Sustained Stimulus Research Articles

The role of ongoing oscillation in pain perception: Absence of modulation by a concomitant arithmetic task

Sustained nociceptive stimuli have been shown to modulate the amplitude of ongoing neural oscillations in the theta, alpha and beta frequency bands at the frequency of stimulation, suggesting a relationship between these ongoing oscillations and pain perception. Yet, whether these ongoing oscillations are actually related to the pain experience remains unclear. If it were the case, then cognitive processes that are known to affect pain intensity should also affect these ongoing oscillations. To this end, we used electroencephalography (EEG) to investigate whether distraction – an attentional state known to affect pain perception – also modulates the amplitude of these neural oscillations. More specifically, we hypothesized that performing an unrelated arithmetic task during sustained nociceptive stimulation would lead to a decrease in the modulations of ongoing oscillations exerted by the stimulation. To assess the selectivity of this modulation for nociception, we compared the modulations of ongoing oscillations exerted by sustained periodic thermonociceptive and non-nociceptive vibrotactile stimulation (.2 Hz, 75 sec), while participants were either asked to solve an unrelated arithmetic task (distraction task) or received no specific instruction (baseline). The intensity of perception was significantly reduced by the arithmetic task in both the thermonociceptive and the vibrotactile modality, and the sustained periodic stimulation elicited a periodic response at the frequency of stimulation in both modalities. However, the distraction task did not show a differential effect for the two stimulation modalities in any of the frequency bands. The fact that, unlike pain perception, these oscillations did not appear to be affected by the task suggests that they are dissociable from pain perception. Whether a different task (leading to a stronger degree of distraction) could lead to different results is unclear.

Iontronic Neuromorphic Signaling with Conical Microfluidic Memristors.

Experiments have shown that the conductance of conical channels, filled with an aqueous electrolyte, can strongly depend on the history of the applied voltage. These channels hence have a memory and are promising elements in brain-inspired (iontronic) circuits. We show here that the memory of such channels stems from transient concentration polarization over the ionic diffusion time. We derive an analytic approximation for these dynamics which shows good agreement with full finite-element calculations. Using our analytic approximation, we propose an experimentally realizable Hodgkin-Huxley iontronic circuit where micrometer cones take on the role of sodium and potassium channels. Our proposed circuit exhibits key features of neuronal communication such as all-or-none action potentials upon a pulse stimulus and a spike train upon a sustained stimulus.

Achromatic and chromatic contrast discrimination in patients with type 2 diabetes

Effects of type 2 diabetes on achromatic and chromatic contrast sensitivity (CS) are still controversial. In this study, we aimed to investigate CS in patients without diabetic retinopathy (no-DR) and in those with non-proliferative DR (NPDR) and proliferative DR (PDR) using psychophysical methods with transient and sustained achromatic stimuli and color patches. Achromatic CS was measured with the pulsed pedestal (PP) paradigm (7, 12, and 19 cd/m2) and pedestal-△-pedestal (P-△-P) paradigm (11.4, 18, and 28.5 cd/m2). A chromatic discrimination paradigm that assesses protan, deutan, and tritan color vision was adopted. Forty-two patients (no-DR n = 24, NPDR n = 12, PDR = 6; male n = 22, mean age = 58.1 y/o) and 38 controls (male n = 18, mean age = 53.4 y/o) participated. In patients, mean thresholds were higher than in controls and linear trends were significant in most conditions. For the PP paradigm, differences were significant in the PDR and NPDR groups in the 7 and 12 cd/m2 condition. For the P-△-P paradigm, differences were only significant in the PDR group in the 11 cd/m2 condition. Chromatic contrast loss was significant in the PDR group along the protan, deutan and tritan axes. The results suggest independent involvements of achromatic and chromatic CS in diabetic patients.

Development of pre-seeded tissue-engineered vascular grafts in vitro

Current vascular surgery employs reconstruction of occluded blood vessels using autologous grafts. As a considerable proportion of patients lack healthy autologous vessels to be used as the grafts, the development of tissue-engineered, small-diameter vascular grafts has significant clinical relevance. Biodegradable vascular grafts, which have a defined degradation rate upon the implantation, provide an opportunity for the controlled vascular regeneration. Such polymer framework acts as a guiding matrix for organising the patient's newly formed tissues to ensure consistent and complete vessel remodeling. The crucial aspect of tissue-engineered vascular graft regeneration is endothelialisation, as non-endothelialised blood vessels suffer from the thrombosis if having < 5 mm diameter because of low blood flow. This review describes two approaches to stimulate endothelialization. The first is the biofunctionalization of the luminal surface with the bioactive peptides with the following in situ implantation. Using the body as a bioreactor, this approach relies on the selective recruitment of endothelial cells. The second approach includes in vitro pre-seeding of a luminal surface with an endothelial cell monolayer. The development of such pre-seeded vascular grafts requires the choice of an appropriate polymer for the manufacture of a 3D matrix, isolation of endothelial cell culture, and tuning of mechanical stimuli to control the cell specification during the pre-seeding. In addition to the pre-seeding of endothelial cells on the luminal surface, it is necessary to adapt them to the flow to prevent shedding or incorrect orientation. Cell adhesion can be enhanced by the attachment of extracellular matrix proteins to the luminal surface or by mimicking natural blood flow conditions. Sustained mechanical stimuli facilitate the adaptation of endothelial cells to the flow and contribute to the maturation of endothelial progenitor cells.

One-Dimensional Ferroelectric Nanoarrays with Wireless Switchable Static and Dynamic Electrical Stimulation for Selective Regulating Osteogenesis and Antiosteosarcoma.

Preventing local tumor recurrence and simultaneously improving bone-tissue regeneration are in great demand for osteosarcoma therapy. However, the current therapeutic implants fail to selectively suppress tumor growth and enhance osteogenesis, and antitumor therapy may compromise osseointegration of the bone implant. Here, based on the different responses of bone tumor cells and osteoblasts to different electric stimulations, we constructed ferroelectric BaTiO3 nanorod arrays (NBTO) on the surface of titanium implants with switchable dynamic and static electrical stimulation for selective bone-tumor therapy and bone tissue regeneration. Polarized NBTO (PNBTO) generated a sustained dynamic electrical stimulus in response to wireless ultrasonic irradiation ("switch-on"), which disrupted the orientation of the spindle filaments of the tumor cell, blocked the G2/M phase of mitosis, and ultimately led to tumor cell death, whereas it had almost no cytotoxic effect on normal bone cells. Under the switch-off state, PNBTO with a high surface potential provided static electrical stimulation, accelerating osteogenic differentiation of mesenchymal stem cells and enhancing the quality of bone regeneration both in vitro and in vivo. This study broadens the biomedical potential of electrical stimulation therapy and provides a comprehensive and clinically feasible strategy for the overall treatment and tissue regeneration in osteosarcoma.

Financial friction, rare disaster, and recovery policy

The paper introduces financial intermediation into the New Keynesian model with rare disasters, analyzes the impacts of rare disaster shock on the macro economy, and compares the effects of different economic recovery policies. Based on the numerical analysis, this study finds that: (1) rare disaster risk shock retains a negative relationship with consumption levels, and banks increase their leverage ratios to cause risk accumulation; (2) refinance policy and consumer coupon policy can alleviate economic fluctuations caused by disaster risks from various channels; (3) the consumer coupon policy is conducive to reducing the average social welfare loss caused by disaster risks. It is believed that the establishment of a sustainable economic stimulus mechanism to fundamentally reduce the impact of catastrophic events on the macro economy and achieve economic recovery in a short period are essential issues that should be urgently addressed by countries.

Envelope following responses following partial cochlear deafferentation in guinea pigs

The sound-induced loss of ribbon synapses connecting inner hair cells to auditory nerve fibers primarily exhibiting high thresholds has been the subject of numerous investigations. The condition resulting from this inner ear abnormality is commonly referred to as hidden hearing loss, a name that reflects the relative invulnerability of low threshold auditory nerve fibers that survive noise-exposure and function normally. Although auditory sensitivity recovers completely among animals experiencing hidden hearing loss, recovery of auditory brainstem response amplitudes is incomplete. The residual loss of function reflected in diminished response amplitudes to transient stimuli serves as a highly reliable indicator of the condition. The extent to which responses to sustained stimuli might serve as indicators of pathology is less clear. To that end, we will review findings related to differences in spectral magnitudes of envelope following responses to a battery of sinusoidally-amplitude modulated test conditions that include level dependent response growth, modulation transfer functions under a variety of carrier conditions, the influence of varying modulation depths, as well as the influence of maskers on responses acquired from control and noise-exposed animals. [Work supported by the Department of Defense Award #W81XWH-19-1-0862.]

Temporal Dynamics of Neural Responses in Human Visual Cortex.

Neural responses to visual stimuli exhibit complex temporal dynamics, including subadditive temporal summation, response reduction with repeated or sustained stimuli (adaptation), and slower dynamics at low contrast. These phenomena are often studied independently. Here, we demonstrate these phenomena within the same experiment and model the underlying neural computations with a single computational model. We extracted time-varying responses from electrocorticographic recordings from patients presented with stimuli that varied in duration, interstimulus interval (ISI) and contrast. Aggregating data across patients from both sexes yielded 98 electrodes with robust visual responses, covering both earlier (V1-V3) and higher-order (V3a/b, LO, TO, IPS) retinotopic maps. In all regions, the temporal dynamics of neural responses exhibit several nonlinear features. Peak response amplitude saturates with high contrast and longer stimulus durations, the response to a second stimulus is suppressed for short ISIs and recovers for longer ISIs, and response latency decreases with increasing contrast. These features are accurately captured by a computational model composed of a small set of canonical neuronal operations, that is, linear filtering, rectification, exponentiation, and a delayed divisive normalization. We find that an increased normalization term captures both contrast- and adaptation-related response reductions, suggesting potentially shared underlying mechanisms. We additionally demonstrate both changes and invariance in temporal response dynamics between earlier and higher-order visual areas. Together, our results reveal the presence of a wide range of temporal and contrast-dependent neuronal dynamics in the human visual cortex and demonstrate that a simple model captures these dynamics at millisecond resolution.SIGNIFICANCE STATEMENT Sensory inputs and neural responses change continuously over time. It is especially challenging to understand a system that has both dynamic inputs and outputs. Here, we use a computational modeling approach that specifies computations to convert a time-varying input stimulus to a neural response time course, and we use this to predict neural activity measured in the human visual cortex. We show that this computational model predicts a wide variety of complex neural response shapes, which we induced experimentally by manipulating the duration, repetition, and contrast of visual stimuli. By comparing data and model predictions, we uncover systematic properties of temporal dynamics of neural signals, allowing us to better understand how the brain processes dynamic sensory information.

A Self‐Powered, Single‐Mode Tactile Sensor Based on Sensory Adaptation Using Piezoelectric‐Driven Ion Migration

AbstractA piezoelectric tactile sensor is beneficial for creating a self‐powered system with a compact design, which is essential in electronic‐skin technology. However, piezoelectricity is only capable of dynamic pressure detection because it responds to sudden environmental changes. Since it is common to add another sensing unit to detect static pressure that accompanies bulkiness, including a measuring apparatus, we demonstrate a self‐powered, single‐mode piezoelectric tactile sensor by fabricating a piezoelectric gel through the electrospinning technique. As piezoelectricity senses the dynamic pressure without an external power supply, ions detect the static pressure by maintaining the potential difference upon sustained pressure. Since each component outputs a voltage signal of the same type but different profiles upon pressure, it is possible to distinguish dynamic and static pressure in a single mode. Moreover, inspired by the sensory adaptation of mammalian skin, an ion‐assisted piezoelectric tactile sensor efficiently detects concurrently stacked stimuli by decreasing the output signal for sustained stimuli. The sensitivity for superimposed pressure upon initial 14.7 kPa increases by more than four times compared to that without sensory adaptation for both dynamic and static pressure.

Synaptic plasticity of inhibitory synapses onto medial olivocochlear efferent neurons.

The descending auditory system modulates the ascending system at every level. The final descending, or efferent, stage comprises lateral olivocochlear and medial olivocochlear (MOC) neurons. MOC somata in the ventral brainstem project axons to the cochlea to synapse onto outer hair cells (OHC), inhibiting OHC‐mediated cochlear amplification. MOC suppression of OHC function is implicated in cochlear gain control with changing sound intensity, detection of salient stimuli, attention and protection against acoustic trauma. Thus, sound excites MOC neurons to provide negative feedback of the cochlea. Sound also inhibits MOC neurons via medial nucleus of the trapezoid body (MNTB) neurons. However, MNTB–MOC synapses exhibit short‐term depression, suggesting reduced MNTB–MOC inhibition during sustained stimuli. Further, due to high rates of both baseline and sound‐evoked activity in MNTB neurons in vivo, MNTB–MOC synapses may be tonically depressed. To probe this, we characterized short‐term plasticity of MNTB–MOC synapses in mouse brain slices. We mimicked in vivo‐like temperature and extracellular calcium conditions, and in vivo‐like activity patterns of fast synaptic activation rates, sustained activation and prior tonic activity. Synaptic depression was sensitive to extracellular calcium concentration and temperature. During rapid MNTB axon stimulation, postsynaptic currents in MOC neurons summated but with concurrent depression, resulting in smaller, sustained currents, suggesting tonic inhibition of MOC neurons during rapid circuit activity. Low levels of baseline MNTB activity did not significantly reduce responses to subsequent rapid activity that mimics sound stimulation, indicating that, in vivo, MNTB inhibition of MOC neurons persists despite tonic synaptic depression.Key points Inhibitory synapses from the medial nucleus of the trapezoid body (MNTB) onto medial olivocochlear (MOC) neurons exhibit short‐term plasticity that is sensitive to calcium and temperature, with enhanced synaptic depression occurring at higher calcium concentrations and at room temperature.High rates of background synaptic activity that mimic the upper limits of spontaneous MNTB activity cause tonic synaptic depression of MNTB–MOC synapses that limits further synaptic inhibition.High rates of activity at MNTB–MOC synapses cause synaptic summation with concurrent depression to yield a response with an initial large amplitude that decays to a tonic inhibition.

Retinopathy of prematurity: contribution of inflammatory and genetic factors.

Retinopathy of prematurity (ROP) is a retinal vasoproliferative disorder that represents an important cause of childhood visual impairment and blindness. Although oxidative stress has long been implicated in ROP etiology, other prenatal and perinatal factors are also involved. This review focuses on current research involving inflammation and genetic factors in the pathogenesis of ROP. Increasing evidence suggests that perinatal inflammation or infection contributes to ROP pathogenesis. Cytokines and chemokines with a fundamental role in inflammatory responses and that significantly contributing to angiogenesis are analyzed. Microglia cells, the retinal-resident macrophages, are crucial for retinal homeostasis, however, under sustained pathological stimuli release exaggerated amounts of inflammatory mediators and can promote pathological neovascularization. Current modulation of angiogenic cytokines, such as treatment with antibodies to vascular endothelial growth factor (anti-VEGF), has shown efficacy in the treatment of ocular neovascularization; however, some patients are refractory to anti-VEGF agents, suggesting that other angiogenic or anti-angiogenic cytokines need to be identified. Much evidence suggests that genetic factors contribute to the phenotypic variability of ROP. Several studies have implicated the involvement of candidate genes from different signaling pathways in the development of ROP. However, a genetic component with a major impact on ROP has not yet been discovered. Most studies have limitations and did not replicate results. Future research involving bioinformatics, genomics, and proteomics may contribute to finding more genes associated with ROP and may allow discovering better solutions in the management and treatment of ROP.

Relating individual motion sickness levels to subjective discomfort ratings

High levels of vehicle automation are expected to increase the risk of motion sickness, which is a major detriment to driving comfort. The exact relation between motion sickness and discomfort is a matter of debate, with recent studies suggesting a relief of discomfort at the onset of nausea. In this study, we investigate whether discomfort increases monotonously with motion sickness and how the relation can best be characterized in a semantic experiment (Experiment 1) and a motion sickness experiment (Experiment 2). In Experiment 1, 15 participants performed pairwise comparisons on the subjective discomfort associated with each item on the popular MIsery SCale (MISC) of motion sickness. In Experiment 2, 17 participants rated motion sickness using the MISC during exposures to four sustained motion stimuli, and provided (1) numerical magnitude estimates of the discomfort experienced for each level of the MISC, and (2) verbal magnitude estimates with seven qualifiers, ranging between feeling ‘excellent’ and ‘terrible’. The data of Experiment 1 show that the items of the MISC are ranked in order of appearance, with the exception of 5 (‘severe dizziness, warmth, headache, stomach awareness, and sweating’) and 6 (‘slight nausea’), which are ranked in opposite order. However, in Experiment 2, we find that discomfort associated with each level of the MISC, as it was used to express motion sickness during exposure to a sickening stimulus, increases monotonously; following a power law with an exponent of 1.206. While the results of Experiment 1 replicate the non-linearity found in recent studies, the results of Experiment 2 suggest that the non-linearity is due to the semantic nature of Experiment 1, and that there is a positive monotonous relation between MISC and discomfort in practice. These results support the suitability of MISC to assess motion sickness.

Inattentive Perception, Time, and the Incomprehensibility of Consciousness.

Cerebral energy supply is insufficient to support continuous neuronal processing of the plethora of time-constant objects that we are aware of. As a result, the brain is forced to limit processing resources to (the most relevant) cases of change. The neuronally generated world is thus temporally discontinuous. This parallels the fact that, in all relevant microscopic fundamental equations of nature, temporal change plays a dominant role. When a scientist calculates a “solution” to such an equation, integration over time is an essential step. The present Hypothesis expresses that the step from neuronal activity to phenomenal content of consciousness is reflective of a (phenomenal) “solution:” the main source of the incomprehensibility of consciousness is proposed to result from the introduction of phenomenal time-constant entities. These are “filled-in” via integration, even though neuronal data only exists for changes to these entities. In this way, a temporally continuous picture of the world phenomenally appears. Qualia are “initial conditions,” which are required for integration and cannot be deduced from present data. Phenomenal “identity” (vs. “high similarity”) is related to qualia. Inattentive visual perception, which is only rarely investigated, offers insights into these relationships. Introspectively, unattended vision appears rich because percepts are cumulated over long time spans, whereas attentive perception relies purely on present neuronal signals. The present Hypothesis is that a brief neuronal activity can signify long-lasting and constant phenomenal content of consciousness. Experimental support is presented that comes from discrepancies between neuronal activity and perception: transient neuronal responses to sustained stimuli, “filling-in,” change blindness, identity vs. close resemblance.

3170 – SINGLE-CELL MULTI-OMICS RESOLVES THE EVOLUTION OF TP53-MUTANT LEUKEMIA

TP53 regulates self-renewal and quiescence of hematopoietic stem cells, and its disruption leads to the development of hematological malignancies. In myeloid neoplasms, TP53 mutations define a distinct clinical entity, associated with complex cytogenetics and dismal outcomes. Understanding the cellular and molecular framework through which TP53 mutation drives clonal evolution is a crucial step towards the design of rational therapeutic strategies. Here, we carry out TARGET-seq single-cell multi-omic analysis of haematopoietic stem/progenitor cells (HSPC) from patients with a myeloproliferative neoplasm who had transformed to TP53-mutant secondary acute myeloid leukaemia (sAML), a trackable model of TP53-driven clonal evolution. We invariably identified convergent clonal evolution leading to complete loss of TP53 wild-type (WT) alleles and gain of multiple chromosomal abnormalities upon transformation. TP53-mutant leukaemia stem cells (LSC) were transcriptionally distinct from de novo AML, with evidence of inflammation-associated transcription and aberrant erythroid differentiation. We identified a TP53-mutant LSC signature which was strongly predictive of adverse outcome in both TP53-mutant (HR:3.4) and WT AML (HR:3.1). Finally, we demonstrate a hitherto unrecognised effect of chronic inflammation in promoting disease progression. Sustained inflammatory stimuli (pIpC) led to a 2.5-fold expansion of TP53-mutant cells in WT:TP53R172H/+ chimeras, whereas WT cells were depleted. This indicates that pro-inflammatory cues promote fitness advantage of TP53-mutant cells whilst suppressing antecedent clones. In summary, we present a comprehensive single-cell multi-omic analysis ofTP53-mediated transformation, providing unique insights into the evolution of chronic hematological malignancies towards an aggressive acute leukemia and of broader relevance to other cancer types. TP53 regulates self-renewal and quiescence of hematopoietic stem cells, and its disruption leads to the development of hematological malignancies. In myeloid neoplasms, TP53 mutations define a distinct clinical entity, associated with complex cytogenetics and dismal outcomes. Understanding the cellular and molecular framework through which TP53 mutation drives clonal evolution is a crucial step towards the design of rational therapeutic strategies. Here, we carry out TARGET-seq single-cell multi-omic analysis of haematopoietic stem/progenitor cells (HSPC) from patients with a myeloproliferative neoplasm who had transformed to TP53-mutant secondary acute myeloid leukaemia (sAML), a trackable model of TP53-driven clonal evolution. We invariably identified convergent clonal evolution leading to complete loss of TP53 wild-type (WT) alleles and gain of multiple chromosomal abnormalities upon transformation. TP53-mutant leukaemia stem cells (LSC) were transcriptionally distinct from de novo AML, with evidence of inflammation-associated transcription and aberrant erythroid differentiation. We identified a TP53-mutant LSC signature which was strongly predictive of adverse outcome in both TP53-mutant (HR:3.4) and WT AML (HR:3.1). Finally, we demonstrate a hitherto unrecognised effect of chronic inflammation in promoting disease progression. Sustained inflammatory stimuli (pIpC) led to a 2.5-fold expansion of TP53-mutant cells in WT:TP53R172H/+ chimeras, whereas WT cells were depleted. This indicates that pro-inflammatory cues promote fitness advantage of TP53-mutant cells whilst suppressing antecedent clones. In summary, we present a comprehensive single-cell multi-omic analysis ofTP53-mediated transformation, providing unique insights into the evolution of chronic hematological malignancies towards an aggressive acute leukemia and of broader relevance to other cancer types.

Behavioral, hormonal, and neural alterations induced by social contagion for pain in mice

Neurobiology of social contagion/empathy aims to collaborate with the development of treatments for human disorders characterized by the absence of this response – autism spectrum disorder, schizophrenia, and antisocial personality disorder. Previous studies using sustained aversive stimuli (e.g., neuropathic pain or stress) to induce social contagion behaviors in rodents have demonstrated that these conditions may increase hypernociception, anxiogenic-like effects, and defensive behaviors in cagemates. To amplify the knowledge about behavioral, hormonal, and neural alterations induced by cohabitation with a pair in neuropathic pain, we investigated the effects of this protocol on (i) pain (writhing, formalin, hot plate tests) and depression (sucrose splash test) responses, (ii) the serum levels of corticosterone, testosterone, and oxytocin, (iii) noradrenalin, dopamine and its metabolite (DOPAC and HVA) levels in the amygdaloid complex and insular cortex, (iv) neuronal activation pattern (FosB labeling) in the ventral tegmental area (VTA), paraventricular nucleus of the hypothalamus (PVN) and supraoptic nucleus (SO). One day after weaning, male Swiss mice were housed in pairs for 14 days. Then, they were divided into two groups: sciatic nerve constricted cagemate [CNC; i.e., one animal of each pair was subjected to sciatic nerve constriction (NC)], and cagemate sham (CS; a similar procedure but with no nerve constriction), and housed for further 14 days. After 28 days of cohabiting, four independent groups were subjected to (a) behavioral analyses (Exp. 1) and (b) blood samples collected for Elisa assays of corticosterone, testosterone, and oxytocin (Exp. 2), remotion of brains for the (c) HPLC in the noradrenaline dopamine and metabolites quantification (Exp. 3) or (d) immunoassays analyses for FosB labeling (Exp. 4). Results showed that cohabitation with a conspecific in chronic pain induces hypernociception and antinociception in the writhing and formalin tests, respectively, and anhedonic-like effects in the sucrose splash test. Hormonal results indicated a decrease in plasma corticosterone only in nerve constricted mice, in testosterone (CNC and NC animals), and an increase in oxytocin serum levels. The neurochemical analyses demonstrated that the social contagion for pain protocol increases in dopamine turnover in the amygdala and insula. This assay also revealed an increase in noradrenaline levels and dopamine turnover within the insula of NC mice. In the FosB labeling measure, we observed a rise in the VTA, PVN and SO in the CNC group whereas for the NC group an increase of this activation pattern occurred only in the VTA. Present results suggest the role of hormones (testosterone and oxytocin) and neurotransmitters (dopamine) in the modulation of behavioral changes induced by social contagion in animals cohabitating with a conspecific in pain.This article is part of the special Issue on ‘Stress, Addiction and Plasticity'.

Single-Cell Multi-Omics Reveals the Genetic, Cellular and Molecular Landscape of TP53 Mutated Leukemic Transformation in MPN

Single-Cell Multi-Omics Reveals the Genetic, Cellular and Molecular Landscape of TP53 Mutated Leukemic Transformation in MPN

Transient Electrically Driven Stiffness-Changing Materials from Liquid Metal Polymer Composites.

Stiffness-changing materials (SCMs) have received lots of interests due to their reversible transition between their soft and rigid states for modern applications. However, the irreversible stiffness transition, slow response, and sustained external stimuli strictly hinder the broad utilizations of SCMs. Here, this work reports electrically driven SCMs based on supercooled liquid metals (LMs). A small voltage (5 V) can successfully initiate the stable and reversible stiffness change of the SCMs in electrolyte solution. Surprisingly, the LM-based SCMs (LM-SCMs) exhibited a significant change in 1000 times difference of moduli (65 kPa versus 79 MPa). Moreover, such a stiffness transition of the LM-SCM was ultrarapidly completed in a few seconds (<30 s). Importantly, after transient stimulation of LM nucleation, the rigidity of the LM-SCM could be maintained when the external stimulus (voltage) was removed, highly different from previously reported SCMs that require sustained energy to maintain their mechanical states. Based on the unique features of LM-SCMs, advanced robotics like smart valves and mechanical paws in seawater were successfully fabricated.

Temporal responsiveness of adipose-derived stem/stromal cell immune plasticity

We determined the role of time in adipose-derived stem/stromal cell (ASC) response to a model inflammatory environment. ASCs and other mesenchymal stem/stromal cells exhibit immune plasticity. We evaluated the persistence of pro- and anti-inflammatory phenotypes for ASCs exposed to a sustained or pulse inflammatory stimulus. Using qPCR, flow cytometry, and immunocytochemistry, we monitored the temporal expression and up-regulation patterns of a pro-inflammatory gene (caspase 1), a pleiotropic gene/protein (interleukin 6, IL-6), and an anti-inflammatory gene/protein (indoleamine 2, 3-dioxygenase, IDO1) after exposing ASCs to the cytokines tumor necrosis factor-α and interferon-γ. In response to sustained cytokine stimulation, we discovered that time played a role in the balance of pro- and anti-inflammatory ASC phenotypes. IL-6 was present at all time points for both cytokine-stimulated and non-stimulated conditions, whereas IDO1 was heterogeneously up-regulated in stimulated conditions at later time points. After a pulse stimulus, ASC immunoresponse remained consistent for 96–168 h. As a final measure of immune plasticity, we cultured cytokine-stimulated ASCs with blood-derived macrophages to observe macrophage polarization. While the presence of ASCs altered macrophage phenotype, there was no dependency on the length of ASC cytokine exposure time.

The impact of repeated, local heating-induced increases in blood flow on lower limb endothelial function in young, healthy females.

The purpose of the present study was to examine the effect of repeated, single leg heating on lower limb endothelial function. Macrovascular function was assessed with superficial femoral artery (SFA) reactive hyperemia flow-mediated dilation (RH-FMD) and sustained stimulus FMD (SS-FMD). Calf microvascular function was assessed as the peak and area under the curve of SFA reactive hyperemia (RH). Participants (n = 13 females, 23 ± 2 yrs) had one leg randomized to the single leg heating intervention (EXP; other leg: control (CON)). The EXP leg underwent 8weeks of single leg heating via immersion in 42.5℃ water for five 35-min sessions/week. At weeks 0, 2, 4, 6, and 8, SFA RH-FMD, SS-FMD (shear stress increased via plantar flexion exercise), and SFA RH flow were measured. None of the variables changed with repeated, single leg heating (interaction week*limb RH-FMD: p = 0.076; SS-FMD: p = 0.958; RH flow p = 0.955). Covariation for the shear stress stimulus did not alter the FMD results. Eight weeks of single leg heating did not change SFA endothelial or calf microvascular function. These results are in contrast with previous findings that limb heating improves upper limb endothelial function.

Sensory adaptation at ribbon synapses in the zebrafish lateral line.

Adaptation is used by sensory systems to adjust continuously their sensitivity to match changes in environmental stimuli. In the auditory and vestibular systems, the release properties of glutamate-containing vesicles at the hair-cell ribbon synapses play a crucial role in sensory adaptation, thus shaping the neural response to sustained stimulation. How ribbon synapses regulate the release of glutamate and how they modulate afferent responses in vivo is still largely unknown. Here, we have used two-photon imaging and electrophysiology to investigate the synaptic transfer characteristics of the hair cells in the context of sensory adaptation in live zebrafish. Prolonged and repeated water-jet stimulation of the hair-cell stereociliary bundles caused adaptation of the action potential firing rate elicited in the afferent neurons. By monitoring glutamate at ribbon synapses using time-lapse imaging, we identified two kinetically distinct release components: a rapid response that was exhausted within 50-100 ms and a slower and sustained response lasting the entire stimulation. After repeated stimulations, the recovery of the fast component followed a biphasic time course. Depression of glutamate release was largely responsible for the rapid firing rate adaptation recorded in the afferent neurons. However, postsynaptic Ca2+ responses had a slower recovery time course than that of glutamate release, indicating that they are also likely to contribute to the afferent firing adaptation. Hair cells also exhibited a form of adaptation during inhibitory bundle stimulations. We conclude that hair cells have optimised their synaptic machinery to encode prolonged stimuli and to maintain their sensitivity to new incoming stimuli.