Loss Of Synchrony Research Articles

Developing oral chronotherapy for cortisol replacement in congenital adrenal hyperplasia.

The sun imposes a 24-h periodicity to life and circadian rhythms have evolved to maintain homoeostasis through the day/night cycle. In humans, there is a central clock that controls the sleep/wake cycle which is paralleled metabolically by a fast/feed cycle. The clock maintains homoeostasis by synchronising metabolism to the time of feeding. Loss of synchrony between the clock and hormonal rhythms results in loss of homoeostasis as evidenced by obesity, depression, and diabetes in people undertaking shift work. Cortisol has a distinct circadian rhythm; peaking on waking and low at sleep onset. Loss of this rhythm in adrenal insufficiency is associated with a poor quality of life and increased mortality. To replace the cortisol rhythm requires chronotherapy and for this you need to define the key parameters of the target rhythm, create a formulation to replicate that rhythm, and then prove clinical benefit. The physiology of hormones is more complex than that of nonnative drugs. Hormones are secreted with varied rhythms, bound to multiple cognate binding proteins, and actively transported and cleared through enzymatic pathways in multiple organs. We have examined the diurnal rhythm of cortisol in healthy volunteers, created physiologically-based pharmacokinetic models, and tested various oral delayed and sustained formulations of hydrocortisone (development name, Chronocort) in clinical trials. The outcome from this work was the manufacture of modified-release hydrocortisone hard capsules (tradename Efmody, Diurnal Ltd), that replicate the cortisol diurnal rhythm and improve the disease control of congenital adrenal hyperplasia the commonest hereditary form of adrenal insufficiency.

Learning without contingencies: A loss of synergy between memory and reward circuits in schizophrenia.

Motivational deficits in schizophrenia may interact with foundational cognitive processes including learning and memory to induce impaired cognitive proficiency. If such a loss of synergy exists, it is likely to be underpinned by a loss of synchrony between the brains learning and reward sub-networks. Moreover, this loss should be observed even during tasks devoid of explicit reward contingencies given that such tasks are better models of real world performance than those with artificial contingencies. Here we applied undirected functional connectivity (uFC) analyses to fMRI data acquired while participants engaged in an associative learning task without contingencies or feedback. uFC was estimated and inter-group differences (between schizophrenia patients and controls, n=54 total, n=28 patients) were assessed within and between reward (VTA and NAcc) and learning/memory (Basal Ganglia, DPFC, Hippocampus, Parahippocampus, Occipital Lobe) sub-networks. The task paradigm itself alternated between Encoding, Consolidation, and Retrieval conditions, and uFC differences were quantified for each of the conditions. Significantly reduced uFC dominated the connectivity profiles of patients across all conditions. More pertinent to our motivations, these reductions were observed within and across classes of sub-networks (reward-related and learning/memory related). We suggest that disrupted functional connectivity between reward and learning sub-networks may drive many of the performance deficits that characterize schizophrenia. Thus, cognitive deficits in schizophrenia may in fact be underpinned by a loss of synergy between reward-sensitivity and cognitive processes.

Pregastrular Development of Amphibians: Ontogenetic Diversity and Eco-Devo

Comparative and ecological aspects of the reorganizations of early development in the class Amphibia are analyzed. We used data on the developmental diversity in a number of families belonging to the orders Anura and Caudata, in which many species had lost their connection with the aquatic environment. Model representatives of the class Amphibia (Ambystoma mexicanum, Rana temporaria, and Xenopus laevis) have small eggs (no more than 2.5 mm in diameter). In these species, the slowdown in the rate of cell divisions and the loss of synchrony occur at the midblastula stage. However, phylogenetically basal amphibian species (Ascaphus truei, Cryptobranchus alleganiensis) are characterized by the large (4–6 mm in diameter) yolky eggs and a short series of synchronous blastomere divisions (the synchrony is already lost at the 8-cell stage of cleavage). They do not have a “midblastula transition”, which is characteristic of the above model species. On the other hand, many evolutionarily advanced non-model species of caudate and anuran amphibians (for example, Desmognathus fuscus, Gastrotheca riobambae, Philoria sphagnicolus), as well as the basal species, are characterized by the large, yolk-rich eggs and the early loss of cell division synchrony. Phylogenetic analysis suggests that the cleavage pattern of the most extensively studied amphibians, the Mexican axolotl (Caudata) and the African clawed frog (Anura), represents a homoplasy. The midblastula transition, which is characteristic of these two species, might have evolved convergently in these two orders of amphibians as an embryonic adaptation to development in lentic water.

Multi-Omics Reveal Interplay between Circadian Dysfunction and Type2 Diabetes.

Type 2 diabetes is one of the leading threats to human health in the 21st century. It is a metabolic disorder characterized by a dysregulated glucose metabolism resulting from impaired insulin secretion or insulin resistance. More recently, accumulated epidemiological and animal model studies have confirmed that circadian dysfunction caused by shift work, late meal timing, and sleep loss leads to type 2 diabetes. Circadian rhythms, 24-h endogenous biological oscillations, are a fundamental feature of nearly all organisms and control many physiological and cellular functions. In mammals, light synchronizes brain clocks and feeding is a main stimulus that synchronizes the peripheral clocks in metabolic tissues, such as liver, pancreas, muscles, and adipose tissues. Circadian arrhythmia causes the loss of synchrony of the clocks of these metabolic tissues and leads to an impaired pancreas β-cell metabolism coupled with altered insulin secretion. In addition to these, gut microbes and circadian rhythms are intertwined via metabolic regulation. Omics approaches play a significant role in unraveling how a disrupted circadian metabolism causes type 2 diabetes. In the present review, we emphasize the discoveries of several genes, proteins, and metabolites that contribute to the emergence of type 2 diabetes mellitus (T2D). The implications of these discoveries for comprehending the circadian clock network in T2D may lead to new therapeutic solutions.

When should I eat: A circadian view on food intake and metabolic regulation.

The circadian clock is a hierarchical timing system regulating most physiological and behavioral functions with a period of approximately 24 h in humans and other mammalian species. The circadian clock drives daily eating rhythms that, in turn, reinforce the circadian clock network itself to anticipate and orchestrate metabolic responses to food intake. Eating is tightly interconnected with the circadian clock and recent evidence shows that the timing of meals is crucial for the control of appetite and metabolic regulation. Obesity results from combined long-term dysregulation in food intake (homeostatic and hedonic circuits), energy expenditure, and energy storage. Increasing evidence supports that the loss of synchrony of daily rhythms significantly impairs metabolic homeostasis and is associated with obesity. This review presents an overview of mechanisms regulating food intake (homeostatic/hedonic) and focuses on the crucial role of the circadian clock on the metabolic response to eating, thus providing a fundamental research axis to maintain a healthy eating behavior.

Ion gradient-driven bifurcations of a multi-scale neuronal model

Metabolic limitations within the brain frequently arise in the context of aging and disease. As the largest consumers of energy within the brain, ion pumps that maintain the neuronal membrane potential are the most affected when energy supply becomes limited. To characterize the effects of such limitations, we analyze the ion gradients present in a conductance-based (Morris–Lecar) neural mass model. We show the existence and locations of Neimark–Sacker and period-doubling bifurcations in the sodium, calcium, and potassium reversal potentials and demonstrate that these bifurcations form physiologically relevant bounds of ion gradient variability. Within these bounds, we show how depolarization of the gradients causes decreased neural activity. We also show that the depolarization of ion gradients decreases inter-regional coherence, causing a shift in the critical point at which the coupling occurs and thereby inducing loss of synchrony between regions. In this way, we show that the Larter-Breakspear model captures ion gradient variability present at the microscale level and propagates these changes to the macroscale effects such as those observed in human neuroimaging studies.

Timing-Dependent Potentiation and Depression of Electrical Synapses Contribute to Network Stability in the Crustacean Cardiac Ganglion.

Central pattern generators produce many rhythms necessary for survival (e.g., chewing, breathing, locomotion), and doing so often requires coordination of neurons through electrical synapses. Because even neurons of the same type within a network are often differentially tuned, uniformly applied neuromodulators or toxins can result in uncoordinated activity. In the crab (Cancer borealis) cardiac ganglion, potassium channel blockers and serotonin cause increased depolarization of the five electrically coupled motor neurons as well as loss of the normally completely synchronous activity. Given time, compensation occurs that restores excitability and synchrony. One of the underlying mechanisms of this compensation is an increase in coupling among neurons. However, the salient physiological signal that initiates increased coupling has not been determined. Using male C. borealis, we show that it is the loss of synchronous voltage signals between coupled neurons that is at least partly responsible for plasticity in coupling. Shorter offsets in naturalistic activity across a gap junction enhance coupling, whereas longer delays depress coupling. We also provide evidence on why a desynchronization-specific potentiation or depression of the synapse could ultimately be adaptive through using a hybrid network created by artificially coupling two cardiac ganglia. Specifically, a stray neuron may be brought back in line by increasing coupling if its activity is closer to the remainder of the network. However, if a the activity of a neuron is far outside network parameters, it is detrimental to increase coupling, and therefore depression of the synapse removes a potentially harmful influence on the network.SIGNIFICANCE STATEMENT Understanding how neural networks maintain output over years despite environmental and physiological challenges requires understanding the regulatory principles of these networks. Here, we study how cells that are synchronously active at baseline respond to becoming desynchronized. In this system, a loss of synchrony causes different parts of the heart to receive uncoordinated stimulation. We find a calcium-dependent control mechanism that alters the strength of electrical connections between motor neurons. Although others have described similar control mechanisms, here, we demonstrate that voltage changes are sufficient to elicit regulation. Furthermore, we demonstrate that strong connections in a sufficiently perturbed network can prevent any neuron from producing its target activity, thus suggesting why the connections are not constitutively as strong as possible.

Effects of Intra‐arterial Fentanyl and Codeine on Medullary Respiratory Network Organization

The actions of mu‐opioid agonists to depress breathing are currently controversial, encompassing several proposed mechanisms that are focused on preferential effects in specific locations in the brainstem. We hypothesized that opioids have multiple actions at the respiratory network scale which include loss of synchrony and/or network dynamics. Experiments were conducted in 4 anesthetized, spontaneously breathing and 11 decerebrated, artificially ventilated, paralyzed and vagal intact cats. In spontaneously breathing animals, EMGs were recorded from diaphragm, parasternal, abdominal and upper airway muscles. In paralyzed animals, neurograms were recorded from phrenic and abdominal nerves. Fentanyl or codeine were administered via the vertebral artery (i.a.; fentanyl, 1‐10 ng/kg, codeine 1‐3000 μg/kg) while simultaneously recording from multiple medullary neurons. Analyses included assessment of autocorrelation histograms (ACH), significant features in cross correlation histograms (CCHs), and discharge identity (phenotype of firing frequency of a neuron during the breathing cycle). Qualitatively similar opioid‐induced changes in neuron firing rates, ACHs, CCHs, and discharge identity were observed during either fentanyl or codeine dose responses. Some neurons lost or gained excitability during the dose responses. ACHs of some neurons exhibited changes in spiking periodicity. Features in CCHs changed during administration of opioids including loss of some central or offset peaks. Detectability index (a metric of the magnitude of significant functional interactions) in some neuron pairs increased during opioid administration. Further, the discharge identity of many neurons changed during the dose responses with most of these changes occurring in neurons with tonic discharge during breathing. The extent of these changes strongly suggest that opioids induce significant changes in network organization including reduced synchrony and altered discharge identity of network members. These changes can occur at low doses of opioids that do not profoundly alter the breathing pattern.

Larval parasitism in a specialist herbivore is explained by phenological synchrony and host plant availability.

Parasitism is a key factor in the population dynamics of many herbivorous insects, although its impact on host populations varies widely, for instance, along latitudinal and altitudinal gradients. Understanding the sources of geographical variation in host-parasitoid interactions is crucial for reliably predicting the future success of the interacting species under a context of global change. Here, we examine larval parasitism in the butterfly Aglais urticae in south-west Europe, where it is a mountain specialist. Larval nests were sampled over 2years along altitudinal gradients in three Iberian mountain ranges, including the Sierra Nevada, home to its southernmost European population. Additional data on nettle condition and adult butterflies were obtained in the study areas. These data sources were used to investigate whether or not differences in parasitism rates are related to the geographical position and phenology of the host, and to the availability of the host plants. Phenological differences in the host populations between regions were related to the severity of summer drought and the corresponding differences in host plant availability. At the trailing-edge of its distribution, the butterfly's breeding season was restricted to the end of winter and spring, while in its northern Iberian range the season was prolonged until mid-summer. Although parasitism was an important source of mortality in all regions, parasitism rates and parasitoid richness were highest in the north and lowest in the south. Moreover, within a region, there was a notable increase in parasitism rates over time, which probably led to selection against an additional late summer host generation in northern regions. Conversely, the shorter breeding season in Sierra Nevada resulted in a loss of synchrony between the host and one important late season parasitoid, Sturmia bella, which may partly explain the high density of this butterfly species at the trailing-edge of its range. Our results support the key role of host phenology in accounting for differences in parasitism rates between populations. They also provide insights into how climate through host plant availability affects host phenology and, ultimately, the impact of parasitism on host populations.

Deficient Recurrent Cortical Processing in Congenital Deafness.

The influence of sensory experience on cortical feedforward and feedback interactions has rarely been studied in the auditory cortex. Previous work has documented a dystrophic effect of deafness in deep cortical layers, and a reduction of interareal couplings between primary and secondary auditory areas in congenital deafness which was particularly pronounced in the top-down direction (from the secondary to the primary area). In the present study, we directly quantified the functional interaction between superficial (supragranular, I to III) and deep (infragranular, V and VI) layers of feline’s primary auditory cortex A1, and also between superficial/deep layers of A1 and a secondary auditory cortex, namely the posterior auditory field (PAF). We compared adult hearing cats under acoustic stimulation and cochlear implant (CI) stimulation to adult congenitally deaf cats (CDC) under CI stimulation. Neuronal activity was recorded from auditory fields A1 and PAF simultaneously with two NeuroNexus electrode arrays. We quantified the spike field coherence (i.e., the statistical dependence of spike trains at one electrode with local field potentials on another electrode) using pairwise phase consistency (PPC). Both the magnitude as well as the preferred phase of synchronization was analyzed. The magnitude of PPC was significantly smaller in CDCs than in controls. Furthermore, controls showed no significant difference between the preferred phase of synchronization between supragranular and infragranular layers, both in acoustic and electric stimulation. In CDCs, however, there was a large difference in the preferred phase between supragranular and infragranular layers. These results demonstrate a loss of synchrony and for the first time directly document a functional decoupling of the interaction between supragranular and infragranular layers of the primary auditory cortex in congenital deafness. Since these are key for the influence of top-down to bottom-up computations, the results suggest a loss of recurrent cortical processing in congenital deafness and explain the outcomes of previous studies by deficits in intracolumnar microcircuitry.

Epidemiology, Pathophysiology, and Management of Native Atrioventricular Valve Regurgitation in Heart Failure Patients

Atrioventricular regurgitation is frequent in the setting of heart failure. It is due to atrial and ventricular remodelling, as well as rhythmic disturbances and loss of synchrony. Once atrioventricular regurgitation develops, it can aggravate the underlying heart failure, and further participate and aggravate its own severity. Its presence is therefore concomitantly a surrogate of advance disease and a predictor of mortality. Heart failure management, including medical therapy, cardiac resynchronization therapy, and restoration of sinus rhythm, are the initial steps to reduce atrioventricular regurgitation. In the current review, we analyse the current data assessing the epidemiology, pathophysiology, and impact of non-valvular intervention on atrioventricular regurgitation including medical treatment, cardiac resynchronization and atrial fibrillation ablation.

Elevated CO2 Impacts on Plant–Pollinator Interactions: A Systematic Review and Free Air Carbon Enrichment Field Study

Simple SummaryClimate change is having a profound impact on pollination systems, yet we still do not know to what extent increasing concentrations of carbon dioxide (CO2) will directly affect the interactions between plants and their pollinators. We review all the existing published literature on the effect of elevated CO2 (eCO2) on flowering time, nectar and pollen production and plant–pollinator interactions. We also conduct a field experiment to test the effect of eCO2 on bluebells and their pollinators. We found that few studies have assessed the impact of eCO2 on pollination, and our field data found that bluebells flowered on average 6 days earlier under eCO2 conditions. Hoverflies and bumble bees were the main visitors to bluebell flowers, but insect activity was low early in the flowing period. Although we did not find a difference in the number of visits made by insects to bluebell flowers under eCO2, or the amount of seeds those flowers produced, the change in the timing of flowering could mean that a mismatch could develop between bluebells and their pollinators in the future, which would affect pollination success.The impact of elevated CO2 (eCO2) on plant–pollinator interactions is poorly understood. This study provides the first systematic review of this topic and identifies important knowledge gaps. In addition, we present field data assessing the impact of eCO2 (150 ppm above ambient) on bluebell (Hyacinthoides non-scripta)–pollinator interactions within a mature, deciduous woodland system. Since 1956, only 71 primary papers have investigated eCO2 effects on flowering time, floral traits and pollination, with a mere 3 studies measuring the impact on pollination interactions. Our field experiment documented flowering phenology, flower visitation and seed production, as well as the abundance and phenology of dominant insect pollinators. We show that first and mid-point flowering occurred 6 days earlier under eCO2, but with no change in flowering duration. Syrphid flies and bumble bees were the dominant flower visitors, with peak activity recorded during mid- and late-flowering periods. Whilst no significant difference was recorded in total visitation or seed set between eCO2 and ambient treatments, there were clear patterns of earlier flowering under eCO2 accompanied by lower pollinator activity during this period. This has implications for potential loss of synchrony in pollination systems under future climate scenarios, with associated long-term impacts on abundance and diversity.

Desynchrony and synchronisation underpinning sleep–wake cycles

This paper studies mechanisms of synchronisation and loss of synchrony among the three key oscillatory processes controlling sleep–wake cycles in the human brain: the 24-h circadian oscillator, the homeostatic sleep drive, and the environmental light–dark cycle. Synchronisation of these three rhythms promotes sleep and brain clearance and is critical for human health. Their desynchrony, on the other hand, is associated with impaired performance and disease development, including cancer, cardiovascular disease, and mental disorders. A biophysical model of arousal dynamics simulating sleep–wake cycles and circadian rhythms is used as the study system. It is based on established neurobiological mechanisms controlling sleep–wake transitions and incorporates the three oscillatory processes. Nonlinear dynamics methods and synchronisation theory are used to numerically investigate model dynamics under conditions that are not easily achievable in experiments. The role of homeostatic brain clearance rate in synchronisation is investigated, and selective turning on and off of coupling strengths between the oscillators allows us to determine their role in oscillators’ dynamics. We find that, in the absence of coupling between the circadian and homeostatic oscillators, the default state of the model corresponds to the endogenous homeostatic period that is far from $$\sim $$ 24-h rhythm of the circadian and light–dark cycles. Combined action of light and circadian oscillator on the homeostatic rhythm is required to achieve the typical sleep–wake pattern that is observed in young healthy people. Under 12-/12-h light–dark conditions with light at 80 lux, change of homeostatic clearance rate is found to induce two types of desynchronisation: (i) fast clearance rates $$\tau _H<58.1$$ h desynchronise the homeostatic oscillator from the circadian, while the circadian rhythm remains entrained to the light–dark cycle, and (ii) slow clearance rates $$\tau _H>69$$ h maintain synchronisation between the homeostatic and circadian oscillators, but the period of both is different from that of the light–dark cycle. Between these regimes, all three rhythms are synchronised under the studied conditions. The model predicts that the system is highly sensitive to external inputs to the neuronal populations of the sleep–wake switch, which affect the endogenous period of the homeostatic oscillator and can lead to complete loss of sleep. Model dynamics show that loss of synchronisation, which is traditionally ascribed solely to impairment of the circadian oscillator, can be caused by changes in the homeostatic clearance rate of the brain or external input to the neuronal populations of the sleep–wake switch. Thus, changes in circadian, homeostatic, and external factors (combined or specific) may be responsible for conditions of desynchronisation. This has significant implications for understanding individual variability in sleep–wake patterns and in mechanisms of sleep and circadian disorders, indicating that both the homeostatic and circadian mechanisms can be responsible for the same clinical or behavioural presentation of a disease.

Spatial and Temporal Variation in the Aphid–Parasitoid Interaction under Different Climates

Global warming will increase pest insect population sizes and diminish the effectiveness of biological control. This biological control failure scenario appears to be of particular concern for areas with a significant increase in maximum temperatures, such as the increase experienced in the Central Valley of Chile over the last 40 years. We assessed the impact of different climatic zones and maximum temperatures along the coast and the Chilean Central Valley on the grain aphid (Sitobion avenae) density, parasitism rate, and facultative endosymbionts in wheat fields during the growing season in the springs of 2017 and 2018. A significant effect on aphid density due to zones and maximum temperatures was detected; however, this depended on the zone and year analyzed. Changes between zones and seasons were observed for parasitism rates, while maximum temperatures only significantly affected the parasitism rate in 2017. The main parasitoid wasp found was Aphidius ervi in both zones and seasons. Regiella insecticola infected 95% of the samples in both zones, although it does not seem to have a protective role at the field level. Our findings suggest that, at present, global warming does not significantly affect the grain aphid outbreaks and their biological control in Chile. However, this study points out the importance of pre-emptive monitoring to detect aphids and the synchrony loss of their parasitoid wasps.

Too bright to breed

Light Pollution Most coral species reproduce through broadcast spawning. For such a strategy to be successful, coordination has had to evolve such that gametes across clones are released simultaneously. Over millennia, lunar cycles have facilitated this coordination, but the recent development of bright artificial light has led to an overpowering of these natural signals. Ayalon et al. tested for the direct impact of different kinds of artificial light on different species of corals. The authors found that multiple lighting types, including cold and warm light-emitting diode (LED) lamps, led to loss of synchrony and spawning failure. Further, coastal maps of artificial lighting globally suggest that it threatens to interfere with coral reproduction worldwide and that the deployment of LED lights, the blue light of which penetrates deeper into the water column, is likely to make the situation even worse. Curr. Biol. 10.1016/j.cub.2020.10.039 (2020).

The Role of the Subthalamic Nucleus in Sequential Working Memory in De Novo Parkinson's Disease.

ABSTRACTBackgroundDeficits in maintaining and manipulating sequential information online can occur even in patients with mild Parkinson's disease. The subthalamic nucleus may play a modulatory role in the neural system for sequential working memory, which also includes the lateral prefrontal cortex.ObjectivesThe objective of this study was to investigate neural markers of sequential working memory deficits in patients with de novo Parkinson's disease.MethodsA total of 50 patients with de novo Parkinson's disease and 50 healthy controls completed a digit ordering task during functional magnetic resonance imaging scanning. The task separated the maintenance (“pure recall”) and manipulation of sequences (“reorder & recall” vs “pure recall”).ResultsIn healthy controls, individual participants' task accuracy was predicted by the regional activation and functional connectivity of the subthalamic nucleus. Healthy participants who showed lower subthalamic nucleus activation and stronger subthalamic nucleus connectivity with the putamen performed more accurately in maintaining sequences (“pure recall”). Healthy participants who showed greater ordering‐related subthalamic nucleus activation change exhibited smaller accuracy costs in manipulating sequences (“reorder & recall” vs “pure recall”). Patients performed less accurately than healthy controls, especially in “reorder & recall” trials, accompanied by an overactivation in the subthalamic nucleus and a loss of synchrony between the subthalamic nucleus and putamen. Individual patients' task accuracy was predicted only by the subthalamic nucleus connectivity. The contribution of the subthalamic nucleus activation or activation change was absent. We observed no change in the lateral prefrontal cortex.ConclusionsThe overactivation and weakened functional connectivity of the subthalamic nucleus are the neural markers of sequential working memory deficits in de novo Parkinson's disease. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Coupling delay controls synchronized oscillation in the segmentation clock.

Individual cellular activities fluctuate but are constantly coordinated at the population level via cell-cell coupling. A notable example is the somite segmentation clock, in which the expression of clock genes (such as Hes7) oscillates in synchrony between the cells that comprise the presomitic mesoderm (PSM)1,2. This synchronization depends on the Notch signalling pathway; inhibiting this pathway desynchronizes oscillations, leading to somite fusion3-7. However, how Notch signalling regulates the synchronicity of HES7 oscillations is unknown. Here we establish a live-imaging system using a new fluorescent reporter (Achilles), which we fuse with HES7 to monitor synchronous oscillations in HES7 expression in the mouse PSM at a single-cell resolution. Wild-type cells can rapidly correct for phase fluctuations in HES7 oscillations, whereas the absence of the Notch modulator gene lunatic fringe (Lfng) leads to a loss of synchrony between PSM cells. Furthermore, HES7 oscillations are severely dampened in individual cells of Lfng-null PSM. However, when Lfng-null PSM cells were completely dissociated, the amplitude and periodicity of HES7 oscillations were almost normal, which suggests that LFNG is involved mostly in cell-cell coupling. Mixed cultures of control and Lfng-null PSM cells, and an optogenetic Notch signalling reporter assay, revealed that LFNG delays the signal-sending process of intercellular Notch signalling transmission. These results-together with mathematical modelling-raised the possibility that Lfng-null PSM cells shorten the coupling delay, thereby approaching a condition known as the oscillation or amplitude death of coupled oscillators8. Indeed, a small compound that lengthens the coupling delay partially rescues the amplitude and synchrony of HES7 oscillations in Lfng-null PSM cells. Our study reveals a delay control mechanism of the oscillatory networks involved in somite segmentation, and indicates that intercellular coupling with the correct delay is essential for synchronized oscillation.

Light Entrains Diurnal Changes in Insulin Sensitivity of Skeletal Muscle via Ventromedial Hypothalamic Neurons

Loss of synchrony between geophysical time and insulin action predisposes to metabolic diseases. Yet the brain and peripheral pathways linking proper insulin effect to diurnal changes in light-dark and feeding-fasting inputs are poorly understood. Here, we show that the insulin sensitivity of several metabolically relevant tissues fluctuates during the 24h period. For example, in mice, the insulin sensitivity of skeletal muscle, liver, and adipose tissue is lowest during the light period. Mechanistically, by performing loss- and gain-of-light-action and food-restriction experiments, we demonstrate that SIRT1 in steroidogenic factor 1 (SF1) neurons of the ventromedial hypothalamic nucleus (VMH) convey photic inputs to entrain the biochemical and metabolic action of insulin in skeletal muscle. These findings uncover a critical light-SF1-neuron-skeletal-muscle axis that acts to finely tune diurnal changes in insulin sensitivity and reveal a light regulatory mechanism of skeletal muscle function.

Long-term changes on estuarine ciliates linked with modifications on wind patterns and water turbidity

Planktonic ciliates constitute a fundamental component among microzooplankton and play a prominent role in carbon transport at the base of marine food webs. How these organisms respond to shifting environmental regimes is unclear and constitutes a current challenge under global ocean changes. Here we examine a multiannual field survey covering 25 years in the Bahía Blanca Estuary (Argentina), a shallow, flood-plain system dominated by wind and tidal energy. We found that the estuary experienced marked changes in wind dominant regimes and an increase in water turbidity driven from the joint effect of persistent long-fetch winds and the indirect effect of the Southern Annular Mode. Along with these changes, we found that zooplankton components, i.e. ciliates and the dominant estuarine copepod Acartia tonsa, showed a negative trend during the period 1986–2011. We showed that the combined effects of wind and turbidity with other environmental variables (chlorophyll, salinity and nutrients) consistently explained the variability of observed shifts. Tintinnids were more vulnerable to wind patterns and turbidity while showed a loss of synchrony with primary productivity. Water turbidity produced a dome-like pattern on tintinnids, oligotrichs and A. tonsa, implying that the highest abundance of organisms occurred under moderate values (∼50 NTU) of turbidity. In contrast, the response to wind patterns was not generalizable probably owing to species-specific traits. Observed trends denote that wind-induced processes in shallow ecosystems with internal sources of suspended sediments, are essential on ciliate dynamics and that such effects can propagate trough the interannual variability of copepods.

Multiplexing topologies and time scales: The gains and losses of synchrony.

Inspired by the recent interest in collective dynamics of biological neural networks immersed in the glial cell medium, we investigate the frequency and phase order, i.e., Kuramoto type of synchronization in a multiplex two-layer network of phase oscillators of different time scales and topologies. One of them has a long-range connectivity, exemplified by the Erdős-Rényi random network, and supports both kinds of synchrony. The other is a locally coupled two-dimensional lattice that can reach frequency synchronization but lacks phase order. Drastically different layer frequencies disentangle intra- and interlayer synchronization. We find that an indirect but sufficiently strong coupling through the regular layer can induce both phase order in the originally nonsynchronized random layer and global order, even when an isolated regular layer does not manifest it in principle. At the same time, the route to global synchronization is complex: an initial onset of (partial) synchrony in the regular layer, when its intra- and interlayer coupling is increased, provokes the loss of synchrony even in the originally synchronized random layer. Ultimately, a developed asynchronous dynamics in both layers is abruptly taken over by the global synchrony of both kinds.