Onset Of Response Research Articles

Molecular MRI quantification of extracellular aldehyde pairs for early detection of liver fibrogenesis and response to treatment.

Liver fibrosis plays a critical role in the evolution of most chronic liver diseases and is characterized by a buildup of extracellular matrix, which can progress to cirrhosis, hepatocellular carcinoma, liver failure, or death. Now, there are no noninvasive methods available to accurately assess disease activity (fibrogenesis) to sensitively detect early onset of fibrosis or to detect early response to treatment. Here, we hypothesized that extracellular allysine aldehyde (LysAld) pairs formed by collagen oxidation during active fibrosis could be a target for assessing fibrogenesis with a molecular probe. We showed that molecular magnetic resonance imaging (MRI) using an extracellular probe targeting these LysAld pairs acts as a noninvasive biomarker of fibrogenesis and demonstrated its high sensitivity and specificity in detecting fibrogenesis in toxin- and dietary-induced mouse models, a cholestasis rat model of liver fibrogenesis, and in human fibrotic liver tissues. Quantitative molecular MRI was highly correlated with fibrogenesis markers and enabled noninvasive detection of early onset fibrosis and response to antifibrotic treatment, showing high potential for clinical translation.

PolyGA targets the ER stress-adaptive response by impairing GRP75 function at the MAM in C9ORF72-ALS/FTD

ER stress signaling is linked to the pathophysiological and clinical disease manifestations in amyotrophic lateral sclerosis (ALS). Here, we have investigated ER stress-induced adaptive mechanisms in C9ORF72-ALS/FTD, focusing on uncovering early endogenous neuroprotective mechanisms and the crosstalk between pathological and adaptive responses in disease onset and progression. We provide evidence for the early onset of ER stress-mediated adaptive response in C9ORF72 patient-derived motoneurons (MNs), reflected by the elevated increase in GRP75 expression. These transiently increased GRP75 levels enhance ER–mitochondrial association, boosting mitochondrial function and sustaining cellular bioenergetics during the initial stage of disease, thereby counteracting early mitochondrial deficits. In C9orf72 rodent neurons, an abrupt reduction in GRP75 expression coincided with the onset of UPR, mitochondrial dysfunction and the emergence of PolyGA aggregates, which co-localize with GRP75. Similarly, the overexpression of PolyGA in WT cortical neurons or C9ORF72 patient-derived MNs led to the sequestration of GRP75 within PolyGA inclusions, resulting in mitochondrial calcium (Ca2+) uptake impairments. Corroborating these findings, we found that PolyGA aggregate-bearing human post-mortem C9ORF72 hippocampal dentate gyrus neurons not only display reduced expression of GRP75 but also exhibit GRP75 sequestration within inclusions. Sustaining high GRP75 expression in spinal C9orf72 rodent MNs specifically prevented ER stress, normalized mitochondrial function, abrogated PolyGA accumulation in spinal MNs, and ameliorated ALS-associated behavioral phenotype. Taken together, our results are in line with the notion that neurons in C9ORF72-ALS/FTD are particularly susceptible to ER–mitochondrial dysfunction and that GRP75 serves as a critical endogenous neuroprotective factor. This neuroprotective pathway, is eventually targeted by PolyGA, leading to GRP75 sequestration, and its subsequent loss of function at the MAM, compromising mitochondrial function and promoting disease onset.

Ustekinumab Is Rapid-Acting and Is an Effective Long-Term Treatment for Patients with Active Psoriatic Arthritis: Real-World Evidence from the Non-interventional SUSTAIN Study.

IntroductionPsoriatic arthritis (PsA) is a chronic, progressive disease that places a significant burden on patients and healthcare systems. The SUSTAIN study collected real-world evidence on long-term effectiveness, impact on quality of life, and safety of ustekinumab treatment for PsA.MethodsSUSTAIN was a prospective, non-interventional study conducted in Germany. Patients with active PsA received ustekinumab for 160 weeks in routine clinical care, with assessments at baseline, week 4, and every 12 weeks thereafter. This analysis focuses on patients who remained in SUSTAIN until week 160.ResultsOf 337 patients enrolled, 129 were documented at week 160, of which 123 (95.3%) had received previous PsA medication, including biologics. Decreases from baseline to week 4 were observed for tender joint count (TJC, 8.0 to 5.8) and swollen joint count (SJC, 4.5 to 3.1); these decreases continued to week 28 and were maintained to week 160 (1.0 and 0.4, respectively). Similarly, skin assessments in patients with PsA and psoriasis revealed improvement at week 4, which continued to week 28, with a sustained effect until week 160. Similar patterns of response were observed for patient-assessed pain, sleep quality, and health scores. Improvements in TJC, SJC, Psoriasis Area and Severity Index, and affected body surface area were observed irrespective of the number of prior biologic therapies used. Minimal disease activity was achieved by 36 (31.9%) patients at week 28, and by 38 (33.6%) at week 52. Ustekinumab-related adverse events (AEs) and serious AEs were reported in 61 (47.3%) and 4 (3.1%) patients, respectively. At week 160, 100% of patients assessed ustekinumab tolerability as good or very good.ConclusionsIn a real-world setting, patients with active PsA who received ustekinumab until 160 weeks (3 years), including those who received prior biologic therapies, had a rapid onset of effect and sustained response to treatment, with high tolerability.Trial registrationPEI NIS No. 290.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40744-022-00484-3.

Encoding category-level and context-specific phonological information at different stages: An EEG study of Mandarin third-tone sandhi word production

Pronunciation of words or morphemes may vary systematically in different phonological contexts, but it remains unclear how different levels of phonological information are encoded in speech production. In this study, we investigated the online planning process of Mandarin Tone 3 (T3) sandhi, a case of phonological alternation whereby a low-dipping tone (T3) changes to a Tone 2 (T2)-like rising tone when followed by another T3. To examine the time course of the encoding of the abstract category-level (underlying form) and context-specific phonological form (surface form) of T3, we conducted an electroencephalographic (EEG) study with a phonologically-primed picture naming task and examined the event-related potentials (ERPs) time-locked to the stimulus onset as well as speech response onset. The behavioral results showed that targets primed by T3 or T2 primes yielded shorter naming latencies than those primed by control primes. Importantly, the EEG data revealed that T3 primes elicited larger positive amplitude over broad frontocentral regions roughly in the 320–550 ms time window of stimulus-locked ERP and −500 to −400 ms time window of response-locked ERP, whereas T2 primes elicited larger negative amplitude over left frontocentral regions roughly in the −240 to −100 ms time window of response-locked ERP. These results indicate that the underlying and the surface form are encoded at different processing stages. The former presumably occurs in the earlier phonological encoding stage, while the latter probably occurs in the later phonetic encoding or motor preparation stage. The current study offers important implications for understanding the processing of phonological alternations and tonal encoding in Chinese word production.

Latency correction in sparse neuronal spike trains

Background:In neurophysiological data, latency refers to a global shift of spikes from one spike train to the next, either caused by response onset fluctuations or by finite propagation speed. Such systematic shifts in spike timing lead to a spurious decrease in synchrony which needs to be corrected. New Method:We propose a new algorithm of multivariate latency correction suitable for sparse data for which the relevant information is not primarily in the rate but in the timing of each individual spike. The algorithm is designed to correct systematic delays while maintaining all other kinds of noisy disturbances. It consists of two steps, spike matching and distance minimization between the matched spikes using simulated annealing. Results:We show its effectiveness on simulated and real data: cortical propagation patterns recorded via calcium imaging from mice before and after stroke. Using simulations of these data we also establish criteria that can be evaluated beforehand in order to anticipate whether our algorithm is likely to yield a considerable improvement for a given dataset. Comparison with Existing Method(s):Existing methods of latency correction rely on adjusting peaks in rate profiles, an approach that is not feasible for spike trains with low firing in which the timing of individual spikes contains essential information. Conclusions:For any given dataset the criterion for applicability of the algorithm can be evaluated quickly and in case of a positive outcome the latency correction can be applied easily since the source codes of the algorithm are publicly available.

Cortical mechanisms of visual brightness.

SUMMARYThe primary visual cortex signals the onset of light and dark stimuli with ON and OFF cortical pathways. Here, we demonstrate that both pathways generate similar response increments to large homogeneous surfaces and their response average increases with surface brightness. We show that, in cat visual cortex, response dominance from ON or OFF pathways is bimodally distributed when stimuli are smaller than one receptive field center but unimodally distributed when they are larger. Moreover, whereas small bright stimuli drive opposite responses from ON and OFF pathways (increased versus suppressed activity), large bright surfaces drive similar response increments. We show that this size-brightness relation emerges because strong illumination increases the size of light surfaces in nature and both ON and OFF cortical neurons receive input from ON thalamic pathways. We conclude that visual scenes are perceived as brighter when the average response increments from ON and OFF cortical pathways become stronger.

Energized Oxygen in the Magnetotail: Onset and Evolution of Magnetic Reconnection.

Oxygen ions are a major constituent of magnetospheric plasma, yet the role of oxygen in processes such as magnetic reconnection continues to be poorly understood. Observations show that significant amounts of energized O+ can be present in a magnetotail current sheet (CS). A population of thermal O+ only has a relatively minor effect on magnetic reconnection. Despite this, published studies have so far only concentrated on the role of the low-energy thermal O+. We present a study of magnetic reconnection in a thinning CS with energized O+ present. Well-established, three-species, 2.5D particle-in-cell (PIC) kinetic simulations are used. Simulations of thermal H+ and thermal O+ validate our setup against published results. We then energize a thermal background O+ based on published in situ measurements. A range of energization is applied to the background O+. We discuss the effects of energized O+ on CS thinning and the onset and evolution of magnetic reconnection. The presence of energized O+ causes a two-regime onset response in a thinning CS. As energization increases in the lower-regime, reconnection develops at a single primary X-line, increases time-to-onset, and suppresses the rate of evolution. As energization continues to increase in the higher-regime, reconnection develops at multiple X-lines, forming a stochastic plasmoid chain; decreases time-to-onset; and enhances evolution via a plasmoid instability. Energized O+ drives a depletion of the background H+ around the central CS. As the energization increases, the CS thinning begins to slow and eventually reverses.

PLPP/CIN-mediated DARPP-32 serine 97 dephosphorylation delays the seizure onset in response to kainic acid in the mouse hippocampus

Dopamine and cAMP-regulated phosphoprotein, 32 kDa (DARPP-32)-mediated protein phosphatase 1 (PP1) inhibition leads to the increase in phosphorylation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor (AMPAR), which potentiates channel activity and current and thereby may facilitate seizure activity. In the present study, we found that pyridoxal-5′-phosphate phosphatase/chronophin (PLPP/CIN) transiently dephosphorylated DARPP-32 serine (S) 97 site in the early time window, and casein kinase 2 (CK2) subsequently phosphorylated this site in the later time points after kainic acid (KA) injection, which increased the latency of seizure onset in response to KA, but exacerbated the intensity (severity), duration and progression of seizures. TMCB (a CK2 inhibitor) delayed the seizure onset in response to KA, concomitant with the reduced DARPP-32 S97 phosphorylation. Therefore, our findings suggest that PLPP/CIN may play an important role in the latency of seizure onset via DARPP-32-PP1-AMPAR signaling pathway, and may be one of the potential therapeutic targets for medication of seizure or epilepsy.

Offset Responses in the Auditory Cortex Show Unique History Dependence.

Sensory responses typically vary depending on the recent history of sensory experience. This is essential for processes, including adaptation, efficient coding, and change detection. In the auditory cortex (AC), the short-term history dependence of sound-evoked (onset) responses has been well characterized. Yet many AC neurons also respond to sound terminations, and little is known about the history dependence of these “offset” responses, whether the short-term dynamics of onset and offset responses are correlated, or how these properties are distributed among cell types. Here we presented awake male and female mice with repeating noise burst stimuli while recording single-unit activity from primary AC. We identified parvalbumin and somatostatin interneurons through optotagging, and also separated narrow-spiking from broad-spiking units. We found that offset responses are typically less depressive than onset responses, and this result was robust to a variety of stimulus parameters, controls, measurement types, and selection criteria. Whether a cell's onset response facilitates or depresses does not predict whether its offset response facilitates or depresses. Cell types differed in the dynamics of their onset responses, and in the prevalence, but not the dynamics, of their offset responses. Finally, we clustered cells according to spiking responses and found that response clusters were associated with cell type. Each cluster contained cells of several types, but even within a cluster, cells often showed cell type-specific response dynamics. We conclude that onset and offset responses are differentially influenced by recent sound history, and discuss the implications of this for the encoding of ongoing sound stimuli.SIGNIFICANCE STATEMENT Sensory neuron responses depend on stimulus history. This history dependence is crucial for sensory processing, is precisely controlled at individual synapses and circuits, and is adaptive to the specific requirements of different sensory systems. In the auditory cortex, neurons respond to sound cessation as well as to sound itself, but how history dependence is used along this separate, “offset” information stream is unknown. We show that offset responses are more facilitatory than sound responses, even in neurons where sound responses depress. In contrast to sound onset responses, offset responses are absent in many cells, are relatively homogeneous, and show no cell type-specific differences in history dependence. Offset responses thus show unique response dynamics, suggesting their unique functions.

Auditory response patterns of mouse primary auditory cortex to sound stimuli

To investigate the auditory response patterns of mouse primary auditory cortex (A1) neurons. In vivo cell-attached recordings and neural network modeling were performed to detect the changes in response patterns of A1 neurons of awake C57BL/6J mice to sound stimulation with varying lengths. A1 neuron signals were recorded for 216 neurons in 20 awake mice using a target sound stimulation sequence, and the classification and response characteristics of A1 neuron response patterns were examined using post-stimulus spike time histograms. To simulate the diversity of the A1 neuron response patterns, an A1 neuron model was established based on the Wilson-Cowan model and integral-firing model. The neuron connection weight parameters in the model were calculated by examining the micro loop structure of the pyramidal neurons, parvalbumin neurons, and somatostatin neurons in the A1 region, and the A1 neural network information coding model was constructed. The Onset response neurons only had fast spike response within 10 to 40 ms after the beginning of noise stimulation (122 neurons). The Sustained response neurons had spike response continuously during the noise stimulation (26 neurons). The On-off response neurons had fast spike response after the beginning and the end of noise stimulation (40 neurons). The Offset response neurons only had fast spike response within 10 to 40 ms after the end of noise stimulation (22 neurons). In the neural network model, the Onset peak neural activities of A1 pyramidal neurons, parvalbumin neurons, and somatostatin neurons were 0.7483, 0.5236 and 0.9427, respectively, and their response half peak widths were 18.5 ms, 12 ms and 31 ms during the 100 ms noise stimulation, respectively. By changing the feedforward excitation and synaptic inhibition time constants in the model, the neurons generated numerous different types of spike train. The auditory response of mouse A1 neurons to sound stimuli shows mainly the Onset, Sustained, On-off, and Offset response patterns.

Autoimmune nodopathies, an emerging diagnostic category.

In the last decade, antibodies targeting cell adhesion molecules of the node of Ranvier were described in patients with autoimmune neuropathies. These nodal/paranodal antibodies associate with specific clinicopathological features that are different from classical chronic inflammatory demyelinating polyneuropathy (CIDP). In this review, we will summarize recent findings establishing autoimmune nodopathies (AN) as a new category of autoimmune neuropathies. AN include anti-contactin 1, anti-contactin-associated protein 1, anti-neurofascin 155 and anti-pan-neurofascin antibody-mediated neuropathies. Their clinical spectrum includes acute, subacute or chronic onset sensory-motor neuropathies mimicking Guillain-Barré syndrome (GBS) and CIDP, although they differ in their response to standard therapy with intravenous immunoglobulin (IVIG). Neurophysiologically they overlap with acquired demyelinating neuropathies, but ultrastructural studies and animal models demonstrated antibody-mediated pathology restricted to the node of Ranvier. Anti-contactin1 and anti-pan-neurofascin also associate with nephrotic syndrome. Nodal/paranodal antibodies are predominantly of the immunoglobulin (IgG)4 subclass during the chronic phase of the disease, but complement-fixing IgG3 antibodies are detected during the early phase and associate with aggressive onset and IVIG response. Nodal/paranodal antibodies testing is key in the diagnosis of AN. AN have emerged as a new diagnostic category pathologically different from acquired demyelinating neuropathies. Clinically they overlap with GBS and CIDP although they associate with specific clinical features that should lead to clinical suspicion. Nodal/paranodal antibodies are key effector mechanisms of disease and good diagnostic and disease-monitoring biomarkers in AN.

Rapid titration of VNS therapy reduces time-to-response in epilepsy

BackgroundCommon titration strategies for vagus nerve stimulation (VNS) prioritize monitoring of tolerability during small increases in stimulation intensity over several months. Prioritization of tolerability is partially based on how quickly side effects can be perceived and reported by patients, and the delayed onset of clinical benefits from VNS. However, many practices assess the clinical benefit of VNS at one year after implantation, and excessive caution during the titration phase can significantly delay target dosing or prevent a patient from reaching a therapeutic dose entirely. ObjectiveThis study aimed to characterize the relationship between titration speed and the onset of clinical response to VNS. MethodsTo assess differences between more aggressive titration strategies and more conservative ones, we analyzed the relationship between time-to-dose and time-to-response using a weighted Cox regression. The target dose was empirically defined as 1.625 mA output current delivered at 250 microsecond pulse widths at 20 Hz. Patient-level outcomes and dosing data were segregated into fast (<3 months), medium (3–6 months), and slow (>6 months) cohorts based on their titration speed. ResultsThe statistical model revealed a significant relationship between titration speed and onset of clinical response, defined as a 50% reduction from baseline in seizure frequency. Frequency of adverse events reported between each cohort trended toward higher rates of adverse events in adults who were titrated quickly; however, the pediatric population appeared to be more tolerant of titration at any speed. ConclusionsThis analysis indicates that faster titration yields faster onset of clinical benefit and is especially practical in the pediatric population, though attempts to accelerate adult titration may still be warranted.

Molecular basis of MHC I quality control in the peptide loading complex

Major histocompatibility complex class I (MHC I) molecules are central to adaptive immunity. Their assembly, epitope selection, and antigen presentation are controlled by the MHC I glycan through a sophisticated network of chaperones and modifying enzymes. However, the mechanistic integration of the corresponding processes remains poorly understood. Here, we determine the multi-chaperone-client interaction network of the peptide loading complex (PLC) and report the PLC editing module structure by cryogenic electron microscopy at 3.7 Å resolution. Combined with epitope-proofreading studies of the PLC in near-native lipid environment, these data show that peptide-receptive MHC I molecules are stabilized by multivalent chaperone interactions including the calreticulin-engulfed mono-glucosylated MHC I glycan, which only becomes accessible for processing by α-glucosidase II upon loading of optimal epitopes. Our work reveals allosteric coupling between peptide-MHC I assembly and glycan processing. This inter-process communication defines the onset of an adaptive immune response and provides a prototypical example of the tightly coordinated events in endoplasmic reticulum quality control.

Dynamics and Mechanisms of Contrast-Dependent Modulation of Spatial-Frequency Tuning in the Early Visual Cortex.

The spatial-frequency (SF) tuning of neurons in the early visual cortex is adjusted for stimulus contrast. As the contrast increases, SF tuning is modulated so that the transmission of fine features is facilitated. A variety of mechanisms are involved in shaping SF tunings, but those responsible for the contrast-dependent modulations are unclear. To address this, we measured the time course of SF tunings of area 17 neurons in male cats under different contrasts with a reverse correlation. After response onset, the optimal SF continuously shifted to a higher SF over time, with a larger shift for higher contrast. At high contrast, whereas neurons with a large shift of optimal SF exhibited a large bandwidth decrease, those with a negligible shift increased the bandwidth over time. Between these two extremes, the degree of SF shift and bandwidth change continuously varied. At low contrast, bandwidth generally decreased over time. These dynamic effects enhanced the processing of high-frequency range under a high-contrast condition and allowed time-average SF tuning curves to show contrast-dependent modulation, like that of steady-state SF tuning curves reported previously. Combinations of two mechanisms, one that decreases bandwidth and shifts optimal SF, and another that increases bandwidth without shifting optimal SF, would explain the full range of SF tuning dynamics. Our results indicate that one of the essential roles of tuning dynamics of area 17 neurons, which have been observed for various visual features, is to adjust tunings depending on contrast.SIGNIFICANCE STATEMENT The spatial scales of features transmitted by cortical neurons are adjusted depending on stimulus contrast. However, the underlying mechanism is not fully understood. We measured the time course of spatial frequency tunings of cat area 17 neurons under different contrast conditions and observed a variety of dynamic effects that contributed to spatial-scale adjustment, allowing neurons to adjust their spatial frequency tuning range depending on contrast. Our results suggest that one of the essential roles of tuning dynamics of area 17 neurons, which have been observed for various visual features, is to adjust tunings depending on contrast.

The influence of error detection and error significance on neural and behavioral correlates of error processing in a complex choice task

Error detection and error significance form essential mechanisms that influence error processing and action adaptation. Error detection often is assessed by an immediate self-evaluation of accuracy. Our study used cognitive neuroscience methods to elucidate whether self-evaluation itself influences error processing by increasing error significance in the context of a complex response selection process. In a novel eight-alternative response task, our participants responded to eight symbol stimuli with eight different response keys and a specific stimulus-response assignment. In the first part of the experiment, the participants merely performed the task. In the second part, they also evaluated their response accuracy on each trial. We replicated variations in early and later stages of error processing and action adaptation as a function of error detection. The additional self-evaluation enhanced error processing on later stages, probably reflecting error evidence accumulation, whereas earlier error monitoring processes were not amplified. Implementing multivariate pattern analysis revealed that self-evaluation influenced brain activity patterns preceding and following the response onset, independent of response accuracy. The classifier successfully differentiated between responses from the self- and the no-self-evaluation condition several hundred milliseconds before response onset. Subsequent exploratory analyses indicated that both self-evaluation and the time on task contributed to these differences in brain activity patterns. This suggests that in addition to its effect on error processing, self-evaluation in a complex choice task seems to have an influence on early and general processing mechanisms (e.g., the quality of attention and stimulus encoding), which is amplified by the time on task.

Receptor for Advanced Glycation End Products (RAGE): A Pivotal Hub in Immune Diseases.

As a critical molecule in the onset and sustainment of inflammatory response, the receptor for advanced glycation end products (RAGE) has a variety of ligands, such as advanced glycation end products (AGEs), S100/calcium granule protein, and high-mobility group protein 1 (HMGB1). Recently, an increasing number studies have shown that RAGE ligand binding can initiate the intracellular signal cascade, affect intracellular signal transduction, stimulate the release of cytokines, and play a vital role in the occurrence and development of immune-related diseases, such as systemic lupus erythematosus, rheumatoid arthritis, and Alzheimer’s disease. In addition, other RAGE signaling pathways can play crucial roles in life activities, such as inflammation, apoptosis, autophagy, and endoplasmic reticulum stress. Therefore, the strategy of targeted intervention in the RAGE signaling pathway may have significant therapeutic potential, attracting increasing attention. In this paper, through the systematic induction and analysis of RAGE-related signaling pathways and their regulatory mechanisms in immune-related diseases, we provide theoretical clues for the follow-up targeted intervention of RAGE-mediated diseases.

Opportunities to monitor animal welfare using the five freedoms with precision livestock management on rangelands

Advances in technology have led to precision livestock management, a developing research field. Precision livestock management has potential to improve sustainable meat production through continuous, real-time tracking which can help livestock managers remotely monitor and enhance animal welfare in extensive rangeland systems. The combination of global positioning systems (GPS) and accessible data transmission gives livestock managers the ability to locate animals in arduous weather, track animal patterns throughout the grazing season, and improve handling practices. Accelerometers fitted to ear tags or collars have the potential to identify behavioral changes through variation in the intensity of movement that can occur during grazing, the onset of disease, parturition or responses to other environmental and management stressors. The ability to remotely detect disease, parturition, or effects of stress, combined with appropriate algorithms and data analysis, can be used to notify livestock managers and expedite response times to bolster animal welfare and productivity. The “Five Freedoms” were developed to help guide the evaluation and impact of management practices on animal welfare. These freedoms and welfare concerns differ between intensive (i.e., feed lot) and extensive (i.e., rangeland) systems. The provisions of the Five Freedoms can be used as a conceptual framework to demonstrate how precision livestock management can be used to improve the welfare of livestock grazing on extensive rangeland systems.

Dynamic onset response of the internal carotid artery to hypercapnia is blunted in children compared with adults.

Intracranial blood velocity reactivity to a steady‐state hypercapnic stimulus has been shown to be similar in children and adults, but the onset response to hypercapnia is slower in the child. Given the vasodilatory effect of hypercapnia on the cerebrovasculature, assessment of vessel diameter, and blood flow are vital to fully elucidate whether the temporal hypercapnic response differs in children versus adults. Assessment of internal carotid artery (ICA) vessel diameter (ICAd), blood velocity (ICAv), volumetric blood flow (Q ICA), and shear rate (ICASR) in response to a 4 min hypercapnic challenge was completed in children (n = 14, 8 girls; 9.8 ± 0.7 years) and adults (n = 17, 7 females; 24.7 ± 1.8 years). The dynamic onset responses of partial pressure of end‐tidal CO2 (PETCO2), Q ICA, ICAv, and ICASR to hypercapnia were modeled, and mean response time (MRT) was computed. Following 4 min of hypercapnia, ICA reactivity and ICAd were comparable between the groups. Despite a similar MRT in PETCO2 in children and adults, children had slower Q ICA (children 108 ± 60 s vs. adults 66 ± 37 s; p = 0.023), ICAv (children 120 ± 52 s vs. adults 52 ± 31 s; p = 0.001), and ICASR (children 90 ± 27 s vs. adults 47 ± 36 s; p = 0.001) MRTs compared with adults. This is the first study to show slower hypercapnic hyperemic kinetic responses of the ICA in children. The mechanisms determining these differences and the need to consider the duration of hypercapnic exposure when assessing CVR in children should be considered in future studies.

Latency of Motion Onset Response as an Integrative Measure of Processing Sound Movement

—The characteristics of a specific event-related potential elicited by sound motion onset (motion-onset response, MOR) were estimated. Moving sound stimuli with delayed motion onset were presented to right-handed subjects in dichotic conditions. Sound motion was produced by linear changes of interaural time differences. The amplitude and latency of cN1 and cP2 components of evoked potentials were measured in a wide range of velocities. The latency of cN1 increased linearly with the increase in time of 1° azimuthal shift of a stimulus, whereas the cP2 latency remained nearly constant. The time interval of motion integration was about 140–180 ms. Thus, the latency of cN1 deflection may be considered as an electrophysiological correlate of integrative neuronal processes activated by sound motion presented as a separate auditory event.

Cardiotoxicity of Zebrafish Induced by 6-Benzylaminopurine Exposure and Its Mechanism.

6-BA is a common plant growth regulator, but its safety has not been conclusive. The heart is one of the most important organs of living organisms, and the cardiogenesis process of zebrafish is similar to that of humans. Therefore, based on wild-type and transgenic zebrafish, we explored the development of zebrafish heart under 6-BA exposure and its mechanism. We found that 6-BA affected larval cardiogenesis, inducing defective expression of key genes for cardiac development (myl7, vmhc, and myh6) and AVC differentiation (bmp4, tbx2b, and notch1b), ultimately leading to weakened cardiac function (heart rate, diastolic speed, systolic speed). Acridine orange staining showed that the degree of apoptosis in zebrafish hearts was significantly increased under 6-BA, and the expression of cell-cycle-related genes was also changed. In addition, HPA axis assays revealed abnormally expressed mRNA levels of genes and significantly increased cortisol contents, which was also consistent with the observed anxiety behavior in zebrafish at 3 dpf. Transcriptional abnormalities of pro- and anti-inflammatory factors in immune signaling pathways were also detected in qPCR experiments. Collectively, we found that 6-BA induced cardiotoxicity in zebrafish, which may be related to altered HPA axis activity and the onset of inflammatory responses under 6-BA treatment.