Significant Stimuli Research Articles

The structural logic of dynamic signaling in the Escherichia coli serine chemoreceptor.

The experimental challenges posed by integral membrane proteins hinder molecular understanding of transmembrane signaling mechanisms. Here, we exploited protein crosslinking assays in living cells to follow conformational and dynamic stimulus signals in Tsr, the Escherichia coli serine chemoreceptor. Tsr mediates serine chemotaxis by integrating transmembrane serine-binding inputs with adaptational modifications of a methylation helix bundle to regulate a signaling kinase at the cytoplasmic tip of the receptor molecule. We created cysteine replacements at Tsr residues adjacent to hydrophobic packing faces of the bundle helices and crosslinked them with a cell-permeable, bifunctional thiol-reagent. We identified an extensively crosslinked dynamic junction midway through the methylation helix bundle that seemed uniquely poised to respond to serine signals. We explored its role in mediating signaling shifts between different packing arrangements of the bundle helices by measuring crosslinking in receptor molecules with apposed pairs of cysteine reporters in each subunit and assessing their signaling behaviors with an in vivo kinase assay. In the absence of serine, the bundle helices evinced compact kinase-ON packing arrangements; in the presence of serine, the dynamic junction destabilized adjacent bundle segments and shifted the bundle to an expanded, less stable kinase-OFF helix-packing arrangement. AlphaFold models of kinase-active Tsr showed a prominent bulge and kink at the dynamic junction that might antagonize stable structure at the receptor tip. Serine stimuli might inhibit kinase activity by shifting the bundle to a less stably-packed conformation that relaxes structural strain at the receptor tip, thereby allowing it to stabilize and freeze kinase activity.

Measuring Microplastic Concentrations in Water by Electrical Impedance Spectroscopy

Plastics are vital for society, but their usage has grown exponentially and contributes to the growth of pollution worldwide. The World Health Organization, WHO, already reported that microplastics (MPs) are found everywhere, in waste and fresh water, and in the air and soil. Regarding water effluents, waste-water treatment plants only minimize the problem, trapping only larger size particles. In contrast, smaller ones remain in oxidation ponds or sewage sludges, or are even released to aquifers environment. Classic procedures for MPs detection are still quite laborious, and are usually conducted off-line, involving several steps and expensive equipment. Electrical Impedance Spectroscopy, EIS, is a technique that allows the analysis of a system’s electrical response, yielding helpful information about its domain-dependent on physical-chemical properties. Due to the superficial electronegativity of MPs’ particles, EIS may allow to attain the purpose of the present work: to provide a fast and reliable method to detect/estimate MPs’ concentration in water effluents. Among the most common microplastics are Polyethylene, PE, and Polyvinyl Chloride, PVC. Using the developed setup and experimental data collection methodology, the authors could differentiate between MPs’ suspensions containing the same concentration of the different evaluated MPs, PVC and PE, and assess PVC concentration variation, in the interval between 0.03 to 0.5 g (w/w), with an error, estimated based on the obtained impedance modulus, around or below 3% for the entire stimulus signal frequency range (from 100 Hz to 40 MHz) for the PVC particles.

Mechanisms and treatment of atherosclerosis: focus on macrophages.

Macrophages are the basic mediators and coordinators of various types of chronic inflammation and play a crucial role in the formation and development of atherosclerosis (AS). In the complex microenvironment of atherosclerotic plaques, macrophages of different sources are exposed to different signal stimuli and thus polarized into various subpopulations. Various types of macrophages with predominantly M1 and M2 phenotypes also play different regulatory roles in the initiation and progression of AS. Lipid-lowering drugs, mainly statins, are widely used in clinical practice, but the adverse reactions are obvious and there is a lack of personalized treatment. Emerging targeted macrophage and Traditional Chinese medicine (TCM)-related therapies can regulate the cellular microenvironment, inhibit the polarization of M1 macrophages, and promote the activation of M2 macrophages, providing new ideas for the prevention and treatment of AS.

Gelatin-Modified Bioactive Glass for Treatment of Dentin Hypersensitivity.

When dentin is directly exposed to the oral cavity for various reasons, such as a lack of enamel on the tooth surface, external stimuli to the dentin often cause transient discomfort known as dentin hypersensitivity. In order to block the incoming stimulus signal, an ideal treatment is to induce the production of minerals to block the dentinal tubules. In this work, a dentin-desensitizing plugging material was prepared by modifying mesoporous bioactive glass with gelatin, the mineralization and desensitization effects of which were compared with Gluma in in vitro experiments. These experiments confirmed that gelatin-modified bioactive glass (MBG@PDA@Gel) is more effective than traditional desensitizing agents at blocking dentin tubules. Following the successful synthesis of MBG@PDA@Gel, as confirmed by scanning electron microscopy, transmission electron microscopy, and other tests, the treatment of demineralized dentin with MBG@PDA@Gel demonstrated that the dentinal tubules were tightly blocked under scanning electron microscopy. MBG@PDA@Gel induces minerals in deeper layers of dentinal tubules, promoting remineralization and forming a unified structure with the tubule blockage. Animal studies showed that MBG@PDA@Gel can remineralize demineralized dentin, and it is stable in the oral cavity and does not fall out. MBG@PDA@Gel not only enhances the biocompatibility of the nanoparticle but also results in an overall uniform and rapid remineralization of the demineralized dentin.

Design of Optogenetic Microimplants for the Treatment of Neurodegenerative Disease

In the context of global aging, neurodegenerative diseases such as Alzheimer’s disease have become important issues in global public health and scientific research. This is due to their soaring incidence, serious impact on patients’ quality of life, and the huge burden they place on families and social economies. However, current treatments, such as drug therapy and deep brain stimulation, have obvious shortcomings. Moreover, there is a lack of precise neuromodulation tools to study the pathogenesis of these diseases In order to solve these problems, optogenetics has attracted attention in recent years, which uses light as a stimulus signal carrier and can realize the detection and control of neurodegenerative diseases at the level of neurons and neural circuits by implanting micro-implants such as μ leds. This review summarize the recent advances in microimplant technology in the fields of optogenetics and neuroscience, and summarize the development and application of optogenetic microimplants for the treatment of neurodegenerative diseases in detail.

How the Structure of Signaling Regulation Evolves: Insights from an Evolutionary Model.

To remain responsive to environmental changes, signaling pathways attenuate their activity with negative feedback loops (NFLs), where proteins produced upon stimulation downregulate the response. NFLs function both upstream of signaling to reduce input and downstream to reduce output. Unlike upstream NFLs, downstream NFLs directly regulate gene expression without the involvement of intermediate proteins. Thus, we hypothesized that downstream NFLs evolve under more stringent selection than upstream NFLs. Indeed, genes encoding downstream NFLs exhibit a slower evolutionary rate than upstream genes. Such differences in selective pressures could result in the robust evolution of downstream NFLs while making the evolution of upstream NFLs more sensitive to changes in signaling proteins and stimuli. Here, we test these assumptions within the context of immune signaling. Our minimal model of immune signaling predicts robust evolution of downstream NFLs to changes in model parameters. This is consistent with their critical role in regulating signaling and the conservative rate of evolution. Furthermore, we show that the number of signaling steps needed to activate a downstream NFL is influenced by the cost of signaling. Our model predicts that upstream NFLs are more likely to evolve under a shorter half-life of signaling proteins, absence of host-pathogen co-evolution, and a high infection rate. Although it has been proposed that NFLs evolve to reduce the cost of signaling, we show that a high cost does not necessarily predict the evolution of upstream NFLs. The insights from our model have broad implications for understanding the evolution of regulatory mechanisms across signaling pathways.

Suppression of Visceral Nociception by Selective C-Fiber Transmission Block Using Temporal Interference Sinusoidal Stimulation.

Chronic visceral pain management remains challenging due to limitations in selective targeting of C-fiber nociceptors. This study investigates temporal interference stimulation (TIS) on dorsal root ganglia (DRG) as a novel approach for selective C-fiber transmission block. We employed (1) GCaMP6 recordings in mouse whole DRG using a flexible, transparent microelectrode array for visualizing L6 DRG neuron activation, (2) ex vivo single-fiber recordings to assess sinusoidal stimulation effects on peripheral nerve axons, (3) in vivo behavioral assessment measuring visceromotor responses (VMR) to colorectal distension in mice, including a TNBS-induced visceral hypersensitivity model, and (4) immunohistological analysis to evaluate immediate immune responses in DRG following TIS. We demonstrated that TIS (2000 Hz and 2020 Hz carrier frequencies) enabled tunable activation of L6 DRG neurons, with the focal region adjustable by altering stimulation amplitude ratios. Low-frequency (20-50 Hz) sinusoidal stimulation effectively blocked C-fiber and Aδ-fiber transmission while sparing fast-conducting A-fibers, with 20 Hz showing highest efficacy. TIS of L6 DRG reversibly suppressed VMR to colorectal distension in both control and TNBS-induced visceral hypersensitive mice. The blocking effect was fine-tunable by adjusting interfering stimulus signal amplitude ratios. No apparent immediate immune responses were observed in DRG following hours-long TIS. In conclusion, TIS on lumbosacral DRG demonstrates promise as a selective, tunable approach for managing chronic visceral pain by effectively blocking C-fiber transmission. This technique addresses limitations of current neuromodulation methods and offers potential for more targeted relief in chronic visceral pain conditions.

Evoked Component Analysis (ECA): Decomposing the Functional Ultrasound Signal With GLM-Regularization.

Analysis of functional neuroimaging data aims to unveil spatial and temporal patterns of interest. Existing analysis methods fall into two categories: fully data-driven approaches and those reliant on prior information, e.g. the stimulus time course. While using the stimulus signal directly can help identify the activated brain areas, it is known that the relationship between stimuli and the brain's response exhibits nonlinear and time-varying characteristics. As such, relying completely on the stimulus signal to describe the brain's temporal response leads to a restricted interpretation of the brain function. In this paper, we present a new technique called Evoked Component Analysis (ECA), which leverages prior information up to a defined extent. This is achieved by including the general linear model (GLM) design matrix as a regulatory term and estimating the factor matrices in both space and time through an alternating minimization approach. We apply ECA to 2D and swept-3D functional ultrasound (fUS) experiments conducted with mice. When decomposing 2D fUS data, we employ GLM regularization at various intensities to emphasize the role of prior information. Furthermore, we show that incorporating multiple hemodynamic response functions within the design matrix can provide valuable insights into region-specific characteristics of evoked activity. Finally, we use ECA to analyze swept-3D fUS data recorded from five mice engaged in two distinct visual tasks. Swept-3D fUS images the 3D brain sequentially using a moving probe, resulting in different slice acquisition time instants. We show that ECA can estimate factor matrices with a fine resolution at each slice acquisition time instant and yield higher t-statistics compared to GLM and correlation analysis for all subjects.

Neuromodulation effect of temporal interference stimulation based on network computational model.

Deep brain stimulation (DBS) has long been the conventional method for targeting deep brain structures, but noninvasive alternatives like transcranial Temporal Interference Stimulation (tTIS) are gaining traction. Research has shown that alternating current influences brain oscillations through neural modulation. Understanding how neurons respond to the stimulus envelope, particularly considering tTIS's high-frequency carrier, is vital for elucidating its mechanism of neuronal engagement. This study aims to explore the focal effects of tTIS across varying amplitudes and modulation depths in different brain regions. An excitatory-inhibitory network using the Izhikevich neuron model was employed to investigate responses to tTIS and compare them with transcranial Alternating Current Stimulation (tACS). We utilized a multi-scale model that integrates brain tissue modeling and network computational modeling to gain insights into the neuromodulatory effects of tTIS on the human brain. By analyzing the parametric space, we delved into phase, amplitude, and frequency entrainment to elucidate how tTIS modulates endogenous alpha oscillations. Our findings highlight a significant difference in current intensity requirements between tTIS and tACS, with tTIS requiring notably higher intensity. We observed distinct network entrainment patterns, primarily due to tTIS's high-frequency component, whereas tACS exhibited harmonic entrainment that tTIS lacked. Spatial resolution analysis of tTIS, conducted via computational modeling and brain field distribution at a 13 Hz stimulation frequency, revealed modulation in deep brain areas, with minimal effects on the surface. Notably, we observed increased power within intrinsic and stimulation bands beneath the electrodes, attributed to the high stimulus signal amplitude. Additionally, Phase Locking Value (PLV) showed slight increments in non-deep areas. Our analysis indicates focal stimulation using tTIS, prompting further investigation into the necessity of high amplitudes to significantly affect deep brain regions, which warrants validation through clinical experiments.

High Stability Hydrogel Magnetic Relaxation Switch Sensor Driven by pH for the Sensitive Detection of Cd2.

The traditional magnetic relaxation switching (MRS) sensors have excellent sensitivity, but their stability is poor because the magnetic relaxation signal is easily affected by the external magnetic field or environmental oxidation. In this study, a highly stable hydrogel bead-based MRS (Gel-MRS) sensor was established for the accurate and sensitive detection of Cd2+ in rice. A pH-responsive hydrogel bead was applied as a core element for the target stimulus and transverse relaxation signal transduction. The stability experiments showed that the transverse relaxation time (T2) change of the Gel-MRS sensor was one-seventh that of traditional magnetic nanoparticles under an external magnetic field and less than a fifth that of Fe2+/Fe3+ conversion in air. The excellent stability was due to the fact that T2 of the Gel-MRS sensor came from the swelling system mediated by pH rather than the traditional aggregation/dispersion or Fe2+/Fe3+ conversion of magnetic nanoparticles. In addition, the target Cd2+ could exclusively trigger a pH response of the hydrogel beads, altering the T2, thus resulting in excellent relaxation properties (R2 = 56.89) and pH responsiveness of the Gel-MRS sensor. The swelling process of the hydrogel beads followed quasi-second-order dynamics. The Gel-MRS sensor demonstrated a remarkable limit of detection as low as 0.009 ng/mL for Cd2+, with a linear range of 0.01-5 ng/mL. The excellent stability and sensitivity made the Gel-MRS sensor have great application potential in food and environmental detection.

Characterizing third-order intermodulation distortion of photodetectors based on de-coupling and de-embedding modulation distortion of modulators

A novel, to the best of our knowledge, electro-optical modulation method is proposed for measuring third-order intermodulation distortion of photodetectors (PDs) based on de-coupling and de-embedding modulation distortion of modulators. The method utilizes dual parallel intensity modulation to generate electro-optical stimulus signals with fast and fine sweeping capability, and it eliminates the nonlinear impact of modulators by using low-frequency bias swing, allowing a direct extraction of the third-order output intercept point (OIP3) of PD from the combined nonlinear response contributed by both the modulators and the PD. The OIP3 of PD is frequency-swept measured with our method and compared to those with the conventional method to check for consistency. The proposed method enables a modulator-distortion-free, fast, and fine sweeping measurement of PDs using a simple system.

Pigeons' (Columba livia) intertemporal choice in binary-choice and patch-leaving contexts.

Typical approaches to study self-control present subjects with a simultaneous choice between a larger-later (LL) reinforcer and a smaller-sooner (SS) reinforcer. In contrast, in patch-leaving tasks, subjects choose between staying at a patch for an SS (or LL) reinforcer and leaving for an LL (or SS) reinforcer. Previous studies show that blue jays, monkeys, humans, and rats prefer the SS reinforcer in binary-choice tasks, whereas the same subjects prefer the LL reinforcer in equivalent patch-leaving tasks. The current study systematically replicated this research using pigeons. Six pigeons responded in a binary-choice task and in two patch-leaving tasks in which staying led to an LL (Patch-L) or SS (Patch-S) reinforcer. Across conditions, the SS reinforcer delay varied from 5 to 55 s; the LL reinforcer delay was always 60 s. In binary-choice conditions, subjects preferred the SS reinforcer. In Patch-L and Patch-S conditions, subjects preferred the LL and SS reinforcer, respectively, reflecting a bias to stay at the patch. This bias persisted when the stay response was more effortful and when the delays to both reinforcers were equal. This may reflect a species-specific win-stay bias and the differential consequences of staying (which led to a stimulus signaling food) versus leaving (which led to a stimulus never associated with food). Thus, we propose a conditioned-reinforcement account of intertemporal choice in patch-leaving contexts. We suggest several avenues for further investigations of the mechanisms underlying intertemporal choice in different contexts and question the economic equivalence of the operant and patch-leaving procedures. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Performance During a Task That Simulates Passive Sonar Operator Duties Under Conditions of Varying Workloads.

It is critical to develop and implement lab-based computer experiments that simulate real-world tasks in order to characterize operational requirements and challenges or identify potential solutions. Achieving a high degree of laboratory control, operational generalizability, and ease-of-use for a task is challenging, often leading to the development of tasks that can satisfy some facets but not all. This can result in insufficient solutions that leave real-world stakeholders with unsolved problems. This issue is addressed using a customized passive sonar simulator application that provides extensive researcher control over the design and manipulation of a sonar task; a visual appearance and cognitive demand similar to a true submarine-based sonar task; and a convenient and short training routine for sonar novices. The task requires participants to watch for multiple signal sources of varying appearance and salience and subsequently classify these signals into their respective categories. The current study investigated the effects of stimulus signal strength and signal density on sonar task performance-including metrics of classification accuracy, classification confidence, and response times-finding an interaction between signal density and signal strength that resulted in greater performance errors with high signal density at the weakest signal strength. The lab-based sonar application provides new possibilities for research, not limited to signal intensity and signal density but also through the manipulation of parameters such as the number of unique targets, target appearance, and task duration. This application may illuminate the operational demands that each of these factors may have on operator behavior within the dynamic tasks.

Feasibility exploration of cortical auditory evoked potentials evoked by spectro-temporal modulation signals

Background An objective measurement of speech perception would be valuable in hearing-impaired patients who are unable to perform auditory tasks reliably. Objectives To investigate the feasibility of cortical auditory evoked potentials (CAEPs) evoked by different spectro-temporal modulation (STM) signals and provide reference for the further exploration of acoustic change complex (ACC) in hearing-impaired patients. Method 29 normal hearing (NH) adults were recruited and stimulated randomly by STM signals at 6 spectral modulation rates: 0, 1, 2, 4, 8, 16 cycles/octave, at each of 4 temporal modulation rates: 0, 2, 4, 8 Hz, to elicit ACC response. Results The change of spectral modulation rates ≤ 16 cycles/octave at 0 Hz temporal modulation rate had different impacts on latency. 0, 1 cycles/octave, and 4, 8 Hz made a difference to the P2-N1 amplitude easily. 8, 16 cycles/octave were more unstable in rejection rate. No significant difference existed in waveform repetition rate among different STM rates. No significant interaction effect existed in spectral and temporal modulation. Conclusions STM as a stimulus signal to induce ACC response had its feasibility. 2 cycles/octave at spectral modulation rate and 2 Hz at temporal modulation rate had better stability and waveform repeatability in NH adults.

Increased risky choice during forced abstinence from fentanyl on the cued rat gambling task.

The use of illicit opioids has arguably never been more risky; street drug potency can be dangerously high, is often unknown to the consumer, and results in multiple daily fatalities worldwide. Furthermore, substance use disorder (SUD) is associated with increased maladaptive, risky decisions in laboratory-based gambling tasks. Animal studies can help determine whether this decision-making deficit is a cause or consequence of drug use. However, most experiments have only assessed psychostimulant drugs. To assess differences in decision-making strategies both before, during, and after self-administration of fentanyl in male and female Long Evans rats. Male and female Long Evans rats were trained to perform the rat gambling task (rGT), loosely based on the Iowa Gambling Task (IGT) used clinically, and/or self-administer fentanyl. We used the cued version of the rGT, in which sound and light stimuli signal sugar pellet rewards, as cocaine self-administration has the greatest effects on decision making in this task variant. After training on the cued rGT, female rats self-administered fentanyl more readily, an effect that was most apparent in optimal decision-makers. Contrary to previous reports using cocaine self-administration, decision-making was unaffected during fentanyl self-administration training in either sex. However, risky decision-making increased throughout forced abstinence from fentanyl in males. These findings complement those from human subjects, in whom preference for uncertain outcomes increased before relapse. These data highlight an abstinence-induced change in cognition that is unique to opiates as compared to psychostimulants, and which may critically contribute to the maintenance of addiction and relapse.

Bionic Microstructure‐Inspired Dual‐Mode Flexible Sensor with Photothermal Effect for Ultrasensitive Temperature and Strain Monitoring

AbstractFlexible dual‐mode sensors play a pivotal role in information exchange between humans and the environment. However, achieving dual‐mode sensing encompassing both flexibility and stretchability, while accurately quantifying stimulus signals such as temperature, remains a significant challenge. This paper presents a novel flexible dual‐mode strain/temperature sensor (DMSTS) that utilizes graphite powder (GR)/polyaniline (PANI)/silicone rubber composites, inspired by the bionic microstructure of a centipede's foot. The DMSTS exhibits an exceptional strain detection range (≈177%), and a low limit of detection (0.5% strain). Regarding temperature sensing, the DMSTS demonstrates a positive temperature coefficient effect within the range of 25–90 °C, with an ultrahigh sensitivity of 10.3 within the 75–90 °C range. Leveraging the photothermal characteristics of GR and PANI, the DMSTS holds significant promise for applications in human motion detection, infrared imaging, and photothermal effects. When integrated into an intelligent sensing system, it enables dynamic noncontact temperature measurement, human micro‐expression detection, and motion joint monitoring. Additionally, by incorporating a flexible thermochromic film with color‐changing ink, the DMSTS transforms temperature detection into a visually intuitive operation. With its versatile dual‐mode sensing capabilities, the DMSTS exhibits substantial potential in the fields of wearable electronics and healthcare.

A Multielectrode Layout for High Reliability of Flexible Piezoresistive Sensor: One Stimulus Signal to Three Sensing Signals.

Flexible sensors have developed rapidly due to their great application potential in the intelligent era. However, the frequent bending work requirements pose a serious challenge to the mechanical reliability of flexible sensors. Herein, a strategy of using a new multielectrode layout to achieve multiple sensing signals based on one external signal is proposed for the first time to improve the reliability of flexible piezoresistive sensors. The multielectrode layout consists of a pair of interdigital electrodes and a bottom electrode. The interdigitated electrodes are used to sense the change in the surface resistance of the sensor, and the interdigital electrodes and the bottom electrode are used to sense the change in the bulk resistance of the sensor. As a result, without increasing the sensing unit area, the electrode layout allows the sensor to generate three response electrical signals when sensing an external pressure, thus improving the reliability of the sensor. Based on the electrode layout, a highly reliable flexible piezoresistive sensor with a multilevel porous structure is obtained by a microwave foaming method with a template. In the working state of sensing surface resistance, the sensor has a 22.12 kPa-1 sensitivity. Meanwhile, in the working state of sensing bulk resistance, the sensor shows a 55.17 kPa-1 sensitivity. Furthermore, the sensor is applied to monitor human pulse and speech signals, demonstrating its multisignal output characteristics and potential applications in flexible electronics. In conclusion, the new strategy of using the proposed electrode layout to improve the reliability of flexible sensors is expected to greatly promote the practical application of flexible electronics.

Two pathways regulate insulin-like growth factor genes in the brain and liver of the tropical damselfish Chrysiptera cyanea: A possible role for melatonin in the actions of growth and thyroid hormones

External and internal factors are involved in controlling the growth of fishes. However, little is known about the mechanisms by which external factors trigger stimulus signals. This study explored the physiological roles of melatonin in the transcription of growth-related genes in the brain and liver of Chrysiptera cyanea, a tropical damselfish with long-day preference. In brain samples of this species collected at 4-h intervals, the transcript levels of arylalkylamine N-acetyltransferase2 (aanat2), the rate-limiting enzyme of melatonin synthesis, and growth hormone (gh) peaked at 20:00 and 00:00, respectively. Concomitantly, the transcript levels of insulin-like growth factors (igf1 and igf2) in the brain and liver were upregulated during the scotophase. Levels of iodothyronine deiodinases (dio2 and dio3), enzymes that convert thyroxine (T4) to triiodothyronine (T3) and reverse T3, respectively, increased in the brain (dio2 and dio3) and liver (dio2) during the photophase, whereas dio3 levels in the liver showed the opposite trend. Fish reared in melatonin-containing water exhibited significant increases in the transcription levels of gh and igf1 in the brain and igf1 in the liver, suggesting that growth in this fish is positively regulated by the GH/IGF pathway on a daily basis. Melatonin treatment also stimulated the transcript levels of dio2 and dio3 in the liver, but not in the brain. Fish consuming pellets containing T3, but not T4, showed significant increases in gh and igf1 in the brain and igf1 and igf2 in the liver, suggesting that the intercellular actions of the TH/IGF pathway have an impact on growth on a daily basis. In summary, IGF synthesis and action in the brain and liver undergo dual regulation by distinct hormone networks, which may also be affected by daily, seasonal, or nutritional factors.

Pretreatment with inflammatory factors altered the secretome of human amniotic epithelial cells.

Human amniotic epithelial cells (hAECs) are novel and promising therapeutic agents for patients suffering from degenerative diseases. Studies have demonstrated that the therapeutic effects of hAECs mainly depend on their paracrine components. Currently, appropriate pretreatment is a widely confirmed strategy for enhancing the repair potential of stem cells; however, the effect of proinflammatory factor pretreatment on hAECs and their secretome is still unclear. In this study, we used the well-characterized proinflammatory factors tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) to stimulate hAECs and analyzed the effect of TNF-α and IFN-γ on hAECs, including gene expression profile, paracrine proteins and miRNAs in exosomes. Results showed that TNF-α and IFN-γ pretreatment improved the viability of hAECs, but inhibited the proliferation of hAECs. TNF-α and IFN-γ pretreatment altered the gene expression profile of hAECs, and upregulated differentially expressed genes (DEGs) were predominantly enriched in biological adhesion, antioxidant activity and response to IFN-beta. In addition, TNF-α and IFN-γ pretreatment enhanced the paracrine secretion of cytokines by hAECs. The upregulated differentially expressed proteins (DEPs) were mainly enriched in tissue remodeling proteins and cytokine-cytokine receptor. Notably, the expression of miRNAs in exosomes from hAECs was also changed by TNF-α and IFN-γ pretreatment. The target genes of upregulated exosomal miRNAs substantially contributed to the response to stimulus, metabolic pathways and PI3K-Akt signaling pathway. Our findings improve our understanding of the biological characteristics of hAECs after proinflammatory factor pretreatment and provide novel insights to strengthen and optimize the therapeutic potential of hAECs and their secretome in regenerative medicine.

Study of the Bias of the Initial Phase Estimation of a Sinewave of Known Frequency in the Presence of Phase Noise.

The estimation of the parameters of a sinusoidal signal is of paramount importance in various applications in the fields of sensors, signal processing, parameter estimation, and device characterization, among others. The presence, in the measurement system, of non-ideal phenomena such as additive noise in the signals, phase noise in the stimulus generation, jitter in the sampling system, frequency error in the experimental setup, among others, leads to increased uncertainty and bias in the estimated quantities obtained by least squares methods and those derived from them. Therefore, from a metrological point of view, it is important to be able to theoretically predict and quantify those uncertainties in order to properly design the measurement system and its parameters, such as the number of samples to acquire or the stimulus signal amplitude to use to minimize the uncertainty in the estimated values. Previous works have shown that the presence of these non-ideal phenomena leads to increased uncertainty and bias in the estimation of the sinewave amplitude. The present work complements this knowledge by focusing specifically on the effect of phase noise and sampling jitter in the bias of the initial phase estimation of a sinusoidal signal of known frequency (three‑parameter sine fitting procedure). A theoretical derivation of the bias of initial phase estimation that takes into consideration the presence of phase noise in the sinewave is presented. Since a Taylor series approximation was used where only the first term was retained, it was necessary to validate the analytical derivations with numerical simulations using a Monte Carlo type of procedure. This process was applied to different conditions regarding the phase noise standard deviation, initial phase value, and number of samples. It is concluded that, in most scenarios, initial phase estimation using sine fitting is unbiased in the presence of phase noise or jitter. It is shown, however, that in cases of extremely high phase noise standard deviation and a very low number of samples, a bias occurs.