Spontaneous Waves Research Articles

The Rho-kinase inhibitor Y27632 promotes ureteral relaxation in an in vivo rat model for partial ureteral obstruction.

Aim of this study was to evaluate the effect of intravenous Y27632 (a ROK inhibitor) on intra-ureteral pressures and on blood pressure in an in vivo rat model for unilateral partial ureteral obstruction (PUO). 15 Male Sprague Dawley rats were used. Under isofluran anesthesia, saline was continuously infused via polyethylene (PE)-10 catheters inserted in the ureters beneath the kidney pelvis. Left psoas muscle was sutured around the distal left ureter to create a partial obstruction. Carotid artery and femoral vein were cannulated with PE catheters for registration of mean arterial blood pressure (MAP) and for administration of drugs. Left and right ureter pressures and MAP were simultaneously recorded. Y27632 (0.03 and 0.1mg/kg each n = 6-7) was given intravenously. T-test was used for comparisons. Spontaneous peristaltic pressure waves were recorded at baseline for both ureters. After the obstruction, Y27632 reduced maximum pressure (MaxP) by 10.5 ± 1.9% (0.03mg/kg; p = 0.004) and 29.1 ± 4.8% (0.1mg/kg; p < 0.001), minimum pressure (MinP) by 5.2 ± 2.3% (0.03mg/kg; p = 0.02) and 12.2 ± 3.4% (0.1mg/kg; p = 0.009), the area under the curve (AUC) by 7.8 ± 2.4% (0.03mg/kg; p = 0.008) and 16.5 ± 3.7% (0.1mg/kg;p = 0.007), the waves amplitude by 23.4 ± 11.3% (0.03mg/kg; p = 0.098) and 38.7 ± 7.5% (0.1mg/kg; p < 0.001), with no effect on contraction frequency. During simultaneous recordings from the normal ureter at the investigated doses, Y27632 reduced MaxP, MinP, AUC and waves amplitude by 1-7%. The MAP was reduced by 12.5 ± 5.3% (0.03mg/kg; p = 0.07) and 15.8 ± 1.8% (0.1mg/kg; p < 0.001). Y27632 decreased intra-ureteral pressures of a partially obstructed ureter with limited effect on blood pressure in an animal model of unilateral PUO.

Spontaneous periodic polarization wave in helielectric fluids.

By analogy with spin waves in ferromagnetic systems, the polarization (or dipole) wave is the electric counterpart that remains elusive. Here, we discover that the helielectricity, i.e. a polarization field with helicoidal helices that corresponds to a quasi-layered chiral nematic environment, causes a spontaneous formation of large-scale polarization waves in the form of the sinusoidal function. Both experimental and theoretical analyses reveal that the polarization ordering over a threshold polarization strength violates the inherent periodicity of the polarization helices, thus penalizing the compression energy. It drives a second-order structural transition to a periodically modulated polarization wave state. The roles of chirality and confinement condition are discussed.

Spontaneous near-inertial wave generation from mesoscale eddy: Nonlinear forcing mechanism

The spontaneous generation of near-inertial waves (NIWs) from quasi-geostrophic mesoscale eddies in a stratified fluid is investigated and the process and mechanism clarified by numerical modeling and a theoretical analysis. Mesoscale eddies, as slow balance flows, are inevitably accompanied by unbalanced near-inertial oscillations (NIOs) in their long period evolution. A mesoscale eddy supplies kinetic energy to NIOs through its interaction with perturbations, which exist universally in the world oceans. Afterward, NIWs are generated spontaneously via the nonlinear coupling of the eddy and NIOs. The baroclinicity of mesoscale eddies is an essential condition of this spontaneous NIW generation mechanism. The resonance of the NIWs and NIOs enables the internal wave continuum to be dominated by NIWs, which share the same horizontal wavenumbers with the eddy. After generation, the NIWs radiate energy toward the eddy center and remain stationary as a whole, relative to the propagating eddy. Generally, an anticyclonic mesoscale eddy can emit much stronger NIWs than does a cyclonic eddy. The NIW intensity strengthens exponentially with the Rossby number. The essence of this spontaneous NIW generation mechanism is the nonlinear interaction between slow balance flows and the accompanying fast motions. It represents an effective pathway for mesoscale eddy energy sinks and makes a non-negligible contribution to the global NIW energy.

Dopamine modulates the retinal clock through melanopsin-dependent regulation of cholinergic waves during development

BackgroundThe mammalian retina contains an autonomous circadian clock that controls various aspects of retinal physiology and function, including dopamine (DA) release by amacrine cells. This neurotransmitter plays a critical role in retina development, visual signalling, and phase resetting of the retinal clock in adulthood. Interestingly, bidirectional regulation between dopaminergic cells and melanopsin-expressing retinal ganglion cells has been demonstrated in the adult and during development. Additionally, the adult melanopsin knockout mouse (Opn4−/−) exhibits a shortening of the endogenous period of the retinal clock. However, whether DA and / or melanopsin influence the retinal clock mechanism during its maturation is still unknown.ResultsUsing wild-type Per2Luc and melanopsin knockout (Opn4−/−::Per2Luc) mice at different postnatal stages, we found that the retina generates self-sustained circadian rhythms from postnatal day 5 in both genotypes and that the ability to express these rhythms emerges in the absence of external time cues. Intriguingly, only in wild-type explants, DA supplementation lengthened the endogenous period of the clock during the first week of postnatal development through both D1- and D2-like dopaminergic receptors. Furthermore, the blockade of spontaneous cholinergic retinal waves, which drive DA release in the early developmental stages, shortened the period and reduced the light-induced phase shift of the retinal clock only in wild-type retinas.ConclusionsThese data suggest that DA modulates the molecular core of the clock through melanopsin-dependent regulation of acetylcholine retinal waves, thus offering an unprecedented role of DA and melanopsin in the endogenous functioning and the light response of the retinal clock during development.

Collapse Dynamics Are Diffusive.

Noninterferometric experiments have been successfully employed to constrain models of spontaneous wave function collapse, which predict a violation of the quantum superposition principle for large systems. These experiments are grounded on the fact that, according to these models, the dynamics is driven by noise that, besides collapsing the wave function in space, generates a diffusive motion with characteristic signatures, which, though small, can be tested. The noninterferometric approach might seem applicable only to those models that implement the collapse through noisy dynamics, not to any model, that collapses the wave function in space. Here, we show that this is not the case: under reasonable assumptions, any collapse dynamics (in space) is diffusive. Specifically, we prove that any space-translation covariant dynamics that complies with the no-signaling constraint, if collapsing the wave function in space, must change the average momentum of the system and/or its spread.

Retinal waves align the concentric orientation map in mouse superior colliculus to the center of vision

Neurons in the mouse superior colliculus (SC) are arranged in a concentric orientation map, which is aligned to the center of vision and the optic flow experienced by the mouse. The origin of this map remains unclear. Here, we propose that spontaneous retinal waves during development provide a scaffold to establish the concentric orientation map within the SC and its alignment to the optic flow. We test this hypothesis by modeling the orientation-tuned SC neurons that receive ON/OFF retinal inputs. Our model suggests that the propagation direction bias of stage III retinal waves, together with OFF-delayed responses, shapes the spatial organization of the orientation map. The OFF delay establishes orientation-tuned neurons by segregating their ON/OFF receptive subfields, the wave-like activities form the concentric pattern, and the direction biases align the map to the center of vision. Together, retinal waves may play an instructive role in establishing functional properties of single SC neurons and their spatial organization within maps.

Alzheimer's disease-related presenilin 1 M146L mutation disrupts SERCA2a regulation and increases propensity of Ca waves in ventricular cardiomyocytes.

Presenilin 1 (PS1) is a transmembrane protein expressed in the endoplasmic reticulum (ER) of different cell types. It has been shown that Ca mishandling due to PS1 mutations contributes to the Alzheimer's disease (AD)-related neurodegeneration. PS1 is also expressed in the heart. Several clinical studies revealed that PS1 mutations are associated with cardiomyopathies. We previously showed that PS1 interacts with the cardiac ER Ca ATPase (SERCA2a) and regulates its function. Here, we studied the role of AD-related PS1M146L mutation in regulation of intracellular Ca homeostasis. Fluorescent resonance energy transfer (FRET) experiments in HEK293 cells transfected with fluorescently labeled SERCA2a and PS1M146L revealed that the mutation does not disrupt the interaction between these two proteins. Measurements of SERCA2a-mediated Ca transport showed that at low ER Ca loads ([Ca]ER≤0.15 mM), both PS1WT and PS1M146L enhance ER Ca uptake by a similar level (∼40%) compared to control (no PS1 expression). At high ER Ca loads ([Ca]ER≥0.35 mM), however, PS1WT reduced ER Ca uptake and ER Ca load, whereas PS1M146L was less effective in regulating SERCA2a function. We used in vivo gene delivery in mouse cardiac wall to study the effect of PS1WT and PS1M146L overexpression on Ca regulation in ventricular myocytes. We found that both PS1WT and PS1M146L localized predominantly at the sarcoplasmic reticulum. Analysis of cytosolic Ca dynamics revealed that PS1WT overexpression in cardiomyocytes increases diastolic Ca and decreases Ca transient amplitudes. In contrast, PS1M146L expression increased propensity of spontaneous Ca waves. These results illustrate that the lack of SERCA2a regulation by PS1M146L at high ER Ca loads can lead to ER Ca overload and Ca waves. These defects in Ca regulation might contribute to the onset of cardiomyopathies in patients with PS1 mutations.

Ant waves-Spontaneous activity waves in fire-ant columns.

Active matter, which includes crowds of organisms, is composed of constituents that independently consume and dissipate energy. Some active matter systems have been shown to sustain the propagation of various types of waves, resulting from the interplay between density and alignment. Here, we examine a type of solitary wave in dense two-dimensional columns of Solenopsis invicta, fire ants, in which the local activity, density and alignment all play a key role. We demonstrate that these waves are nonlinear and that they are composed of aligned ants that are constrained at the top by the time it takes disordered ants to activate and align and at the bottom by a density minimum enforced by gravity. Our results suggest that intrinsically switchable activity can be a productive framework to understand and trigger a broad range of wave-like behaviors, including stampedes in crowds and herds.

A comprehensive neural simulation of slow-wave sleep and highly responsive wakefulness dynamics.

Hallmarks of neural dynamics during healthy human brain states span spatial scales from neuromodulators acting on microscopic ion channels to macroscopic changes in communication between brain regions. Developing a scale-integrated understanding of neural dynamics has therefore remained challenging. Here, we perform the integration across scales using mean-field modeling of Adaptive Exponential (AdEx) neurons, explicitly incorporating intrinsic properties of excitatory and inhibitory neurons. The model was run using The Virtual Brain (TVB) simulator, and is open-access in EBRAINS. We report that when AdEx mean-field neural populations are connected via structural tracts defined by the human connectome, macroscopic dynamics resembling human brain activity emerge. Importantly, the model can qualitatively and quantitatively account for properties of empirically observed spontaneous and stimulus-evoked dynamics in space, time, phase, and frequency domains. Large-scale properties of cortical dynamics are shown to emerge from both microscopic-scale adaptation that control transitions between wake-like to sleep-like activity, and the organization of the human structural connectome; together, they shape the spatial extent of synchrony and phase coherence across brain regions consistent with the propagation of sleep-like spontaneous traveling waves at intermediate scales. Remarkably, the model also reproduces brain-wide, enhanced responsiveness and capacity to encode information particularly during wake-like states, as quantified using the perturbational complexity index. The model was run using The Virtual Brain (TVB) simulator, and is open-access in EBRAINS. This approach not only provides a scale-integrated understanding of brain states and their underlying mechanisms, but also open access tools to investigate brain responsiveness, toward producing a more unified, formal understanding of experimental data from conscious and unconscious states, as well as their associated pathologies.

Nanotopography and Microconfinement Impact on Primary Hippocampal Astrocyte Morphology, Cytoskeleton and Spontaneous Calcium Wave Signalling.

Astrocytes' organisation affects the functioning and the fine morphology of the brain, both in physiological and pathological contexts. Although many aspects of their role have been characterised, their complex functions remain, to a certain extent, unclear with respect to their contribution to brain cell communication. Here, we studied the effects of nanotopography and microconfinement on primary hippocampal rat astrocytes. For this purpose, we fabricated nanostructured zirconia surfaces as homogenous substrates and as micrometric patterns, the latter produced by a combination of an additive nanofabrication and micropatterning technique. These engineered substrates reproduce both nanotopographical features and microscale geometries that astrocytes encounter in their natural environment, such as basement membrane topography, as well as blood vessels and axonal fibre topology. The impact of restrictive adhesion manifests in the modulation of several cellular properties of single cells (morphological and actin cytoskeletal changes) and the network organisation and functioning. Calcium wave signalling was observed only in astrocytes grown in confined geometries, with an activity enhancement in cells forming elongated agglomerates with dimensions typical of blood vessels or axon fibres. Our results suggest that calcium oscillation and wave propagation are closely related to astrocytic morphology and actin cytoskeleton organisation.

Schrödinger–Newton Equation with Spontaneous Wave Function Collapse

Based on the assumption that the standard Schrödinger equation becomes gravitationally modified for massive macroscopic objects, two independent proposals have survived from the 1980s. The Schrödinger–Newton equation (1984) provides well-localized solitons for free macro-objects but lacks the mechanism of how extended wave functions collapse on solitons. The gravity-related stochastic Schrödinger equation (1989) provides the spontaneous collapse, but the resulting solitons undergo a tiny diffusion, leading to an inconvenient steady increase in the kinetic energy. We propose the stochastic Schrödinger–Newton equation, which contains the above two gravity-related modifications together. Then, the wave functions of free macroscopic bodies will gradually and stochastically collapse to solitons, which perform inertial motion without momentum diffusion: conservation of momentum and energy is restored.

Existentialism is a humanism

Methodological study of the world-famous French philosopher, playwright, writer J.-P. Sartre (1905-1980) is devoted to the reasoned coverage of the cultural-philosophical achievements of existentialism as a teaching that enables human life and accepts as an axiom the statement that every truth and every action presupposes an environment and subjectivity, which is organized either as a behavior or as a deed. The fundamental principle of this doctrine is formulated in the form of the maxim: “existence precedes essence”, in other words, “it is necessary to proceed from the subject”, which became the indisputable ideologeme of the existential movement for decades. And this means that a person firstly exists, meets, appears in the world and only then is defined and acquires authenticity; therefore, he is primarily a p r o j e c t that is experienced and realized subjectively, thus creating a person out of himself. This is where the humanistic meaning of the worldview doctrine of existentialism emerges: it gives each person ownership of their real being and places full responsibility on them. Moreover, naturalistic determinism is denied in this doctrine, because it supports the opinion that there is no human nature, just as there is no God who would have conceived it. Therefore, the essence of a person is in an irrational plane, associated with complete freedom of actions, feelings of sadness and suffering, spontaneous waves of existential fear, insurmountable absurdity of social everyday life, ultimately with randomness and the experience of abandonment-loneliness. In these dramatic circumstances of a world full of vanity and senselessness, a person is doomed to be free, with the potential of his own consciousness to create personal values and determine the meaning of life, to exist for the constant fulfillment of himself, to establish himself in relations with others through the totality of his actions, expanding the inner horizons of both his own authenticity and specific intersubjectivity. He is always face to face with a changing situation, therefore the choice is always a choice in a clearly defined situational context of being. Therefore, existentialism is a philosophical doctrine of action, a person’s presence in the world, and therefore an optimistic, liberating, humanistic teaching.

Facilitated ignition and detonation initiation of hydrogen-oxygen mixtures by ozone doping

This work computationally studies homogeneous and inhomogeneous ozone addition in hydrogen-oxygen ignition and transition to detonation, with emphasis on the ozone-induced two-stage behaviors in the chemical kinetics and wave dynamics. In 0D homogenous ignitions, ozone addition induces an additional first-stage reaction and substantially reduces the ignition delay time (IDT). At intermediate initial temperatures, e.g. T0 = 600 K, a critical value, αcr, is identified to delineate different regimes for ozone fraction in the total oxidizer, α. Specifically, the first-stage ignition occurs several orders earlier than IDT for α<αcr, while the IDTs for two stages are comparable for α>αcr. Mechanistically, low-to-intermediate temperature HO2 chemistry introduces a quasi-steady intermediate state in the former regime, whereas ozone reactions directly accelerate high-temperature H2O2 reactions in the latter one. Furthermore, according to the Zel'dovich mechanism, ozone concentration non-uniformity can establish reactivity gradient and hence further initiate double spontaneous waves with multiple dynamics. Coherent coupling between the second-stage heat release and pressure (shock) wave can further evolve into detonation, whereas such synchronized enhancement is not observed in the first-stage ignition due to its large excitation time. Corresponding to the multi-timescales in 0D ignition, when the initial α interval are respectively below, across and above αcr, the low- and high- temperature reaction fronts always separate, first separate then merge, and always merge, respectively. It is also noted that at higher initial temperatures αcr decreases, and that the first-stage reaction becomes less concentrated. Consequently, detonation can be initiated with smaller amounts of ozone and is minimally influenced by the first-stage reaction.

A numerical study of the rapid deflagration-to-detonation transition

This paper describes numerically the rapid deflagration-to-detonation transition (DDT) in detail in a high-frequency pulse detonation rocket engine. Different from traditional DDT, reactants are injected into the chamber from near the open end and travel toward the closed end. Previous experiments have implied that the gasdynamic shock by injecting in a confined space and the intensive turbulence generated by the high-speed jet play important roles in the detonation initiation, but explanations of how, when, and where the detonation is generated were not presented clearly due to the limitation of experimental observation. In this work, high-resolution two-dimensional simulations are performed to investigate this process employing a physical model similar to the experimental configuration. A new mechanism manifesting itself as a complicated vortex–flame interaction is found for the flame transition from a laminar to compressible or choking regime. It is discovered that the gasdynamic shock, after reflecting from the end wall, triggers the detonation through the gradient of reactivity with the hot spot formed by the collision of the shock and the flame. A dimensionless criterion defined by the ratio of the acoustic speed to the inverse gradient of the ignition delay time is applied to further describe the spontaneous wave propagation from the perspective of chem-physical dynamics. This criterion quantitatively gives a good prediction of the propagating mode from the subsonic deflagration to a developing detonation, even in such a complex scenario as encountered in this work.

PDE1 inhibition and adenosine A2A receptor activation synergistically potentiates spontaneous calcium waves and transients in mouse ventricular myocytes

Abstract Background The phosphodiesterase-1C (PDE1C) and the adenosine A2A receptor (A2AR) are located in a macromolecular cluster and expected to modulate cAMP-dependent regulation of the intracellular calcium homeostasis in cardiac myocytes. In this contect, atrial fibrillation has been associated with a high incidence of spontanoeus arrhythmogenic calcium waves caused by excessive A2AR activation. On the other hand, inhibition of PDE1C and A2AR activation has also been reported to produce a synergistic and protective effect on cardiomyocyte survival, but little is known about the corresponding effects on the intracellular calcium homeostasis. Purpose This study, therfore, aimed to investigate how PDE1 inhibition and/or A2AR activation modulate sarcoplasmic reticulum (SR) calcium homeostasis in mouse ventricular myocytes. Methods Mouse ventricular myocytes (47 cells from 20 mice) were loaded with the calcium indicator Rhod-2 and spontaneous calcium release events at rest or caffeine induced calcium transients were visualized using resonance-scanning confocal microscopy at a frame rate of 150 Hz. The SR calcium content was estimated as the ratio of the peak fluorescence and the fluoresence the end of a 10 mM caffeine pulse (20s). Calcium leak was estimated as ratio of the flourescence emmision at baseline before and at the end of the caffeine pulse. Results The incidence of spontaneous calcium waves or transients increased from 0.7±0.3 events/min in control to 1.1±0.5 events/min and 3.4±1.0 events/min (p&amp;lt;0.01) after inhibition of PDE1 with the selective antagonist ITI-214 and the A2AR agonist CGS-21680 respectively. Concomitant PDE1 inhibition and A2AR activation synergistically increased the event frequency to 8.4±2.3 events/min (p&amp;lt;0.05). There were no significant differences in the corresponding SR calcium contents (4.4±0.3, 4.5±0.4, 4.7±0.4 and 4.1±0.2 for control, ITI-214, CGS-21680 and ITI-214+CGS-21680 respectively). However, there was a parallel increase in calcium leak from 8.7±4.2% in control to 21.8±9.8% with ITI-214, 17.6±7.2% with CGS-21680 and 37.5±11.1% when myocytes were exposed to both compounds (p&amp;lt;0.05), suggesting that the higher incidence of spontaneous calcium waves and transients observed upon PDE1 inhibition and/or A2AR activation is likely caused by a lowering of the threshold for spontaneous SR calcium release rather than by SR calcium overloading. Conclusion PDE1 inhibition exacerbates the incidence of spontaneous arrhythmogenic SR calcium release events in myocytes with high levels of A2AR activation, suggesting that PDE1 inhibition under these conditions increases the risk of arrhythmia. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Spanish Ministry of Science and Innovation

Large-scale waves of activity in the neonatal mouse brain in vivo occur almost exclusively during sleep cycles.

Spontaneous electrical activity plays major roles in the development of cortical circuitry. This activity can occur highly localized regions or can propagate over the entire cortex. Both types of activity coexist during early development. To investigate how different forms of spontaneous activity might be temporally segregated, we used wide-field trans-cranial calcium imaging over an entire hemisphere in P1-P8 mouse pups. We found that spontaneous waves of activity that propagate to cover the majority of the cortex (large-scale waves; LSWs) are generated at the end of the first postnatal week, along with several other forms of more localized activity. We further found that LSWs are segregated into sleep cycles. In contrast, cortical activity during wake states is more spatially restricted and the few large-scale forms of activity that occur during wake can be distinguished from LSWs in sleep based on their initiation in the motor cortex and their correlation with body movements. This change in functional cortical circuitry to a state that is permissive for large-scale activity may temporally segregate different forms of activity during critical stages when activity-dependent circuit development occurs over many spatial scales. Our data also suggest that LSWs in early development may be a functional precursor to slow sleep waves in the adult, which play critical roles in memory consolidation and synaptic rescaling.

Changes of myocardial calcium currents in rats with myocardial injury induced by running exercise during acute hypoxia

To investigate the changes in myocardial calcium currents in rats subjected to forced running exercise during acute hypoxia and their association with myocardial injury. Forty SD rats were randomized into quiescent group and running group either in normal oxygen (NQ and NR groups, respectively) or in acute hypoxia (HQ and HR groups, respectively). Hypoxia was induced by keeping the rats in a hypobaric oxygen chamber (PaO2=61.6kpa) for 4 h a day; the rats in the two running groups were forced to run on running wheels for 4 h each day. Rat ventricular myocytes was isolated by enzymatic digestion for recording action potentials and currents using patch clamp technique, and confocal Ca2+ imaging was used to monitor intracellular Ca2+ levels. The expressions of Cav1.2 channel and the cardiac ryanodine receptor (RyR2) were determined using Western blotting. Compared with those in NQ group, the rats in HR group showed significantly decreased SOD activity (P < 0.01), increased h-FABP, hs-CRP and IMA levels (P < 0.05 or 0.01), obvious myocardial pathology, and prolonged APD50 and APD90 (P < 0.05). Of the different stress conditions, forced running in acute hypoxia resulted in the most prominent increase of the densities of ICa, L currents, causing also a significant left shift of the steady state activation curve and a significant right shift of the steady state inactivation curve. Compared with those in NQ group, the rats in NR, HQ and HR groups all exhibited higher rates of spontaneous calcium wave events in the cardiac myocytes, increased frequency of calcium sparks with lowered amplitude, enhanced calcium release amplitude in the ventricular myocytes, and delayed calcium ion reabsorption; in particular, these changes were the most conspicuous in HR group (P < 0.05 or 0.01). There was also a significant increase in the protein levels of Cav1.2 channel and RyR2 receptor in HR group (P < 0.05 or 0.01). The mechanism of myocardial injury in rats subjected to forced running in acute hypoxia may involve the increase of oxidative stress and calcium current and intracellular calcium overload.

Inducing oscillations in positive end-expiratory pressure improves assessment of cerebrovascular pressure reactivity in patients with traumatic brain injury.

The cerebral pressure reactivity index (PRx), through intracranial pressure (ICP) measurements, informs clinicians about the cerebral autoregulation (CA) status in adult-sedated patients with traumatic brain injury (TBI). Using PRx in clinical practice is currently limited by variability over shorter monitoring periods. We applied an innovative method to reduce the PRx variability by ventilator-induced slow (1/min) positive end-expiratory pressure (PEEP) oscillations. We hypothesized that, as seen in a previous animal model, the PRx variability would be reduced by inducing slow arterial blood pressure (ABP) and ICP oscillations without other clinically relevant physiological changes. Patients with TBI were ventilated with a static PEEP for 30 min (PRx period) followed by a 30-min period of slow [1/min (0.0167 Hz)] +5 cmH2O PEEP oscillations (induced (iPRx period). Ten patients with TBI were included. No clinical monitoring was discontinued and no additional interventions were required during the iPRx period. The PRx variability [measured as the standard deviation (SD) of PRx] decreased significantly during the iPRx period from 0.25 (0.22-0.30) to 0.14 (0.09-0.17) (P = 0.006). There was a power increase around the induced frequency (1/min) for both ABP and ICP (P = 0.002). In conclusion, 1/min PEEP-induced oscillations reduced the PRx variability in patients with TBI with ICP levels <22 mmHg. No other clinically relevant physiological changes were observed. Reduced PRx variability might improve CA-guided perfusion management by reducing the time to find "optimal" perfusion pressure targets. Larger studies with prolonged periods of PEEP-induced oscillations are required to take it to routine use.NEW & NOTEWORTHY Cerebral autoregulation assessment requires sufficient slow arterial blood pressure (ABP) waves. However, spontaneous ABP waves may be insufficient for reliable cerebral autoregulation estimations. Therefore, we applied a ventilator "sigh-function" to generate positive end-expiratory pressure oscillations that induce slow ABP waves. This method demonstrated a reduced variability of the pressure reactivity index, commonly used as continuous cerebral autoregulation measure in a traumatic brain injury population.

Critical Spatial-Temporal Dynamics and Prominent Shape Collapse of Calcium Waves Observed in Human hNT Astrocytes in Vitro.

Networks of neurons are typically studied in the field of Criticality. However, the study of astrocyte networks in the brain has been recently lauded to be of equal importance to that of the neural networks. To date criticality assessments have only been performed on networks astrocytes from healthy rats, and astrocytes from cultured dissociated resections of intractable epilepsy. This work, for the first time, presents studies of the critical dynamics and shape collapse of calcium waves observed in cultures of healthy human astrocyte networks in vitro, derived from the human hNT cell line. In this article, we demonstrate that avalanches of spontaneous calcium waves display strong critical dynamics, including power-laws in both the size and duration distributions. In addition, the temporal profiles of avalanches displayed self-similarity, leading to shape collapse of the temporal profiles. These findings are significant as they suggest that cultured networks of healthy human hNT astrocytes self-organize to a critical point, implying that healthy astrocytic networks operate at a critical point to process and transmit information. Furthermore, this work can serve as a point of reference to which other astrocyte criticality studies can be compared.

Cardiac gene therapy with PDE2A limits ventricular remodeling, dysfunction and arrhythmias promoted in mice by chronic infusion with catecholamines

Chronic ß-AR activation is detrimental because it promotes cardiac remodeling and leads to heart failure (HF). Multiple cyclic nucleotide phosphodiesterases (PDEs) finely tune ß-AR responses by degrading and compartmentalizing cAMP. PDE2A is upregulated in HF, and PDE2A-transgenic mice are protected against catecholamine-induced arrhythmias. Since chronic treatment with PDE inhibitors increases mortality in HF and PDE2 overexpression seems cardioprotective, we postulated that decreasing cAMP levels by overexpressing PDE2A in the heart using gene therapy may have therapeutic effects. C57BL/6N male mice were injected with serotype 9 adeno-associated viruses (AAV9, 10e12 viral particles) encoding for PDE2A, or luciferase (LUC). Two weeks later, mice were implanted with osmotic pumps infusing NaCl or isoprenaline (Iso) and phenylephrine (IP, 30 mg/kg/day each) for 2 weeks. Cardiac function was assessed by echocardiography, susceptibility to arrhythmias by catheter-mediated ventricular pacing after Iso (1.5 mg/kg) and atropine (1 mg/kg) injection. Ventricular cardiomyocytes were isolated, loaded with 1 μM Fura-2AM and stimulated at 1 Hz to record calcium transients (CaT), sarcomere shortening (SS) and pro-arrhythmogenic spontaneous calcium waves (SCW). In LUC mice, IP treatment increased left ventricular weight over body weight ratio by 35 ± 5.7% ( P = 0.0001) and decreased ejection fraction by 29 ± 2.4% ( P < 0.0001). Both parameters were improved in animals subjected to AAV9-PDE2A injection ( P = 0.039 and P = 0.0003, respectively) increasing by ∼10 fold PDE2A levels. Ventricular tachycardias were triggered in IP-LUC mice ( P = 0.016) but not in animals treated with AAV9-PDE2A. In isolated myocytes from control mice, ß-AR stimulation (3 nM Iso) increased SS by 355% and CaT by 86% ( P < 0.0001). These inotropic effects were blunted in cells from IP treated animals with SS increasing by 157% ( P = 0.0002, vs. LUC-NaCl) and CaT by only 55% ( P = 0.06 vs. IP-LUC at baseline). However, the Iso effects were preserved in cardiomyocytes from animals injected with AAV9-PDE2A (SS: P < 0.0001, CaT: P < 0.0001 vs. IP-PDE2A at baseline), which exhibited less SCW upon maximal ß-AR stimulation (Iso, 100 nM, P = 0.02 vs. IP-LUC). Our results suggest that gene therapy with PDE2A limits cardiac hypertrophy and dysfunction induced by catecholamines as well as ventricular arrhythmias.