopic computational hemodynamic solver. We argue that it may have benefits over the traditional Navier-Stokes techniques. The accuracy of the method is tested by studying time-dependent systolic flow in a 3D straight rigid tube at typical hemodynamic Reynolds and Womersley numbers as an unsteady flow benchmark. Simulation results of steady and unsteady flow in a model of the human aortic bifurcation reconstructed from magnetic resonance angiography, are presented as a typical hemodynamic application.     

Neuropsychopharmacology and Neurogenetic Aspects of Executive Functioning: Should Reward Gene Polymorphisms Constitute a Diagnostic Tool to Identify Individuals at Risk for Impaired Judgment?

Executive functions are processes that act in harmony to control behaviors necessary for maintaining focus and achieving outcomes. Executive dysfunction in neuropsychiatric disorders is attributed to structural or functional pathology of brain networks involving prefrontal cortex (PFC) and its connections with other brain regions. The PFC receives innervations from different neurons associated with a number of neurotransmitters, especially dopamine (DA). Here we review findings on the contribution of PFC DA to higher-order cognitive and emotional behaviors. We suggest that examination of multifactorial interactions of an individual's genetic history, along with environmental risk factors, can assist in the characterization of executive functioning for that individual. Based upon the results of genetic studies, we also propose genetic mapping as a probable diagnostic tool serving as a therapeutic adjunct for augmenting executive functioning capabilities. We conclude that preservation of the neurological underpinnings of executive functions requires the integrity of complex neural systems including the influence of specific genes and associated polymorphisms to provide adequate neurotransmission.     

Kinetics in signal transduction pathways involving promiscuous oligomerizing receptors can be determined by receptor specificity: apoptosis induction by TRAIL

Here we show by computer modeling that kinetics and outcome of signal transduction in case of hetero-oligomerizing receptors of a promiscuous ligand largely depend on the relative amounts of its receptors. Promiscuous ligands can trigger the formation of nonproductive receptor complexes, which slows down the formation of active receptor complexes and thus can block signal transduction. Our model predicts that increasing the receptor specificity of the ligand without changing its binding parameters should result in faster receptor activation and enhanced signaling. We experimentally validated this hypothesis using the cytokine tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its four membrane-bound receptors as an example. Bypassing ligand-induced receptor hetero-oligomerization by receptor-selective TRAIL variants enhanced the kinetics of receptor activation and augmented apoptosis. Our results suggest that control of signaling pathways by promiscuous ligands could result in apparent slow biological kinetics and blocking signal transmission. By modulating the relative amount of the different receptors for the ligand, signaling processes like apoptosis can be accelerated or decelerated and even inhibited. It also implies that more effective treatments using protein therapeutics could be achieved simply by altering specificity.     

HIV reservoirs and immune surveillance evasion cause the failure of structured treatment interruptions: a computational study

Continuous antiretroviral therapy is currently the most effective way to treat HIV infection. Unstructured interruptions are quite common due to side effects and toxicity, among others, and cannot be prevented. Several attempts to structure these interruptions failed due to an increased morbidity compared to continuous treatment. The cause of this failure is poorly understood and often attributed to drug resistance. Here we show that structured treatment interruptions would fail regardless of the emergence of drug resistance. Our computational model of the HIV infection dynamics in lymphoid tissue inside lymph nodes, demonstrates that HIV reservoirs and evasion from immune surveillance themselves are sufficient to cause the failure of structured interruptions. We validate our model with data from a clinical trial and show that it is possible to optimize the schedule of interruptions to perform as well as the continuous treatment in the absence of drug resistance. Our methodology enables studying the problem of treatment optimization without having impact on human beings. We anticipate that it is feasible to steer new clinical trials using computational models.