When it comes to decisions, myeloid progenitors crave positive feedback

Positive feedback is a ubiquitous feature of networks that establish and maintain cellular decisions. In this issue of Cell, Laslo et al. (2006) demonstrate how a feedback loop comprised of two mutual repressors regulates the differentiation of myeloid progenitors into either macrophages or neutrophils.     

The learning process in biofeedback: Is it feed-forward or feedback?

Twenty participants responded to inquiries about strategies used, and thoughts during, each of three electromyograph biofeedback sessions. The purpose of the study was to learn more about what individuals report doing during biofeedback and, specifically, to determine if individuals construct a response using feedback to sense subtle differences in muscle tension (feedback processes), or select a response from an existing repertoire using feedback primarily for confirmation (feed-forward processes). Protocol analyses found considerable support for feed-forward processes and little support for feedback processes. Such results are important because early reliance on feedforward processes may result in limited control and limited transfer.     

The learning process in biofeedback: is it feed-forward or feedback?

Twenty participants responded to inquiries about strategies used, and thoughts during, each of three electromyograph biofeedback sessions. The purpose of the study was to learn more about what individuals report doing during biofeedback and, specifically, to determine if individuals construct a response using feedback to sense subtle differences in muscle tension (feedback processes), or select a response from an existing repertoire using feedback primarily for confirmation (feed-forward processes). Protocol analyses found considerable support for feed-forward processes and little support for feedback processes. Such results are important because early reliance on feed-forward processes may result in limited control and limited transfer.     

EMG feedback for the treatment of upper-extremity dysfunction: can it be effective?

This paper examines the application of EMG feedback for upper-extremity dysfunction secondary to neurologic injury. A rationale for the use of EMG feedback to enhance rotational components of upper-limb movement, train recruitment of the prime movers, and promote inhibition of motor responses that interfere with efficient and effortless movement is presented. Specific strategies that can be used to reinforce functional movement patterns are elaborated. A case study illustrating the application of the feedback strategies is provided. Despite sensory, perceptual, and cognitive impairments, a 53-year-old left hemiplegic obtained significant clinical upper-limb functional gains when given EMG feedback in conjunction with occupational therapy.     

Cell signaling: What is the signal and what information does it carry?

This paper reviews key findings from quantitative study of the yeast pheromone response system. Most come from single cell experiments that quantify molecular events the system uses to operate. After induction, signal propagation is relatively slow; peak activity takes minutes to reach the nucleus. At each measurement point along the transmission chain, signal rises, overshoots, peaks, and declines toward steady state. At at least one measurement point, this decline depends on negative feedback. The system senses and relays percent receptor occupancy, and one effect of the feedback is to maximize precision of this transmitted information. Over time, the system constantly adjusts quantitative behaviors to convey extracellular ligand concentration faithfully. These behaviors and mechanisms that control them are likely to be general for metazoan signaling systems.     

BRing it on: new insights into the mechanism of brassinosteroid action

Several recent breakthroughs have filled in key details of the brassinosteroid (BR) response. Identification of BAK1, a BRI1 interacting protein, the negative regulator BIN2, as well as direct targets of BIN2, BZR1 and BES1, provide a link between BR perception at the cell surface and regulation of gene expression in the nucleus. Global expression studies further defined the downstream events in this pathway, confirming the role of several factors acting in negative feedback regulation on BR levels. New links to the plant hormone, auxin, were also uncovered.     

The knowledge used in vision and where it comes from.

Knowledge is often thought to be something brought from outside to act upon the visual messages received from the eye in a ''top-down'' fashion, but this is a misleadingly narrow view. First, the visual system is a multilevel heterarchy with connections acting in all directions so it has no ''top''; and second, knowledge is provided through innately determined structure and by analysis of the redundancy in sensory messages themselves, as well as from outside. This paper gives evidence about mechanisms analysing sensory redundancy in biological vision. Automatic gain controls for luminance and contrast depend upon feedback from the input, and there are strong indications that the autocorrelation function, and other associations between input variables, affect the contrast sensitivity function and our subjective experience of the world. The associative structure of sensory message can provide much knowledge about the world we live in, and neural mechanisms that discount established associative structure in the input messages by recoding them can improve survival by making new structure more easily detectable. These mechanisms may be responsible for illusions, such as those produced by a concave face-mask, that are classically attributed to top-down influences.     

Running as fast as it can: How spiking dynamics form object groupings in the laminar circuits of visual cortex

How spiking neurons cooperate to control behavioral processes is a fundamental problem in computational neuroscience. Such cooperative dynamics are required during visual perception when spatially distributed image fragments are grouped into emergent boundary contours. Perceptual grouping is a challenge for spiking cells because its properties of collinear facilitation and analog sensitivity occur in response to binary spikes with irregular timing across many interacting cells. Some models have demonstrated spiking dynamics in recurrent laminar neocortical circuits, but not how perceptual grouping occurs. Other models have analyzed the fast speed of certain percepts in terms of a single feedforward sweep of activity, but cannot explain other percepts, such as illusory contours, wherein perceptual ambiguity can take hundreds of milliseconds to resolve by integrating multiple spikes over time. The current model reconciles fast feedforward with slower feedback processing, and binary spikes with analog network-level properties, in a laminar cortical network of spiking cells whose emergent properties quantitatively simulate parametric data from neurophysiological experiments, including the formation of illusory contours; the structure of non-classical visual receptive fields; and self-synchronizing gamma oscillations. These laminar dynamics shed new light on how the brain resolves local informational ambiguities through the use of properly designed nonlinear feedback spiking networks which run as fast as they can, given the amount of uncertainty in the data that they process.     

Having your water and drinking it too: resource limitation modifies density regulation

Determining the interaction between extrinsic and intrinsic drivers of variation in population abundance through time continues to challenge ecologists. Chamaillé-Jammes and colleagues (this issue) examined African elephant time series to explore how water availability alters the density feedback mechanisms restricting population growth. The relationship between population growth rate and density shifted from an upward convex to a more linear form after controlling for rainfall. Spatial variation in water availability also attenuated density dependence as elephants adjusted their distribution relative to current environmental conditions. This work has important climate change implications for the conservation management of African herbivores.     

How long does it take to become fit?

To become fit an individual must generate optimal muscle strength and must develop cardiopulmonary reserve, or stamina. Physical fitness programmes require motivation, a graded series of appropriately designed exercises, and scientific surveillance. Motivation and efficiency in fitness programmes depends on early positive feedback to participants, confirming that stamina and strength are developing. A practical field experiment was performed to determine the minimum time that healthy young adults require to reach an initial plateau in objective measures of fitness. Fifty male university undergraduates were studied during an annual volunteer military training camp. Thirty had volunteered to take part in the fitness programme; the remaining 20 had initially rejected the offer but underwent the programme as part of their military training and acted as unmotivated controls. All the subjects became fit within 14 days of starting training, with objective improvement in both absolute strength and pulse recovery times. Non-motivated individuals, training with motivated individuals for 20 minutes each day, can therefore achieve levels of fitness indistinguishable from those of healthy highly motivated subjects. Fitness programmes must be carefully supervised, however, with medical examinations for those about to undergo vigorous exercise.     

Lose it to use it

In this issue, Wang et al. (2021. J. Cell Biol. https://doi.org/10.1083/jcb.201911114) describe a phenomenon in which neuromuscular junction synapse elimination triggers myelination of terminal motor axon branches. They propose a mechanism initiated by synaptic pruning that depends on synaptic activity, cytoskeletal maturation, and the associated anterograde transport of trophic factors including Neuregulin 1-III.

Neuromuscular junctions (NMJs) are a favorite model system to study the development, maintenance, and function of neuronal synapses because of their accessibility, size, and simplicity. Although many synaptic mechanisms discovered at the peripheral NMJ have provided important insights into synaptic mechanisms in the central nervous system (CNS), the phenomena of synapse elimination and refinement remain poorly understood in both. In the peripheral nervous system (PNS), synapse elimination is an essential developmental step that removes redundant presynaptic inputs to the muscle fiber. In addition, peripheral motor axon terminals must become myelinated to facilitate rapid and synchronized acetylcholine release to the muscle fiber. However, whether these two essential events during PNS development are coordinately regulated remains unknown.The immature rodent NMJ is first innervated by many axons which are then removed until the synapse reaches a dually innervated state (1). These two axons then further compete for synaptic territory, leaving one “winner” that eventually occupies the motor endplate by the end of the second postnatal week. To determine the relationship between synapse elimination and myelination, Wang et al. (2) used the formation of paranodal junctions between axons and Schwann cells as a surrogate for myelination and then determined whether axons that occupied NMJs in a singly or dually innervated state were more or less likely to be myelinated. They found that when the NMJ is dually innervated, myelination of the terminal axon branch is inhibited; neither synaptic occupancy of the competing axons nor axon diameter influenced myelination. However, once synapse elimination at the NMJ is complete, i.e., a single axon terminal innervates the motor endplate, the winner branch becomes myelinated. Thus, synapse elimination precedes myelination of the terminal axon branch, and competition between dually innervated NMJs restricts myelination.What mechanisms regulate the coordinated maturation of the motor neuron, Schwann cell, and muscle circuit? Since previous studies showed that synapse elimination at the NMJ depends on muscle activity (3), Wang et al. (2) inhibited synapse elimination by blocking acetylcholine receptors with α-bungarotoxin (α-Btx). This inhibition of motor endplate and muscle activity increased not only the number of dually innervated NMJs, but also significantly decreased myelination of terminal axon branches of singly innervated NMJs. Thus, neuromuscular activity must induce retrograde signaling mechanisms that promote not only synapse elimination but also myelination.During synapse elimination, the microtubule cytoskeleton of retracting axons is degraded and reduced (4). In contrast, axons that singly innervate NMJs have a higher microtubule content. α-Btx–dependent block of neuromuscular transmission reduced microtubule content in axons that singly innervate NMJs. Thus, α-Btx treatment simultaneously reduces both microtubule content and myelination.To determine if a mature microtubule-based cytoskeleton is causally related to myelination, Wang et al. used spastin knockout (spastin^KO) mice to artificially stabilize microtubules. Although spastin^KO mice had delayed axon branch removal, stabilization of the microtubule cytoskeleton increased myelination of axons that dually innervated NMJs. Thus, the brake that synaptic competition normally places on terminal branch myelination can be overcome by increasing the mass and maturity of the microtubule cytoskeleton.How does axonal microtubule stability influence terminal axon myelination? Microtubules participate in the anterograde and retrograde transport of diverse cargoes including mitochondria and growth factors. To determine if anterograde axonal transport promotes myelination of axons that singly innervate NMJs, Wang et al. used a dominant-negative mutant of kinesin-1 heavy chain which binds cargo, but lacks the protein’s motor domain, thereby impairing transport. After confirming transport inhibition by tracking impaired movement of the β1 subunit of voltage gated sodium channels, they found that myelination and node of Ranvier formation were significantly delayed in singly innervated NMJs expressing the dominant negative kinesin. Taken together, these results suggest that synapse elimination promotes maturation of the microtubule cytoskeleton which allows more efficient delivery of promyelinating signals to the terminal branch.What could these promyelinating signals be? One obvious candidate is Neuregulin 1 type III (Nrg1-III), which has long been known to promote myelination of peripheral nervous system axons (5). Consistent with this idea, conditional deletion of Nrg1-III dramatically reduced the number of myelinated axon terminals that singly innervate NMJs but did not alter the number of dually innervated NMJs. In contrast, overexpression of Nrg1-III in a transgenic mouse removed the competition-dependent block on myelination resulting in more myelination of both dually and singly innervating axon terminals. In these same transgenic Nrg1-III mice, among those NMJs that were singly innervated, their corresponding axons had higher levels of Nrg1-III. Remarkably, even in these same transgenic overexpressers, inhibition of muscle activity reduced the amount of Nrg1-III found on singly innervated axons, consistent with the observed impairment of the microtubule-based cytoskeleton after α-Btx treatment. ERK1/2 and AKT are downstream effectors of Nrg1-III in Schwann cells and implicated in the myelination pathway. Immunostaining of Schwann cells ensheathing singly innervating axon terminals revealed higher levels of pERK and pAKT.Taken together, the experiments performed by Wang et al. (2) suggest that as multiple axons actively compete for synaptic dominance at the NMJ, the myelination of their terminal branches is delayed. Upon synapse elimination, neuromuscular activity promotes a retrograde signal that increases maturity of the microtubule cytoskeleton. Maturation of the microtubule-based cytoskeleton facilitates the transport of promyelinating signals like Nrg1-III which, when presented to Schwann cells, results in myelination of the “winner” terminal axon branch of a singly innervated NMJ (Fig. 1).Open in a separate windowFigure 1.Synapse elimination promotes myelination of terminal motor axon branches. During early development, NMJs are innervated by multiple axons that compete for endplate territory. During this time, the terminal branches of the axons are not myelinated, and the tubulin cytoskeletal network remains immature. Synaptic activity induces elimination of redundant connections, which leads the winner axon’s microtubule-based cytoskeleton to mature and increase, while the microtubule cytoskeleton is degraded in the retracting axon. The maturity of the cytoskeleton allows for kinesin dependent anterograde transport of Neuregulin 1-III, which then initiates a promyelination signaling cascade via AKT and ERK activation.To the best of our knowledge, this is the first demonstration of plasticity of myelination downstream of activity and synapse refinement in the peripheral motor nervous system. Many studies in the CNS demonstrate that de novo myelination occurs in response to neuronal activity and learning paradigms (6, 7), although the mechanisms responsible remain unknown. Thus, synapse refinement and elimination-dependent myelination may be a paradigm to uncover mechanisms of learning- and activity-dependent myelination in the CNS. Functionally, the addition of myelin to the terminal motor axon branch promotes efficient neurotransmitter release through faster action potential propagation, improved metabolic support of the axon, and more efficient depolarization of the presynaptic terminal by clustered Na⁺ channels at the terminal heminode (8). Whether any or all of these benefits also exist in the CNS remains unknown.This is also the first demonstration of postsynaptic activity driving myelination of a presynaptic axon. Although it is clear that a retrograde signal from the muscle promotes the further maturation and subsequent myelination of the terminal axon, the identity of this cue is unknown. One interesting candidate for a muscle-derived competition and axonal maturation cue is the neurotrophin brain-derived neurotrophic factor (BDNF), which is released during muscle activity (9). Consistent with this idea, BDNF promotes axon maturation by stimulating both actin polymerization and microtubule assembly (10). It will be interesting to test the role of trophic factors in activity-dependent synapse elimination and subsequent myelination in both the CNS and PNS.In conclusion, Wang et al. (2) is an excellent addition to a growing body of research that demonstrates how neuronal activity promotes and modulates myelination. Furthermore, it stands as another example of how using simple model systems, such as the NMJ, may provide insights and have important implications for much more complicated biological systems.     

Control of self-motion in dynamic fluids: fish do it differently from bees

To detect and avoid collisions, animals need to perceive and control the distance and the speed with which they are moving relative to obstacles. This is especially challenging for swimming and flying animals that must control movement in a dynamic fluid without reference from physical contact to the ground. Flying animals primarily rely on optic flow to control flight speed and distance to obstacles. Here, we investigate whether swimming animals use similar strategies for self-motion control to flying animals by directly comparing the trajectories of zebrafish (Danio rerio) and bumblebees (Bombus terrestris) moving through the same experimental tunnel. While moving through the tunnel, black and white patterns produced (i) strong horizontal optic flow cues on both walls, (ii) weak horizontal optic flow cues on both walls and (iii) strong optic flow cues on one wall and weak optic flow cues on the other. We find that the mean speed of zebrafish does not depend on the amount of optic flow perceived from the walls. We further show that zebrafish, unlike bumblebees, move closer to the wall that provides the strongest visual feedback. This unexpected preference for strong optic flow cues may reflect an adaptation for self-motion control in water or in environments where visibility is limited.     

Whose trait is it anyways? Coevolution of joint phenotypes and genetic architecture in mutualisms

Evolutionary biologists typically envision a trait’s genetic basis and fitness effects occurring within a single species. However, traits can be determined by and have fitness consequences for interacting species, thus evolving in multiple genomes. This is especially likely in mutualisms, where species exchange fitness benefits and can associate over long periods of time. Partners may experience evolutionary conflict over the value of a multi-genomic trait, but such conflicts may be ameliorated by mutualism’s positive fitness feedbacks. Here, we develop a simulation model of a host–microbe mutualism to explore the evolution of a multi-genomic trait. Coevolutionary outcomes depend on whether hosts and microbes have similar or different optimal trait values, strengths of selection and fitness feedbacks. We show that genome-wide association studies can map joint traits to loci in multiple genomes and describe how fitness conflict and fitness feedback generate different multi-genomic architectures with distinct signals around segregating loci. Partner fitnesses can be positively correlated even when partners are in conflict over the value of a multi-genomic trait, and conflict can generate strong mutualistic dependency. While fitness alignment facilitates rapid adaptation to a new optimum, conflict maintains genetic variation and evolvability, with implications for applied microbiome science.     

Apicoplast: keep it or leave it

Most Apicomplexans possess a relic plastid named apicoplast, originating from secondary endosymbiosis of a red algae. This non-photosynthetic organelle fulfils important metabolic functions and confers sensitivity to antibiotics. The tasks of this organelle is compared across the phylum of Apicomplexa, highlighting its role in metabolic adaptation to different intracellular niches     

Ablation surgery for atrial fibrillation: "freeze it or buzz it; just do it and cure it"

Patients in normal sinus rhythm have lesser stroke rate, better functional class and quality of life than those in atrial fibrillation. Adding a surgical procedure to cure atrial fibrillation in patients needing correction of structural heart disease has been shown to be a safe option, which benefits the majority in restoration of sinus rhythm. Age is no bar to implement this option. The same does not hold true for lone atrial fibrillation. The affirm trial has shown that there is need for improved treatment strategies for patients in atrial fibrillation, although young patients were not represented in sizable proportion. There is need to develop curative treatment for patients with lone atrial fibrillation. And there are technological advances in the form of ablative energy sources and hardware for applying these with minimal invasion. "Between tomorrow's dream and yesterday's regret is today's opportunity". Let's make the best of it!