Spontaneous Fluctuations Research Articles

Do regular quantum black holes exist?

Regular black holes do not exist in any classical theory of gravity including Einstein's general relativity. This unappealing feature is due to the appearance of a singularity in the interior of the black hole described by any classical theory. As Hawking argued, all known laws of physics must break down at the singularity. It is thus an important question whether this singularity can disappear in a quantum mechanical description of spacetime. In this letter, we therefore quantize the black hole interior in a Kantowski-Sachs minisuperspace representation in the presence of spontaneous Klein-Gordon matter field fluctuations. This leads to a Wheeler-DeWitt equation whose solution yields the interior wave function of the black hole. The regular part of this wave function satisfies the DeWitt boundary condition in that it vanishes at the singularity. Moreover, the wave function is regular and well behaved in the region around the singularity. These features of the wave function suggest that regular black holes do exist in quantum gravity.

Widespread hyperexcitability of nociceptor somata outlasts enhanced avoidance behavior after incision injury.

Nociceptors with somata in dorsal root ganglia (DRGs) readily switch from an electrically silent state to a hyperactive state of tonic, nonaccommodating, low-frequency, irregular discharge of action potentials (APs). Spontaneous activity (SA) during this state is present in vivo in rats months after spinal cord injury (SCI) and has been causally linked to SCI pain. Intrinsically generated SA and, more generally, ongoing activity (OA) are induced by various neuropathic conditions in rats, mice, and humans and are retained in nociceptor somata after dissociation and culturing, providing a powerful tool for investigating its mechanisms and functions. The present study shows that long-lasting hyperexcitability that can generate OA during modest depolarization in probable nociceptors dissociated from DRGs of male and female rats is induced by plantar incision injury. OA occurred when the soma was artificially depolarized to a level within the normal range of membrane potentials where large, transient depolarizing spontaneous fluctuations (DSFs) can approach AP threshold. This hyperexcitability persisted for at least 3 weeks, whereas behavioral indicators of affective pain-hind paw guarding and increased avoidance of a noxious substrate in an operant conflict test-persisted for 1 week or less. The most consistent electrophysiological alteration associated with OA was enhancement of DSFs. An unexpected discovery after plantar incisions was hyperexcitability in neurons from thoracic DRGs that innervate dermatomes distant from the injured tissue. Potential in vivo functions of widespread, low-frequency nociceptor OA consistent with these and other findings are to contribute to hyperalgesic priming and to drive anxiety-related hypervigilance.

Decreases in Sympathetic Activity Due to Low-Intensity Extremely Low-Frequency Electric Field Treatment Revealed by Measurement of Spontaneous Fluctuations in Skin Conductance in Healthy Subjects

Decreases in Sympathetic Activity Due to Low-Intensity Extremely Low-Frequency Electric Field Treatment Revealed by Measurement of Spontaneous Fluctuations in Skin Conductance in Healthy Subjects

Pre-choice midbrain fluctuations affect self-control in food choice: A functional magnetic resonance imaging (fMRI) study.

Recent studies have shown that spontaneous pre-stimulus fluctuations in brain activity affect higher-order cognitive processes, including risky decision-making, cognitive flexibility, and aesthetic judgments. However, there is currently no direct evidence to suggest that pre-choice activity influences value-based decisions that require self-control. We examined the impact of fluctuations in pre-choice activity in key regions of the reward system on self-control in food choice. In the functional magnetic resonance imaging (fMRI) scanner, 49 participants made 120 food choices that required self-control in high and low working memory load conditions. The task was designed to ensure that participants were cognitively engaged and not thinking about upcoming choices. We defined self-control success as choosing a food item that was healthier over one that was tastier. The brain regions of interest (ROIs) were the ventral tegmental area (VTA), putamen, nucleus accumbens (NAc), and caudate nucleus. For each participant and condition, we calculated the mean activity in the 3-s interval preceding the presentation of food stimuli in successful and failed self-control trials. These activities were then used as predictors of self-control success in a fixed-effects logistic regression model. The results indicate that increased pre-choice VTA activity was linked to a higher probability of self-control success in a subsequent food-choice task within the low-load condition, but not in the high-load condition. We posit that pre-choice fluctuations in VTA activity change the reference point for immediate (taste) reward evaluation, which may explain our finding. This suggests that the neural context of decisions may be a key factor influencing human behavior.

Identifying Rare Events in Quantum Molecular Dynamics of Nanomaterials with Outlier Detection Indices.

Nanoscale and condensed matter systems evolve on multiple length- and time-scales, and rare events such as local phase transformation, ion segregation, defect migration, interface reconstruction, and grain boundary sliding can have a profound influence on material properties. We demonstrate how outlier detection indices can be used to identify rare events in machine-learning based, high-dimensional molecular dynamics (MD) simulations. Designed to order data-points from typical to untypical, the indices enable one to capture atomic events that are hard to detect otherwise. We demonstrate the approach with a nanosecond MD simulation of a grain boundary in a metal halide perovskite that is extensively studied for solar energy and optoelectronic applications. The method captures the initial grain boundary sliding and a spontaneous fluctuation half a nanosecond later, both events giving rise to persistent deep electronic trap states that impact charge carrier lifetime and transport and material performance. The approach offers a generalizable and simple method for identifying outlier events in complex condensed matter, molecular, and nanoscale systems.

Natural width of the superconducting transition in epitaxial TiN films

Abstract We investigate the effect of various fluctuation mechanisms on the dc resistance in superconducting devices based on epitaxial titanium nitride (TiN) films. The samples we studied show a relatively steep resistive transition (RT), with a transition width δT/Tc ~ 0.002-0.025, depending on the film thickness (20 nm, 9 nm, and 5 nm) and device dimensions. This value is significantly broader than expected due to conventional superconducting fluctuations ( δT/Tc < 10-3). The shape and width of the RT can be perfectly described by the well-known effective medium theory, which allows us to understand the origin of the inhomogeneity in the superconducting properties of TiN films. We propose that this inhomogeneity can have both dynamic and static origins. The dynamic mechanism is associated with spontaneous fluctuations in electron temperature (T-fluctuations), while the static mechanism is due to a random spatial distribution of surface magnetic disorder (MD). Our analysis has revealed clear correlations between the transition width and material parameters as well as device size for both proposed mechanisms. While T-fluctuations may contribute significantly to the observed transition width, our findings suggest that the dominant contribution comes from the MD mechanism. Our results provide new insights into the microscopic origin of broadening of the superconducting transition and inhomogeneity in thin superconducting films.

Opposing neural processing modes alternate rhythmically during sustained auditory attention

During continuous tasks, humans show spontaneous fluctuations in performance, putatively caused by varying attentional resources allocated to process external information. If neural resources are used to process other, presumably “internal” information, sensory input can be missed and explain an apparent dichotomy of “internal” versus “external” attention. In the current study, we extract presumed neural signatures of these attentional modes in human electroencephalography (EEG): neural entrainment and α-oscillations (~10-Hz), linked to the processing and suppression of sensory information, respectively. We test whether they exhibit structured fluctuations over time, while listeners attend to an ecologically relevant stimulus, like speech, and complete a task that requires full and continuous attention. Results show an antagonistic relation between neural entrainment to speech and spontaneous α-oscillations in two distinct brain networks—one specialized in the processing of external information, the other reminiscent of the dorsal attention network. These opposing neural modes undergo slow, periodic fluctuations around ~0.07 Hz and are related to the detection of auditory targets. Our study might have tapped into a general attentional mechanism that is conserved across species and has important implications for situations in which sustained attention to sensory information is critical.

Spontaneous fluctuation in atrial fibrillation burden and duration in patients with implantable loop monitors.

Most studies of device-detected atrial fibrillation (AF) have recommended indefinite anticoagulation once a patient crosses a particular threshold for AF duration or burden. However, durations and burdens are known to fluctuate over time, but little is known about the magnitude of spontaneous fluctuations and the potential impact on anticoagulation decisions. To quantify spontaneous fluctuations in AF duration and burden in patients with implantable loop recorders (ILRs) METHODS: We reviewed all ILR interrogations for patients with non-permanent AF at our institution from 2018 to 2023. We excluded patients treated with rhythm control. The duration of longest AF episode at each interrogation was classified as<6, 6-24, and>24h, and the AF burden reported at each interrogation was classified as<2%, 2%-11.4%, and>11.4%. Out of 156 patients, the mean age at ILR implant was 70.9±12.5 years, CHA2DS2-VASc score was 4.2±1.8, duration of ILR follow-up was 23.4±11.2 months, and number of ILR interrogations per patient was 18.0±8.9. The duration of longest AF episode at any point during follow-up was<6, 6-24, and>24h in 110, 30, and 16 patients, respectively. Among the 30 patients with a longest AF episode of 6-24h at some point during follow-up, out of 594 total ILR interrogations, only 75 (12%) showed a longest episode of 6-24h. In the remaining 519 interrogations, the longest episode was<6h. In patients with a longest episode of>24h at any point during follow-up (n=16), only 47 out of 320 total ILR interrogations (15%) showed an episode of>24h. When evaluating AF burden, 96, 38, and 22 patients had maximum reported AF burdens of<2%, 2%-11.4%, and>11.4% at any point during ILR follow-up. Among those with a maximum burden of 2%-11.4% at some point during follow-up (n=38), out of 707 ILR interrogations, only 76 (11%) showed a burden of 2%-11.4%. In the remaining 631 interrogations, the burden was<2%. In the 22 patients with a burden>11.4% at some point during follow-up, only 80 out of 480 interrogations (17%) showed a burden of>11.4%. In 65% of interrogations, the burden was<2%. Significant, spontaneous fluctuations in AF burden and duration are common in patients with ILRs. Even in patients with AF episodes of 6-24h or>24h at some point during follow-up, the vast majority of interrogations show episodes of<6h. Similarly, in patients with burdens of 2%-11.4% or>11.4% at some point during follow-up, the vast majority of interrogations show burdens of<2%. More data are needed to determine whether crossing an AF burden or duration threshold once is sufficient to merit lifelong anticoagulation or whether spontaneous fluctuations in AF burden and duration should impact anticoagulation decisions.

Daily Dynamics of Resting-State Electroencephalographic Theta and Gamma Fluctuations Are Associated With Cognitive Performance in Healthy Aging.

Healthy age-related cognitive changes are highly heterogeneous across individuals. This variability is increasingly explained through the lens of spontaneous fluctuations of brain activity, now considered a powerful index of age-related changes. However, brain activity is a biological process modulated by circadian rhythms, and how these fluctuations evolve throughout the day is under investigation. We analyzed data from 101 healthy late middle-aged participants from the Cognitive Fitness in Aging study (68 women and 33 men; aged 50-69 years). Participants completed 5 electroencephalographic (EEG) recordings of spontaneous resting-state activity on the same day. We used weighted phase-lag index (wPLI) analyses as an index of the functional synchrony between brain regions couplings, and we computed daily global PLI fluctuation rates of the 5 recordings to assess the association with cognitive performance and β-amyloid and tau/neuroinflammation pathological markers. We found that theta and gamma daily fluctuations in the salience-control executive internetwork (SN-CEN) are associated with distinct mechanisms underlying cognitive heterogeneity in aging. Higher levels of SN-CEN theta daily fluctuations appear to be deleterious for memory performance and were associated with higher tau/neuroinflammation rates. In contrast, higher levels of gamma daily fluctuations are positively associated with executive performance and were associated with lower rate of β-amyloid deposition. Thus, accounting for daily EEG fluctuations of brain activity contributes to a better understanding of subtle brain changes underlying individuals' cognitive performance in healthy aging. Results also provide arguments for considering the time of day when assessing cognition for old adults in a clinical context.

Spontaneous grip force fluctuations mirror semantic numerical magnitude processing: Larger numbers elicit larger forces

This study investigated the relationship between semantic numerical magnitudes and motor magnitudes. We asked whether the processing of numbers can affect motor behavior such as the size of numbers affecting the size of motor actions. For this, we recorded continuous grip force fluctuations from 43 healthy adults during a symbolic magnitude comparison task. We found that numbers induced spontaneous grip force fluctuations during number processing. Smaller numbers induced lower grip forces, whereas larger numbers induced larger forces. This result constitutes strong behavioral support for a generalized magnitude processing by continuously quantifying the response that challenges binary accounts of cross-domain interactions.

Slow ramping emerges from spontaneous fluctuations in spiking neural networks

The capacity to initiate actions endogenously is critical for goal-directed behavior. Spontaneous voluntary actions are typically preceded by slow-ramping activity in medial frontal cortex that begins around two seconds before movement, which may reflect spontaneous fluctuations that influence action timing. However, the mechanisms by which these slow ramping signals emerge from single-neuron and network dynamics remain poorly understood. Here, we developed a spiking neural-network model that produces spontaneous slow ramping activity in single neurons and population activity with onsets ~2 s before threshold crossings. A key prediction of our model is that neurons that ramp together have correlated firing patterns before ramping onset. We confirmed this model-derived hypothesis in a dataset of human single neuron recordings from medial frontal cortex. Our results suggest that slow ramping signals reflect bounded spontaneous fluctuations that emerge from quasi-winner-take-all dynamics in clustered networks that are temporally stabilized by slow-acting synapses.

Room-Temperature Solution Fluorescence Excitation Correlation Spectroscopy.

Single-molecule fluorescence spectroscopy is a powerful tool for investigating the physical properties of individual molecules, yet elucidating the fast fluctuation dynamics of freely diffusing single molecules in solution at room temperature, where a variety of chemical and biological processes occur, remains challenging. In this study, we report on fluorescence excitation correlation spectroscopy of room-temperature solutions, which enables the study of spontaneous fluctuation of the excitation spectrum with microsecond time resolution. By employing Fourier transform spectroscopy with broadband femtosecond pulses and time-correlated single-photon counting, we achieved fluorescence excitation spectroscopy of a room-temperature solution at the single-molecule level. Building upon this single-molecule measurement, we obtained an excitation wavelength-resolved fluorescence autocorrelation function in the microsecond to millisecond range, demonstrating the potential of this method to elucidate fast, spontaneous, time-dependent changes of excitation spectra in statistically equilibrated systems. With further development, this method will allow the study of spectral exchange associated with transitions between sub-ensembles of solution-phase molecules with unprecedented time resolution.

Pupil-Linked Arousal Modulates Precision of Stimulus Representation in Cortex.

Neural responses are naturally variable from one moment to the next, even when the stimulus is held constant. What factors might underlie this variability in neural population activity? We hypothesized that spontaneous fluctuations in cortical stimulus representations are created by changes in arousal state. We tested the hypothesis using a combination of fMRI, probabilistic decoding methods, and pupillometry. Human participants (20 female, 12 male) were presented with gratings of random orientation. Shortly after viewing the grating, participants reported its orientation and gave their level of confidence in this judgment. Using a probabilistic fMRI decoding technique, we quantified the precision of the stimulus representation in the visual cortex on a trial-by-trial basis. Pupil size was recorded and analyzed to index the observer's arousal state. We found that the precision of the cortical stimulus representation, reported confidence, and variability in the behavioral orientation judgments varied from trial to trial. Interestingly, these trial-by-trial changes in cortical and behavioral precision and confidence were linked to pupil size and its temporal rate of change. Specifically, when the cortical stimulus representation was more precise, the pupil dilated more strongly prior to stimulus onset and remained larger during stimulus presentation. Similarly, stronger pupil dilation during stimulus presentation was associated with higher levels of subjective confidence, a secondary measure of sensory precision, as well as improved behavioral performance. Taken together, our findings support the hypothesis that spontaneous fluctuations in arousal state modulate the fidelity of the stimulus representation in the human visual cortex, with clear consequences for behavior.

Electrodermal lability and sensorimotor preparation: effects on reaction time, contingent negative variation, and heart rate

Electrodermal lability is a trait-like measure of spontaneous sympathetic resting activity. In the present study, we addressed whether interindividual differences in this lability have an impact on the reaction time (RT) and on two physiological indicators of a goal-oriented sensorimotor preparation in a long-running, forewarned RT task (S1-S2 paradigm). The two indicators were the brain’s contingent negative variation (CNV) and a heart rate deceleration (HRD). The interindividual differences were determined by counting spontaneous skin conductance fluctuations during a 5-min resting phase and dividing the subjects into two groups: individuals below (stable) and above (labile) the median of these fluctuations. In the task, labile individuals had a shorter RT compared with stable individuals and showed in the final phase of preparation in both physiological indicators the stronger response. Thus, lability-dependent effects in forewarned RT tasks cannot be explained by differences in stimulus-driven or passively controlled processes alone. Rather, goal-oriented, deliberately controlled processes that serve to adequately prepare for an imperative stimulus—the S2 in our paradigm—also must be considered to explain them. Labile individuals not only react faster than stable ones but also intentionally prepare themselves more appropriately for the imperative stimulus. A norepinephrine hypothesis focusing on the tonic activity of the locus coeruleus (LC) is proposed as an explanation for these and other lability-dependent effects. The frequency of spontaneous electrodermal fluctuations at rest may represent a peripheral, noninvasive, and easily measurable indicator of the baseline LC activity during wakefulness.

Induction of long-term hyperexcitability by memory-related cAMP signaling in isolated nociceptor cell bodies.

Persistent hyperactivity of nociceptors is known to contribute significantly to long-lasting sensitization and ongoing pain in many clinical conditions. It is often assumed that nociceptor hyperactivity is mainly driven by continuing stimulation from inflammatory mediators. We have tested an additional possibility: that persistent increases in excitability promoting hyperactivity can be induced by a prototypical cellular signaling pathway long known to induce late-phase long-term potentiation (LTP) of synapses in brain regions involved in memory formation. This cAMP-PKA-CREB-gene transcription-protein synthesis pathway was tested using whole-cell current clamp methods on small dissociated sensory neurons (primarily nociceptors) from dorsal root ganglia (DRGs) excised from previously uninjured ("naïve") rats. Six-hour treatment with the specific Gαs-coupled 5-HT4 receptor agonist, prucalopride, or with the adenylyl cyclase activator, forskolin, induced long-term hyperexcitability (LTH) in DRG neurons that manifested 12-24 hours later as action potential (AP) discharge (ongoing activity, OA) during artificial depolarization to -45 mV, a membrane potential that is normally subthreshold for AP generation. Prucalopride treatment also induced significant long-lasting depolarization of resting membrane potential (from -69 to -66 mV), enhanced depolarizing spontaneous fluctuations (DSFs) of membrane potential, and indications of reduced AP threshold and rheobase. LTH was prevented by co-treatment of prucalopride with inhibitors of PKA, CREB, gene transcription, and protein synthesis. As in the induction of synaptic memory, many other cellular signals are likely to be involved. However, the discovery that this prototypical memory induction pathway can induce nociceptor LTH, along with reports that cAMP signaling and CREB activity in DRGs can induce hyperalgesic priming, suggest that early, temporary, cAMP-induced transcriptional and translational mechanisms can induce nociceptor LTH that might last for long periods. An interesting possibility is that these mechanisms can also be reactivated by re-exposure to inflammatory mediators such as serotonin during subsequent challenges to bodily integrity, "reconsolidating" the cellular memory and thereby extending the duration of persistent nociceptor hyperexcitability.

Dynamic properties in functional connectivity changes and striatal dopamine deficiency in Parkinson's disease.

Recent studies in Parkinson's disease (PD) patients reported disruptions in dynamic functional connectivity (dFC, i.e., a characterization of spontaneous fluctuations in functional connectivity over time). Here, we assessed whether the integrity of striatal dopamine terminals directly modulates dFC metrics in two separate PD cohorts, indexing dopamine-related changes in large-scale brain network dynamics and its implications in clinical features. We pooled data from two disease-control cohorts reflecting early PD. From the Parkinson's Progression Marker Initiative (PPMI) cohort, resting-state functional magnetic resonance imaging (rsfMRI) and dopamine transporter (DaT) single-photon emission computed tomography (SPECT) were available for 63 PD patients and 16 age- and sex-matched healthy controls. From the clinical research group 219 (KFO) cohort, rsfMRI imaging was available for 52 PD patients and 17 age- and sex-matched healthy controls. A subset of 41 PD patients and 13 healthy control subjects additionally underwent 18F-DOPA-positron emission tomography (PET) imaging. The striatal synthesis capacity of 18F-DOPA PET and dopamine terminal quantity of DaT SPECT images were extracted for the putamen and the caudate. After rsfMRI pre-processing, an independent component analysis was performed on both cohorts simultaneously. Based on the derived components, an individual sliding window approach (44 s window) and a subsequent k-means clustering were conducted separately for each cohort to derive dFC states (reemerging intra- and interindividual connectivity patterns). From these states, we derived temporal metrics, such as average dwell time per state, state attendance, and number of transitions and compared them between groups and cohorts. Further, we correlated these with the respective measures for local dopaminergic impairment and clinical severity. The cohorts did not differ regarding age and sex. Between cohorts, PD groups differed regarding disease duration, education, cognitive scores and L-dopa equivalent daily dose. In both cohorts, the dFC analysis resulted in three distinct states, varying in connectivity patterns and strength. In the PPMI cohort, PD patients showed a lower state attendance for the globally integrated (GI) state and a lower number of transitions than controls. Significantly, worse motor scores (Unified Parkinson's Disease Rating Scale Part III) and dopaminergic impairment in the putamen and the caudate were associated with low average dwell time in the GI state and a low total number of transitions. These results were not observed in the KFO cohort: No group differences in dFC measures or associations between dFC variables and dopamine synthesis capacity were observed. Notably, worse motor performance was associated with a low number of bidirectional transitions between the GI and the lesser connected (LC) state across the PD groups of both cohorts. Hence, in early PD, relative preservation of motor performance may be linked to a more dynamic engagement of an interconnected brain state. Specifically, those large-scale network dynamics seem to relate to striatal dopamine availability. Notably, most of these results were obtained only for one cohort, suggesting that dFC is impacted by certain cohort features like educational level, or disease severity. As we could not pinpoint these features with the data at hand, we suspect that other, in our case untracked, demographical features drive connectivity dynamics in PD. PRACTITIONER POINTS: Exploring dopamine's role in brain network dynamics in two Parkinson's disease (PD) cohorts, we unraveled PD-specific changes in dynamic functional connectivity. Results in the Parkinson's Progression Marker Initiative (PPMI) and the KFO cohort suggest motor performance may be linked to a more dynamic engagement and disengagement of an interconnected brain state. Results only in the PPMI cohort suggest striatal dopamine availability influences large-scale network dynamics that are relevant in motor control.

Altered Corticobrainstem Connectivity during Spontaneous Fluctuations in Pain Intensity in Painful Trigeminal Neuropathy.

Chronic neuropathic pain can result from nervous system injury and can persist in the absence of external stimuli. Although ongoing pain characterizes the disorder, in many individuals, the intensity of this ongoing pain fluctuates dramatically. Previously, it was identified that functional magnetic resonance imaging signal covariations between the midbrain periaqueductal gray (PAG) matter, rostral ventromedial medulla (RVM), and spinal trigeminal nucleus are associated with moment-to-moment fluctuations in pain intensity in individuals with painful trigeminal neuropathy (PTN). Since this brainstem circuit is modulated by higher brain input, we sought to determine which cortical sites might be influencing this brainstem network during spontaneous fluctuations in pain intensity. Over 12 min, we recorded the ongoing pain intensity in 24 PTN participants and classified them as fluctuating (n = 13) or stable (n = 11). Using a PAG seed, we identified connections between the PAG and emotional-affective sites such as the hippocampal and posterior cingulate cortices, the sensory-discriminative posterior insula, and cognitive-affective sites such as the dorsolateral prefrontal (dlPFC) and subgenual anterior cingulate cortices that were altered dependent on spontaneous high and low pain intensity. Additionally, sliding-window functional connectivity analysis revealed that the dlPFC-PAG connection anticorrelated with perceived pain intensity over the entire 12 min period. These findings reveal cortical systems underlying moment-to-moment changes in perceived pain in PTN, which likely cause dysregulation in the brainstem circuits previously identified, and consequently alter the appraisal of pain across time.

Induction of long-term hyperexcitability by memory-related cAMP signaling in isolated nociceptor cell bodies

Persistent hyperactivity of nociceptors is known to contribute significantly to long-lasting sensitization and ongoing pain in many clinical conditions. It is often assumed that nociceptor hyperactivity is mainly driven by continuing stimulation from inflammatory mediators. We have tested an additional possibility: that persistent increases in excitability promoting hyperactivity can be induced by a prototypical cellular signaling pathway long known to induce late-phase long-term potentiation (LTP) of synapses in brain regions involved in memory formation. This cAMP-PKA-CREB-gene transcription-protein synthesis pathway was tested using whole-cell current clamp methods on small dissociated sensory neurons (primarily nociceptors) from dorsal root ganglia (DRGs) excised from previously uninjured (“naïve”) male rats. Six-hour treatment with the specific Gαs-coupled 5-HT4 receptor agonist, prucalopride, or with the adenylyl cyclase activator forskolin induced long-term hyperexcitability (LTH) in DRG neurons that manifested 12–24 h later as action potential (AP) discharge (ongoing activity, OA) during artificial depolarization to −45 mV, a membrane potential that is normally subthreshold for AP generation. Prucalopride treatment also induced significant long-lasting depolarization of resting membrane potential (from −69 to −66 mV), enhanced depolarizing spontaneous fluctuations (DSFs) of membrane potential, and produced trends for reduced AP threshold and rheobase. LTH was prevented by co-treatment of prucalopride with inhibitors of PKA, CREB, gene transcription, or protein synthesis. As in the induction of synaptic memory, many other cellular signals are likely to be involved. However, the discovery that this prototypical memory induction pathway can induce nociceptor LTH, along with reports that cAMP signaling and CREB activity in DRGs can induce hyperalgesic priming, suggest that early, temporary, cAMP-induced transcriptional and translational mechanisms can induce nociceptor LTH that might last for long periods. The present results also raise the question of whether reactivation of primed signaling mechanisms by re-exposure to inflammatory mediators linked to cAMP synthesis during subsequent challenges to bodily integrity can “reconsolidate” nociceptor memory, extending the duration of persistent hyperexcitability.

Probing chromatin condensation dynamics in live cells using interferometric scattering correlation spectroscopy

Chromatin organization and dynamics play important roles in governing the regulation of nuclear processes of biological cells. However, due to the constant diffusive motion of chromatin, examining chromatin nanostructures in living cells has been challenging. In this study, we introduce interferometric scattering correlation spectroscopy (iSCORS) to spatially map nanoscopic chromatin configurations within unlabeled live cell nuclei. This label-free technique captures time-varying linear scattering signals generated by the motion of native chromatin on a millisecond timescale, allowing us to deduce chromatin condensation states. Using iSCORS imaging, we quantitatively examine chromatin dynamics over extended periods, revealing spontaneous fluctuations in chromatin condensation and heterogeneous compaction levels in interphase cells, independent of cell phases. Moreover, we observe changes in iSCORS signals of chromatin upon transcription inhibition, indicating that iSCORS can probe nanoscopic chromatin structures and dynamics associated with transcriptional activities. Our scattering-based optical microscopy, which does not require labeling, serves as a powerful tool for visualizing dynamic chromatin nano-arrangements in live cells. This advancement holds promise for studying chromatin remodeling in various crucial cellular processes, such as stem cell differentiation, mechanotransduction, and DNA repair.

Black hole singularity resolution in Wheeler–DeWitt quantum gravity

Ever since Hawking highlighted the puzzle of the existence of a singularity in the classical spacetime of general relativity, implying breakdown of all laws of physics living in the classical spacetime, singularity resolution became a problem of significantly high importance. This undesirable feature, indicating loss of predictability, has intrigued physicists over several decades. It has been hoped that the classical singularity would be resolved in a quantum theory of gravity. However, no appropriate wave function in the vicinity of the black hole singularity has been obtained so far to reach a definite conclusion.In this paper, we focus upon the interior of the Schwarzschild black hole, plagued by a non-removable classical singularity. We consider the interior spacetime of the black hole to be represented by the Kantowski–Sachs metric. Since in a quantum mechanical scenario, existence of spontaneous fluctuations of matter fields should not be ignored, we include a Klein–Gordon field in the system. Quantizing this simple gravity-matter model in the canonical scheme, we obtain the Wheeler–DeWitt equation and find an exact solution in the minisuperspace variables.We find that there exist three classes of solutions belonging to three different subregions of the eigenvalue space. Two of these classes of solutions admit the DeWitt criterion, a necessary condition for singularity resolution, implied by vanishing of the wave function at the singularity. These solutions are well-behaved and finite in the vicinity of the singularity and they indicate the existence of regular black holes in quantum gravity. In these classes of solutions, we further find that the expectation value of the Kretschmann operator is well-behaved and regular near the singularity, confirming a definite resolution to the puzzle of classical black hole singularity. On the other hand, there exists a small subregion in the eigenvalue space where the solution does not satisfy both conditions, the DeWitt criterion and finiteness of the Kretschmann expectation value at the singularity. This last class of solutions does not represent regular quantum black holes.