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• The estrous cycle does not affect the innate startle but influences fear learning. • In high-anxious females, hormonal increase during proestrus reduces learned fear. • In BLA, 5-HT reduces potentiated startle by combining with estrous cycle hormones. • In BLA, 5-HT interacts with female hormones likely through 5-HT1A receptors. • DPAG stimulation of high-anxious females increases the response to stressful stimuli. Despite significant advances in the study of fear and fear memory formation, little is known about fear learning and expression in females. This omission has been proven surprising, as normal and pathological behaviors are highly influenced by ovarian hormones, particularly estradiol and progesterone. In the current study, we investigated the joint influence of serotonin (5-HT) neurotransmission and estrous cycle phases (low or high levels of estradiol and progesterone) on the expression of conditioned fear in a group of female rats that were previously divided according to their response to stressful stimuli into low or high anxiety-like subjects. The baseline amplitude of the unconditioned acoustic startle responses was high in high-anxiety female rats, with no effect on the estrous cycle observed. Data collected during the proestrus-estrus phase revealed that low-anxiety rats had startle amplitudes similar to those of high-anxiety rats. It is supposed that high-anxiety female rats benefit from increased estradiol and progesterone levels to achieve comparable potentiated startle amplitudes. In contrast, female rats experienced a significant decrease in hormone levels during the Diestrus phase. This decrease is believed to play a role in preventing them from displaying a heightened startle response when faced with strongly aversive stimuli. Data collected after 5-HT and 8-OH-DPAT were administered into the basolateral nuclei and dorsal periaqueductal gray suggest that 5-HT neurotransmission works with progesterone and estrogen to reduce startle potentiation, most likely by activating the serotonin-1A receptor subtype. [ABSTRACT FROM AUTHOR]

22q11.2 deletion syndrome (22q11DS) is one of the most robust genetic predictors of psychosis and other psychiatric illnesses. In this study, we examined 22q11DS subjects' acoustic startle responses (ASRs), which putatively index psychosis risk. Latency of the ASR is a presumptive marker of neural processing speed and is prolonged (slower) in schizophrenia. ASR measures correlate with increased psychosis risk, depend on glutamate and dopamine receptor signaling, and could serve as translational biomarkers in interventions for groups at high psychosis risk. Startle magnitude, latency, and prepulse inhibition were assessed with a standard acoustic startle paradigm in 31 individuals with 22q11.2DS and 32 healthy comparison (HC) subjects. Surface electrodes placed on participants' orbicularis oculi recorded the electromyographic signal in ASR eyeblinks. Individuals without measurable startle blinks in the initial habituation block were classified as non-startlers. Across the startle session, the ASR magnitude was significantly lower in 22q11DS subjects than HCs because a significantly higher proportion of 22q11DS subjects were non-startlers. Latency of the ASR to pulse-alone stimuli was significantly slower in 22q11DS than HC subjects. Due to the overall lower 22q11DS startle response frequency and magnitudes prepulse inhibition could not be analyzed. Reduced magnitude and slow latency of 22q11DS subjects' responses suggest reduced central nervous system and neuronal responsiveness. These findings are consistent with significant cognitive impairments observed in 22q11DS subjects. Further research is needed to untangle the connections among basic neurotransmission dysfunction, psychophysiological responsiveness, and cognitive impairment. [ABSTRACT FROM AUTHOR]

Biological markers for anxiety disorders may further understanding of disorder pathophysiology and suggest potential targeted treatments. The fear-potentiated startle (FPS) (a measure of startle to predictable threat) and anxiety-potentiated startle (APS) (startle to unpredictable threat) laboratory paradigm has been used to detect physiological differences in individuals with anxiety disorders compared with nonanxious control individuals, and in pharmacological challenge studies in healthy adults. However, little is known about how startle may change with treatment for anxiety disorders, and no data are available regarding alterations due to mindfulness meditation training. Ninety-three individuals with anxiety disorders and 66 healthy individuals completed 2 sessions of the neutral, predictable, and unpredictable threat task, which employs a startle probe and the threat of shock to assess moment-by-moment fear and anxiety. Between the two testing sessions, patients received randomized 8-week treatment with either escitalopram or mindfulness-based stress reduction. APS, but not FPS, was higher in participants with anxiety disorders compared with healthy control individuals at baseline. Further, there was a significantly greater decrease in APS for both treatment groups compared with the control group, with the patient groups showing reductions bringing them into the range of control individuals at the end of the treatment. Both anxiety treatments (escitalopram and mindfulness-based stress reduction) reduced startle potentiation during unpredictable (APS) but not predictable (FPS) threat. These findings further validate APS as a biological correlate of pathological anxiety and provide physiological evidence for the impact of mindfulness-based stress reduction on anxiety disorders, suggesting that there may be comparable effects of the two treatments on anxiety neurocircuitry. [ABSTRACT FROM AUTHOR]

• Male and female rats have comparable startle amplitudes when corrected for body weight. • Female rats show higher foot-shock reactivity than males during fear-conditioning. • Male and female rats show comparable levels of cued, non-cued, and contextual fear. • Wistar females show higher startle after fear-conditioning vs. males, regardless of trial type. • Unpredictable threats further increase startle reactivity and contextual fear in Wistar females vs. males. Fear-potentiated startle (FPS) has been widely used to study fear processing in humans and rodents. Human studies showed higher startle amplitudes and exaggerated fear reactivity to unpredictable vs. predictable threats in individuals suffering from post-traumatic stress disorder (PTSD). Although human FPS studies use both sexes, a surprisingly limited number of rodent FPS studies use females. Here we investigate the effects of signal-threat contingency, signal-threat order and threat predictability on FPS in both sexes. We use a classic fear-conditioning protocol (100% contingency of cue and shock pairings, with forward conditioning such that the cue co-terminates with the shock) and compare it to modified fear-conditioning protocols (70% contingency; backward conditioning; or cue and shock un-paired). Although there are no sex differences in the startle amplitudes when corrected for body weight, females consistently demonstrate higher shock reactivity during fear-conditioning. Both sexes and strains demonstrate comparable levels of cued, non-cued, and contextual fear in the classic FPS and FPS following fear-conditioning with 70% contingency or backward order (cue co-starts with shock). However, in the classic FPS, Sprague-Dawley females show reduced proportion between cued fear and cue-elicited vigilant state than males. Lastly, a prominent sex difference is uncovered following unpredictable fear-conditioning (cue and shock un-paired), with Wistar, but not Sprague-Dawley, females showing significantly higher startle overall during the FPS recall, regardless of trial type, and higher contextual fear than males. This striking sex difference in processing unpredictable threats in rodent FPS might help to understand the mechanisms underlying higher incidence of PTSD in women. [ABSTRACT FROM AUTHOR]

Allan-Herndon-Dudley syndrome (AHDS) is caused by mutations in the SLC16A2 gene, encoding for the monocarboxylate transporter 8 (MCT8). Central hypothyroidism and chronic peripheral thyrotoxicosis result in a severe phenotype, mainly characterized by poor growth, intellectual disability, spastic tetraparesis, and movement disorders, including paroxysmal ones (startle reaction and paroxysmal dyskinesias). Seizures are rarely reported. We conducted a retrospective analysis on video electroencephalography (EEG) recordings in four subjects with AHDS, focused on paroxysmal events. Among other manifestations recorded on EEG, we diagnosed repetitive sleep starts (RSS) in all subjects. RSS are a paroxysmal nonepileptic phenomenon occurring during sleep, similar to epileptic spasms in their clinical and electromyography characteristics, but not related to any EEG change. This is the first report on RSS in AHDS. We present video-EEG polygraphic documentation, suggesting that RSS could be underestimated or misdiagnosed. The importance of a correct diagnosis is crucial in a therapeutic perspective. [ABSTRACT FROM AUTHOR]

• The Zwicker tone illusion is a model for tinnitus perception. • No objective behavioral paradigms exist to assess the presence of the Zwicker tone in animals. • We introduce a modified GPIAS paradigm to test the presence of the Zwicker tone in gerbils. • We also compare the modified GPIAS paradigm with a new aversive conditioning learning paradigm. • Results suggest that gerbils perceive the Zwicker tone, providing a neurophysiological model for human tinnitus. The Zwicker tone illusion – an auditory phantom percept after hearing a notched noise stimulus – can serve as an interesting model for acute tinnitus. Recent mechanistic models suggest that the underlying neural mechanisms of both percepts are similar. To date it is not clear if animals do perceive the Zwicker tone, as up to now no behavioral paradigms are available to objectively assess the presence of this phantom percept. Here we introduce, for the first time, a modified version of the gap pre-pulse inhibition of the acoustic startle reflex (GPIAS) paradigm to test if it is possible to induce a Zwicker tone percept in our rodent model, the Mongolian gerbil. Furthermore, we developed a new aversive conditioning learning paradigm and compare the two approaches. We found a significant increase in the GPIAS effect when presenting a notched noise compared to white noise gap pre-pulse inhibition, which is consistent with the interpretation of a Zwicker tone percept in these animals. In the aversive conditioning learning paradigm, no clear effect could be observed in the discrimination performance of the tested animals. When investigating the first 33% of the correct conditioned responses, an effect of a possible Zwicker tone percept can be seen, i.e. animals show identical behavior as if a pure tone was presented, but the paradigm needs to be further improved. Nevertheless, the results indicate that Mongolian gerbils are able to perceive a Zwicker tone and can serve as a neurophysiological model for human tinnitus generation. [ABSTRACT FROM AUTHOR]

Imprinting is a crucial learning behavior by the hatchlings of precocious birds. In nature, hatchlings in a group environment imprint on a hen, but the effect of siblings on the imprinting process remains largely unknown. To investigate this issue, we examined how the social context modulated visual imprinting in domestic chicks. One-day-old postnatal chicks in isolation (RS chicks) or with siblings (RD chicks), were first exposed to an imprinting stimulus, and subsequently the responses to the imprinting stimulus as well as a new stimulus were examined and compared. The experiment constituted three types of siblings: a 20-min pre-trained tutor, a 60-min pre-trained tutor, and a naïve chick. A multiple comparison test revealed that the preference score (PS) to the new stimulus of RD chicks trained with a 60-min pre-trained tutor was significantly lower than that of RS chicks. Multiple linear regression analysis revealed that the length of the tutor's pre-training significantly correlated negatively with the PS to the new stimulus, but this variable did not correlate with the PS to the imprinting stimulus. These results revealed that the presence of highly imprinted siblings could enhance the escape response to the new stimulus. We discussed the possible involvement of the chick's medial amygdala in the social aspect of imprinting. • In this paper, we examined how the social context modulated visual imprinting in domestic chicks. • The presence of highly imprinted siblings during the acquisition phase enhanced the escape response to the new stimulus. • The presence of siblings during the acquisition phase did not affect the following response to the imprinting stimulus. [ABSTRACT FROM AUTHOR]

This paper describes 'gasps' – ingressive vocoids, ingressive nasal stops, and certain sharp inbreaths – expressing stance in Hebrew conversation. A sharp inbreath can be part of a startle reflex, but sequential analysis shows gasps used as carefully coordinated interactional resources. Gasps in themselves express high arousal only; valence and specific affective categories must be gathered from context. Gasps' liminal status, blurring the lines between body and language, self and other, informs their expressive power, making them potent ways to redirect attention, display emotion, and express empathy. Despite their liminal status, gasps fit the usage patterns of established linguistic categories of affective expressions, such as response cries, prompting reconsideration of the limits of linguistic categories. • Gasps (ingressive vowels) are responsive social actions, expressing emotion. • Context and surrounding talk determine the emotion, not limited to surprise. • Gasps negotiate attention and alignment, and express empathy. • Gasps are not entirely linguistic, but used similarly to conventional emotion words. [ABSTRACT FROM AUTHOR]

• A startling acoustic stimulus resulted in the rapid release of the stepping sequence in PD individuals with and without FOG. • The presence or absence of task uncertainty didn't affect motor preparation strategies in PD groups with and without FOG. • The capacity to plan and rapidly initiate the stepping sequence in response to a startling stimulus was intact in PD groups. Freezing of gait (FOG) in Parkinson's disease (PD) is characterized by the inability to initiate stepping, despite the intention to do so. This study used a startling acoustic stimulus paradigm to examine if the capacity to select, prepare and initiate gait under simple and choice reaction time conditions are impaired in people with PD and FOG. Thirty individuals (10 PD with FOG, 10 PD without FOG, and 10 controls) performed an instructed-delay gait initiation task under simple and choice reaction time conditions. In a subset of trials, a startle stimulus (124 dB) was presented 500 ms before the time of the imperative go-cue. Anticipatory postural adjustments preceding and accompanying gait initiation were quantified. The presentation of a startling acoustic stimulus resulted in the rapid initiation of an anticipatory postural adjustment sequence during both the simple and choice reaction time tasks in all groups. The neural capacity to prepare the spatial and temporal components of gait initiation remains intact in PD individuals with and without FOG. The retained capacity to prepare anticipatory postural adjustments in advance may explain why external sensory cues are effective in the facilitation of gait initiation in people with PD with FOG. [ABSTRACT FROM AUTHOR]

There is growing evidence of beneficial effects of mindfulness developed through engaging in mindfulness training/practices on sensory and cognitive processing, emotion regulation and mental health. Mindfulness has also been conceptualised as a dispositional 'trait', i.e. the naturally-occurring ability of meditation-naïve individuals to display, in varying degree, a non-judgmental non-reactive present-moment awareness in everyday life. In this study we examined possible associations between dispositional mindfulness, alexithymia and sensory processing. Eye-blink startle responses to acoustic stimuli of varying intensity [90-dB or 100-dB over 70-dB (A) background] were assessed in 26 meditation-naïve adults (50 % men) using electromyographic recordings of the orbicularis muscle. All participants completed the Five Facet Mindfulness Questionnaire and the 20-item Toronto Alexithymia Scale. A negative association was found between dispositional mindfulness and alexithymia (r = −0.513). There was stronger startle habituation to 100-dB, compared to 90-dB probes. Stronger startle habituation (larger negative habitation slope values) to 100-dB probes was significantly associated with higher dispositional mindfulness (r = −0.528) and with lower alexithymia at trend level (r = 0.333). As indicated by commonality analysis, 10.6 % of explained variance in habituation (100-dB probes) was common to both alexithymia and mindfulness, 17.3 % was unique to mindfulness, but alexithymia made negligible unique contribution (0.5 %). These findings indicate similar startle habituation pattern in people with a high level of dispositional mindfulness to that reported previously by Antonova et al. (2015) in people with moderate mindfulness meditation practice intensity. Future studies should investigate the mechanisms, such as interoceptive awareness, that might underly these relationships. • Dispositional mindfulness (DM) and alexithymia are inversely correlated. • Stronger startle habituation is associated with a higher level of DM. • DM explains more variance in startle habituation than alexithymia. • DM and long-term mild-to-moderate meditation practices may share sensory correlates. [ABSTRACT FROM AUTHOR]

Stimulation of the dorsal half of the rat periaqueductal gray (DPAG) with 60-Hz pulses of increasing intensity, 30-μA pulses of increasing frequency, or increasing doses of an excitatory amino acid elicits sequential defensive responses of exophthalmia, immobility, trotting, galloping, and jumping. These responses may be controlled by voltage-gated calcium channel-specific firing patterns. Indeed, a previous study showed that microinjection of the DPAG with 15 nmol of verapamil, a putative blocker of L-type calcium channels, attenuated all defensive responses to electrical stimulation at the same site as the injection. Accordingly, here we investigated the effects of microinjection of lower doses (0.7 and 7 nmol) of both verapamil and mibefradil, a preferential blocker of T-type calcium channels, on DPAG-evoked defensive behaviors of the male rat. Behaviors were recorded either 24 h before or 10 min, 24 h, and 48 h after microinjection. Effects were analyzed by both threshold logistic analysis and repeated measures analysis of variance for treatment by session interactions. Data showed that the electrodes were all located within the dorsolateral PAG. Compared to the effects of saline, verapamil significantly attenuated exophthalmia, immobility, and trotting. Mibefradil significantly attenuated exophthalmia and marginally attenuated immobility while facilitating trotting. While galloping was not attenuated by either antagonist, jumping was unexpectedly attenuated by 0.7 nmol verapamil only. These results suggest that T-type calcium channels are involved in the low-threshold freezing responses of exophthalmia and immobility, whereas L-type calcium channels are involved in the trotting response that precedes the full-fledged escape responses of galloping and jumping. [Display omitted] • DLPAG stimulation elicits hierarchically organized defensive behaviors. • Blockade of T-type Ca2+ channel attenuated only exophthalmia and immobility. • Blockade of L-type Ca2+ channel produced additional attenuation of trotting. • Blockers either did not affect or had little effect on galloping and jumping. • Data implicate voltage-gated Ca2+ channels in the control of behavioral hierarchy. [ABSTRACT FROM AUTHOR]

Nonmedical use of prescription opioids peaks during late adolescence, a developmental period associated with the maturation of higher-order cognitive processes. To date, however, how chronic adolescent oxycodone (OXY) self-administration alters neurobehavioral (i.e., locomotion, startle reactivity) and/or neurocognitive (i.e., preattentive processes, intrasession habituation, stimulus-reinforcement learning, sustained attention) function has not yet been systematically evaluated. Hence, the rationale was built for establishing the dose-dependency of adolescent OXY self-administration on the trajectory of neurobehavioral and neurocognitive development. From postnatal day (PD) 35 to PD 105, an age in rats that corresponds to the adolescent and young adult period in humans, male and female F344/N rats received access to either oral OXY (0, 2, 5, or 10 mg/kg) or water under a two-bottle choice experimental paradigm. Independent of biological sex or dose, rodents voluntarily escalated their OXY intake across ten weeks. A longitudinal experimental design revealed prominent OXY-induced impairments in neurobehavioral development, characterized by dose-dependent increases in locomotion and sex-dependent increases in startle reactivity. Systematic manipulation of the interstimulus interval in prepulse inhibition supports an OXY-induced impairment in preattentive processes. Despite the long-term cessation of OXY intake, rodents with a history of chronic adolescent oral OXY self-administration exhibited deficits in sustained attention; albeit no alterations in stimulus-reinforcement learning were observed. Taken together, adolescent oral OXY self-administration induces selective long-term alterations in neurobehavioral and neurocognitive development enjoining the implementation of safer prescribing guidelines for this population. • Adolescent male and female rodents voluntarily self-administer oxycodone. • Adolescent oxycodone induces prominent alterations in neurocognitive development. • Despite the cessation of oxycodone intake, neurocognitive deficits persisted. • Neurocognitive impairments support alterations in the dopaminergic system. [ABSTRACT FROM AUTHOR]

Noisy tinnitus is a common auditory system disease characterized by persistent tinnitus symptoms. The TLR4/NF - κ B/NLRP3 signaling pathway plays an important role in neuroinflammatory response. Select 6 control and 6 noise exposed mice for transcriptome sequencing analysis in the hippocampus, conduct high-throughput data analysis, identify differentially expressed genes, and screen for pathways. Auditory brainstem response (ABR) detection was performed to understand the hearing changes, and the modeling effect was evaluated using the GPIAS% inhibition experiment of auditory startle reflex. Morphological observation of the basement membrane was performed to determine whether the inner hair cells were damaged. Immunohistochemistry and immunofluorescence were used to determine the activation of microglia in the hippocampus of noise induced tinnitus mice. Finally, qPCR and Western Blot were used to detect the expression of TLR4, NF kB, NLRP3, caspase-1, and IL-1 β in the hippocampus of each group of mice. Through high-throughput data analysis, it was found that there was no significant difference in the auditory threshold of the three groups of mice; After 2 h of exposure to 100 dB SPL noise, the GPIAS% of mice decreased significantly compared to before exposure, and membrane construction was successful. After 7 days, the GPIAS% of the drug intervention group increased. After noise exposure, mice developed tinnitus, and hippocampus neuroinflammation. Roflupram can inhibit neuroinflammation and improve tinnitus through the TLR4/NF kB/NLRP3/caspase-1/IL-1 β signaling pathway. [ABSTRACT FROM AUTHOR]

Behavioural reactivity is an expression of temperament that may influence an animal's response to stressful situations and impact on handleability and the human-animal relationship. Shortcomings of previously described tests led to the development of a standardized startle protocol in sheep using a tactile stimulus (airblast to the face) and the presence of conspecifics to minimize the effects of social isolation. Here we tested the repeatability of the protocol, the consistency of the response and habituation to the protocol. Twenty sheep were tested across four startle interval test phases. Phases were applied consecutively such that each sheep received up to 17 startles across a six-week period with two to six days between test phases. Phases were; within – up to 5 startles over a 7 min test, Bi-hourly – four repetitions of a single 4-minute startle test 2 hours apart on one day, daily – a single 4-minute startle test repeated over four consecutive days and, weekly – a single 4-minute startle test repeated once per week over four consecutive weeks. Three measures of startle magnitude, retreat distance (zone 1–6) and startle duration (s), startle force (gs), were recorded for each startle. A reduction in response to the startle stimulus over time was identified; however, consistent responses of sheep for the measures of startle magnitude were generally observed across test phases. Repeatability of retreat distance and startle force were moderate to high within test phases (0.56–0.82), whereas startle duration had low to moderate repeatability (0.26–0.50). Strong consistency in individual responses, good repeatability, and the presence of a distinct startle response after repeated applications of the stimulus indicate that the startle test shows promise as a measure of reactive temperament in sheep. Further development to improve the tests access in commercial environments may also facilitate producers use of startle magnitude for the selection of less reactive temperaments to improve handleability, safety and welfare on farm. [Display omitted] • Sheep habituated to the startle stimulus over time but still showed a response. • Responses between sheep for startle magnitude were generally consistent. • Repeatability of retreat distance and startle force were moderate to high. • Repeatability and individual consistency of startle duration was lower. • The startle test shows promise as a measure of reactive temperament in sheep. [ABSTRACT FROM AUTHOR]

CTNNB1 gene loss-of-function variants cause Neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV, OMIM 615075). Although motor impairment represents a core feature of this condition, the motor phenotype remains poorly described. We systematically assessed a cohort of 14 patients with disease-causing CTNNB1 variants to better characterize the movement disorder phenotype. patients were enrolled at Bambino Gesù Children's Hospital in Rome, Italy, between January 2019 and February 2024. 14 participants were included and underwent extensive genetic and neurologic examination. Clinical features, neuroimaging and neurophysiological investigations were retrospectively analyzed from medical charts and video recordings. 13 out of 14 patients showed motor disorders (one only showing mild coordination difficulties). 12 presented abnormal gait (11 patients with broad-based gait, one with narrow-based in-toeing gait, one with broad-based gait with unilateral intoeing). One did not achieve walking ability. 13 patients presented progressive lower limbs hypertonia without overt pyramidal signs. Five patients reported exaggerated startle, three developed upper body (prominently cervical) dystonia in the second decade, with or without bradykinesia (2/13). Treatment efficacy was variable: botulinum toxin was (at least partially) effective in 5/6, levodopa in 1 of 4 treated patients. CTNNB1 -syndrome is associated with a peculiar, but recognizable movement disorder phenotype, encompassing complex gait disorders with progressive lower limb hypertonia, exaggerated startle, and possible occurrence in the second decade of life of upper body dystonia with or without bradykinesia. • CTNNB1 -syndrome shows a complex but recognizable movement disorder phenotype. • The main abnormality is progressive lower limbs hypertonia, producing a stiff, broad-based gait. • Hypertonia likely underlies a combination of dystonia and spasticity. • In the second decade, upper body dystonia with or without bradykinesia may occur. • Exaggerated startle reflex may coexist. [ABSTRACT FROM AUTHOR]

• Olivocochlear and non-olivocochlear neurons in the VNTB lack a distinct topographic pattern, exhibiting a mixed arrangement. • A notable proportion of VNTB cholinergic neurons projecting to the cochlear root nucleus is concentrated at rostral levels. • The VNTB plays a role in the prepulse inhibition of acoustic startle reflex, particularly at short interstimulus intervals. • Non-olivocochlear VNTB neurons are involved in the rapid top-down cholinergic pathway of auditory prepulse inhibition. Cholinergic signaling is essential to mediate the auditory prepulse inhibition (PPI), an operational measure of sensorimotor gating, that refers to the reduction of the acoustic startle reflex (ASR) when a low-intensity, non-startling acoustic stimulus (the prepulse) is presented just before the onset of the acoustic startle stimulus. The cochlear root neurons (CRNs) are the first cells of the ASR circuit to receive cholinergic inputs from non-olivocochlear neurons of the ventral nucleus of the trapezoid body (VNTB) and subsequently decrease their neuronal activity in response to auditory prepulses. Yet, the contribution of the VNTB-CRNs pathway to the mediation of PPI has not been fully elucidated. In this study, we used the immunotoxin anti-choline acetyltransferase (ChAT)-saporin as well as electrolytic lesions of the medial olivocochlear bundle to selectively eliminate cholinergic VNTB neurons, and then assessed the ASR and PPI paradigms. Retrograde track-tracing experiments were conducted to precisely determine the site of lesioning VNTB neurons projecting to the CRNs. Additionally, the effects of VNTB lesions and the integrity of the auditory pathway were evaluated via auditory brain responses tests, ChAT- and FOS-immunohistochemistry. Consequently, we established three experimental groups: 1) intact control rats (non-lesioned), 2) rats with bilateral lesions of the olivocochlear bundle (OCB-lesioned), and 3) rats with bilateral immunolesions affecting both the olivocochlear bundle and the VNTB (OCB/VNTB-lesioned). All experimental groups underwent ASR and PPI tests at several interstimulus intervals before the lesion and 7, 14, and 21 days after it. Our results show that the ASR amplitude remained unaffected both before and after the lesion across all experimental groups, suggesting that the VNTB does not contribute to the ASR. The%PPI increased across the time points of evaluation in the control and OCB-lesioned groups but not in the OCB/VNTB-lesioned group. At the ISI of 50 ms, the OCB-lesioned group exhibited a significant increase in%PPI (p < 0.01), which did not occur in the OCB/VNTB-lesioned group. Therefore, the ablation of cholinergic non-olivocochlear neurons in the OCB/VNTB-lesioned group suggests that these neurons contribute to the mediation of auditory PPI at the 50 ms ISI through their cholinergic projections to CRNs. Our study strongly reinforces the notion that auditory PPI encompasses a complex mechanism of top-down cholinergic modulation, effectively attenuating the ASR across different interstimulus intervals within multiple pathways. [ABSTRACT FROM AUTHOR]

The study aimed at investigating the impact of an innovative Wake Vortex Alert (WVA) avionics on pilots' operation and mental states, intending to improve aviation safety by mitigating the risks associated with wake vortex encounters (WVEs). Wake vortices, generated by jet aircraft, pose a significant hazard to trailing or crossing aircrafts. Despite existing separation rules, incidents involving WVEs continue to occur, especially affecting smaller aircrafts like business jets, resulting in aircraft upsets and occasional cabin injuries. To address these challenges, the study focused on developing and validating an alert system that can be presented to air traffic controllers, enabling them to warn flight crews. This empowers the flight crews to either avoid the wake vortex or secure the cabin to prevent injuries. The research employed a multidimensional approach including an analysis of human performance and human factors (HF) issues to determine the potential impact of the alert on pilots' roles, tasks, and mental states. It also utilizes Human Assurance Levels (HALs) to evaluate the necessary human factors support based on the safety criticality of the new system. Realistic flight simulations were conducted to collect data of pilots' behavioural, subjective and neurophysiological responses during WVEs. The data allowed for an objective evaluation of the WVA impact on pilots' operation, behaviour and mental states (mental workload, stress levels and arousal). In particular, the results highlighted the effectiveness of the alert system in facilitating pilots' preparation, awareness and crew resource management (CRM). The results also highlighted the importance of avionics able to enhance aviation safety and reducing risks associated with wake vortex encounters. In particular, we demonstrated how providing timely information and improving situational awareness, the WVA will minimize the occurrence of WVEs and contribute to safer aviation operations. • Improved Safety: the WVA allowed the pilots to get prepared and secure the cabin. • Reduced PIO: the duration of pilot-induced oscillations was shorter with WVA. • Enhanced Arousal: Pilots exhibited higher arousal with the WVA than without it. • Pilot Acceptance: 90 % of pilots reported that the WVA improved their performance. • Neurophysiological Data: real-time mental workload, stress and arousal assessment. [ABSTRACT FROM AUTHOR]

Intolerance of uncertainty (IU) is a key transdiagnostic feature of internalizing psychopathology. An increasing body of research suggests that IU is associated with increased psychophysiological reactivity in anticipation of unpredictable threat. However, most studies examining the psychophysiological correlates of IU have been conducted in adults. There is a critical need to understand the relationship between IU and psychophysiological reactivity in anticipation of unpredictable threat during adolescence, a key developmental period associated with increased exploration of situations with uncertain outcomes. Thus, the present study examined the association between (1) youth IU and (2) parental IU (as an indicator of risk) in relation to youth defensive motivation (startle reflex) and attention (startle probe N100 and P300) in anticipation of unpredictable threat. The sample included 193 13 to 22-year-old (M = 17.33, SD = 1.97) females and a biological parent. Participants and their parent completed a self-report measure of prospective and inhibitory IU. Youth startle potentiation, probe N100 enhancement, and probe P300 suppression (indicating increased attention to threat) were measured in anticipation of predictable and unpredictable threat. Youth prospective IU and inhibitory IU were not related to youth psychophysiological reactivity to predictable or unpredictable threat. Greater parental prospective IU was associated with greater youth startle potentiation and probe N100 enhancement in anticipation of unpredictable threat. The present study suggests that parental IU, but not concurrent IU, is associated with heightened defensive motivation and attentional engagement in anticipation of unpredictable threat in youth. • Examined the association between youth and parental intolerance of uncertainty (IU) and sensitivity to unpredictable threat • Greater parental IU was associated with greater youth startle potentiation to unpredictable threat • Greater parental IU was associated with greater probe N100 enhancement to unpredictable threat • Youth IU was not related to youth sensitivity to unpredictable threat [ABSTRACT FROM AUTHOR]

Intolerance of uncertainty (IU) represents a transdiagnostic risk factor for internalizing psychopathology. However, little is known regarding its psychophysiological correlates. IU is thought to render individuals hypersensitive to threatening events, even if the occurrence probability is low. To test this, we recruited 90 students who completed two NPU-threat tests separating temporal unpredictability from probabilistic unpredictability (i.e., probability of occurrence): First, a NPU version in which the timing of threat (i.e., shock) was either predictable or unpredictable but the shock probability was 100 % in each trial. Second, a probabilistic NPU version in which the timing of the shock was also either predictable or unpredictable, but the shock probability was 33 % in each trial. Startle reflex, event-related potentials N1 and P3 locked to auditory startle probes, and anxiety ratings were analyzed. As expected, temporally unpredictable threat modulated startle, N1, and anxiety ratings. IU predicted increased startle to lower shock probability, regardless of the temporal predictability. No evidence emerged for IU affecting N1 or P3. However, IU predicted anxiety ratings to threat conditions regardless of temporal or probabilistic predictability. Individual differences in IU shape startle responses to eventual threat: IU increases automatic defensive responding to unpredictable and potentially threatening situations if the threat probability is low. Individuals with higher IU may tend to "err on the side of caution" with a mismatch between physiological preparation and threat probability, such that the effects of IU are particularly observable in low threat probability conditions. • Intolerance of uncertainty (IU) is theorized to lead to hypersensitivity to unlikely threat. • We manipulated temporal predictability and probabilistic predictability of threat using two versions of the NPU-threat test. • Outcome measures were startle reflex, startle probe locked event-related potentials (N1 and P3), and anxiety ratings. • Unpredictable threat modulated startle, N1, and anxiety ratings. • IU predicted increased startle responses to probabilistic unpredictability but not to temporal unpredictability. [ABSTRACT FROM AUTHOR]

Intolerance of uncertainty plays a central role in anxiety and research suggests that it's an important treatment target. Investigating response to uncertainty using other dimensions than self-report, such as physiological responses, can further the effort to understand the role of uncertainty in anxiety more fully. Mindfulness interventions have become increasingly interesting in their application to anxiety, as they foster acceptance of unpleasant aspects of experience. The aims of the study were to examine whether a mindfulness intervention reduced response to uncertainty and anxiety symptoms, and to examine the associations between intolerance of uncertainty, physiological response to uncertainty, mindfulness and anxiety. Participants were 117 students who completed a two-week mindfulness or audiobook control intervention. At pre- and post-intervention assessments, measures of anxiety, mindfulness, and intolerance of uncertainty were completed and a threat-of-shock task assessing startle responding to unpredictable shock was administered. Findings showed a significant effect of the intervention for social anxiety symptoms. Furthermore, intolerance of uncertainty mediated the effect of the intervention on symptoms for social anxiety and worry. No such effects were found for physiological response to uncertainty. The study adds to the understanding of the role of response to uncertainty in anxiety as well as to its mechanistic role in the context of mindfulness practice. Implications and possible explanations for the non-significant main effects of the intervention on anxiety symptoms and physiological response to uncertainty are discussed. • The study investigates a relation between self-report and physiological response to uncertainty. • The study investigates the effect of a mindfulness intervention on response to uncertainty. • Startle during uncertain threat was related to inhibitory intolerance of uncertainty. • Intolerance of uncertainty mediated the effect of a mindfulness intervention on some anxiety symptoms. • Startle response did not mediate the effect of a mindfulness intervention on anxiety symptoms. [ABSTRACT FROM AUTHOR]

• Tested AM frequency discrimination in young and aged rats using prepulse inhibition. • Older rats had good discrimination at 100% AM depth but poorer at 50% depth. • EFRs amplitudes were lower in younger animals with matched wave 1 amplitudes. • AM discrimination was good in matched wave 1 condition despite lower EFR amplitudes. • Implied age and depth rather than EFR amplitudes predicts behavioral responses. Amplitude and frequency modulations are important for speech intelligibility, especially in noise. Neurophysiological responses assessed by envelope following responses (EFRs) are smaller at faster amplitude modulation frequencies (AMF) in older subjects compared to younger subjects. A typical assumption is that a decline in EFRs necessarily results in corresponding perceptual deficits. To test this in an animal model, we investigated the behavioral AMF discrimination of young and aged Fischer-344 rats and compared those abilities to their EFRs. A modified version of prepulse inhibition of the acoustic startle reflex was used to measure behavior. When AMF differences and modulation depths were large, young and aged animals' behavioral performances were comparable. Aged animals' discrimination abilities declined as the difference between background and prepulse AMF decreased and as modulation depth decreased. These declines were larger than in younger animals, even compared to young rats with similar peripheral activation (ABR wave I amplitudes), whose EFR amplitudes were smaller than the aged animals. The results revealed larger age-related deficits in behavioral perception compared to EFRs, suggesting additional factors that affect perception in aging. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Elevated defensive responding, through startle reflex (SR) and skin conductance response (SCR), may contribute to onset and maintenance of depression and anxiety. Most work examining SR and SCR has predicted psychiatric diagnoses. There is a paucity of research examining links between SR or SCR and dimensional measures of psychopathology.Methods: We used latent growth curve modeling to predict longitudinal change in three symptom factors (i.e., General Distress, Fears, Anhedonia-Apprehension) from SR and SCR measured during a fear-potentiated startle paradigm among adolescents oversampled for neuroticism (N = 129).Results: Elevated SCR in danger phases before and after an unpleasant muscle contraction predicted increasing Fears over time. Elevated SR in safe phases post-contraction also predicted increasing Fears over time. Attenuated SR in safe phases post-contraction predicted elevated General Distress longitudinally. Attenuated SCR pre-contraction in danger phases predicted elevated Anhedonia-Apprehension over time.Limitations: Our non-clinical sample may limit generalizability of results. Additionally, we did not assess change in SR and SCR over time.Conclusions: The present study demonstrates that SR and SCR during a fear-potentiated startle paradigm predict longitudinal change in dimensional anxiety and depression symptom factors and relatedly, that SR and SCR may represent risk factors for the exacerbation of symptomatology. [ABSTRACT FROM AUTHOR]

[Display omitted] • Anxioescapic behavior is 'active motor responses in anxiogenic situations'. • Female rats show more anxioescapic behavior and show less freezing behavior during fear extinction compared to males. • Female and male rats have similar fear memory and learning of safety as assessed with avoidance extinction. • Female and male rats have similar unconditioned fear responses. Fear memories are important for survival and are implicated in the etiology of fear disorders such as Post Traumatic Stress Disorder (PTSD). Fear memories are well studied pre-clinically and sex differences in rodent fear expression have been reported: females tend to freeze less than males. Whether this is a difference in fear learning or expression is debated. We aimed to differentiate between these possibilities with a task that allowed female rats to express fear memory by moving, rather than freezing. We assessed fear extinction after contextual fear conditioning in the isolated Shock Arm of a Y-maze in female and male rats by either placing them back in the isolated Shock Arm (Fear Extinction in the Shock Context) or allowing them to move freely in the Y-maze during extinction training and enter/avoid the Shock Arm (Avoidance Extinction). We confirmed that female rats freeze less than males during fear extinction in both settings. During Avoidance Extinction, however, both sexes had similar avoidance of the Shock Context, showing comparable fear memory and extinction. Additionally, female rats made more entries into the non-shock arms. Thus, female and male rats have similar fear learning but females express it with an active motor response. Furthermore, female rats also exhibited an active motor response under other anxiogenic conditions (Elevated Plus Maze) and had higher reactivity (Acoustic Startle Response) but not when fear-eliciting stimuli were present: cat hair and foot-shock. In summary, female rats have an active motor response to anxiogenic stimuli which we termed 'Anxioescapic' behavior strategy. [ABSTRACT FROM AUTHOR]

Post-traumatic stress disorder (PTSD) is a trauma-related condition that produces distressing fear memory intrusions, avoidance behaviors, hyperarousal/startle, stress responses and insomnia. This review focuses on the importance of the orexin neural system as a novel mechanism related to the pathophysiology of PTSD. Orexinergic neurons originate in the lateral hypothalamus and project widely to key neurotransmitter systems, autonomic neurons, the hypothalamic-pituitary-adrenal (HPA) axis, and fear-related neural circuits. After trauma or stress, the basolateral amygdala (BLA) transmits sensory information to the central nucleus of the amygdala (CeA) and in turn to the hypothalamus and other subcortical and brainstem regions to promote fear and threat behaviors. Orexin receptors have a prominent role in this circuit as fear conditioned orexin receptor knockout mice show decreased fear expression while dual orexin receptor antagonists (DORAs) inhibit fear acquisition and expression. Orexin activation of an infralimbic-amygdala circuit impedes fear extinction while DORA treatments enhance it. Increased orexin signaling to the amygdalo-cortical-hippocampal circuit promotes avoidance behaviors. Orexin has an important role in activating sympathetic nervous system (SNS) activity and HPA axis stress responses. Blockade of orexin receptors reduces fear-conditioned startle responses. In PTSD models, individuals demonstrate sleep disturbances such as increased sleep latency and more transitions to wakefulness. Increased orexin activity impairs sleep by promoting wakefulness and reducing total sleep time while DORA treatments enhance sleep onset and maintenance. The orexinergic neural system provides important mechanisms for understanding multiple PTSD behaviors and provides new medication targets to treat this often persistent and debilitating illness. [ABSTRACT FROM AUTHOR]

Hereditary hyperekplexia (HPX) is a genetic neurodevelopmental disorder recently defined by the triad of (1) neonatal hypertonia, (2) excessive startle reflexes, and (3) generalized stiffness following the startle. Defects in GLRA1 are the most common cause of HPX, inherited both in an autosomal dominant and autosomal recessive manner. GLRA1 mutations can also cause milder phenotypes in the startle syndromes spectrum, but the prevalence is uncertain and no clear genotype-phenotype correlation has emerged yet. Moreover, the prevalence of neurodevelopmental outcomes has not been clearly defined. Here we report a new family of patients with a typical HPX phenotype, linked to a novel GLRA1 mutation, inherited with a recessive pattern. We then perform a systematic review of the literature of GLRA1-related HPX, describing the main epidemiological features of 210 patients. We found that GLRA1-related phenotypes do not necessarily fulfill the current criteria for HPX, including also milder and later-onset phenotypes. Among clinical features of the disease, neurodevelopmental issues were reported in a third of the sample; interestingly, we found that these problems, particularly when severe, were more common in homozygous than in heterozygous patients. Additional clinical and preclinical studies are needed to define predictors of adverse neurodevelopmental outcomes and underlying mechanisms. [ABSTRACT FROM AUTHOR]

Despite being considered a valid model for the etiology of anxiety disorders, the fear conditioning paradigm does not always show clear correlations with anxious personality traits that constitute risk factors for the development of anxiety disorders. This may in part due to error variance and the fact that fear conditioning studies are typically underpowered to investigate inter-individual differences. In the current study, we focus on the relationship between conditioned fear acquisition and Intolerance of Uncertainty (IU). In a re-analysis of a large previous study (N = 120), which was conducted using a healthy student sample and a partial reinforcement procedure (75%) with words as Conditioned Stimuli (CSs), the relationship between IU and several outcome measures (i.e., fear ratings, expectancy ratings, skin conductance responses, and startle responses) during fear acquisition was examined. We find that IU is positively related to fear ratings towards the CS+ (r = 0.29), even when controlling for the shared variance with trait anxiety. Furthermore, we find a subtle relationship between IU and startle responses to the CS− (r = −0.23), though this correlation did not survive correction for the shared variance with trait anxiety. Taken together, we replicate some of the correlations previously reported in the literature. However, we recommend that future studies employ even larger samples and more advanced statistical techniques such as structural equation modelling to investigate the correlations between fear acquisition indices and anxious traits in a fine-grained manner. • The relationship between IU and fear conditioning was examined. • This study used a large sample (N = 120) and a partial reinforcement schedule. • IU was positively related to fear ratings to the CS+ (r = 0.29). • IU was negatively related to startle responses to the CS− (r = −0.23). • It is recommended to use even larger samples and advanced statistical modelling. [ABSTRACT FROM AUTHOR]

Hyperekplexia is a rare neurological disorder characterized by exaggerated startle responses affecting newborns with the hallmark characteristics of hypertonia, apnea, and noise or touch-induced nonepileptic seizures. The genetic causes of the disease can vary, and several associated genes and mutations have been reported to affect glycine receptors (GlyRs); however, the mechanistic links between GlyRs and hyperekplexia are not yet understood. Here, we describe a patientwith hyperekplexia froma consanguineous family. Extensive genetic screening using exome sequencing coupled with autozygome analysis and iterative filtering supplemented by in silico prediction identified that the patient carries the homozygous missense mutation A455P in GLRB, which encodes the GlyR ß-subunit. To unravel the physiological and molecular effects of A455PonGlyRs, we used electrophysiology inaheterologous system as well as immunocytochemistry, confocal microscopy, and cellular biochemistry. We found a reduction in glycine-evoked currents in N2A cells expressing the mutation compared toWT cells. Western blot analysis also revealed a reduced amount of GlyR ß protein both in cell lysates andisolatedmembranefractions. In line with the above observations, coimmunoprecipitation assays suggested that the GlyR a1-subunit retained coassembly with ßA455P to form membrane-bound heteromeric receptors. Finally, structural modeling showed that the A455P mutation affected the interaction between theGlyRß-subunit transmembrane domain 4 and the other helices of the subunit. Taken together, our study identifies and validates a novel loss-of-function mutation in GlyRs whose pathogenicity is likely to cause hyperekplexia in the affected individual. [ABSTRACT FROM AUTHOR]

The creatine kinase system is crucial for maintaining cellular energy homeostasis and plays a role in regulating locomotor behavior in organisms, but its significance in the regulating the motionless behavior in olive flounder is limited. In the first experiment of this study, elevated levels of creatine kinase (CK) activity in the spinal cord were detected in the juvenile group (JG) flounder compared to the adult group (AG) flounder. In the second experiment, to further confirm the involvement of CK in the locomotor behavior, the adult flounder was given an intraperitoneal injection of creatine (150 mg/kg), while the flounder in the control group received a saline solution. After one week post-injection, the behavioral analysis revealed that the flounder in the creatine-treated group displayed higher levels of locomotor activity and a greater number of escape attempts in response to external stimuli when compared to the control group. However, the acute stress response, induced by intraperitoneal injection and characterized by tail beating, was significantly alleviated in the flounder in the creatine-treated group. Additionally, there was an upregulation of the UII and AchR genes in the spinal cord, as well as increased levels of UII and AchR in the muscle tissues of the creatine-treated flounder. However, a reduction in UI mRNA levels was observed in the brain of the flounder. Collectively, our data provide the evidence that the elevated enzyme activity and gene expression of creatine kinase play important roles in off-bottom swimming behavior in the JG flounder. Furthermore, administration of creatine improved the locomotor activity and alleviated the stress response in flounder, which is associated with regulation of the locomotor- and stress-related gene in the brain, spinal cord, and muscle. [Display omitted] • High levels of creatine kinase activity were detected in the spinal cord of JG flounder. • Creatine-treated flounder displayed a higher locomotor activity and less struggling behavior. • U-II and PA in spinal cord, AchR and UTR in muscle were up-regulated in the creatine-treated flounder. • UI and slc6a8 mRNA in brain was significantly decreased in the creatine-treated flounder. [ABSTRACT FROM AUTHOR]

CO 2 exposure has been used to investigate the panicogenic response in patients with panic disorder. These patients are more sensitive to CO 2 , and more likely to experience the "false suffocation alarm" which triggers panic attacks. Imbalances in locus coeruleus noradrenergic (LC-NA) neurotransmission are responsible for psychiatric disorders, including panic disorder. These neurons are sensitive to changes in CO 2 /pH. Therefore, we investigated if LC-NA neurons are differentially activated after severe hypercapnia in mice. Further, we evaluated the participation of LC-NA neurons in ventilatory and panic-like escape responses induced by 20% CO 2 in male and female wild type mice and two mouse models of altered LC-NA synthesis. Hypercapnia activates the LC-NA neurons, with males presenting a heightened level of activation. Mutant males lacking or with reduced LC-NA synthesis showed hypoventilation, while animals lacking LC noradrenaline present an increased metabolic rate compared to wild type in normocapnia. When exposed to CO 2 , males lacking LC noradrenaline showed a lower respiratory frequency compared to control animals. On the other hand, females lacking LC noradrenaline presented a higher tidal volume. Nevertheless, no change in ventilation was observed in either sex. CO 2 evoked an active escape response. Mice lacking LC noradrenaline had a blunted jumping response and an increased freezing duration compared to the other groups. They also presented fewer racing episodes compared to wild type animals, but not different from mice with reduced LC noradrenaline. These findings suggest that LC-NA has an important role in ventilatory and panic-like escape responses elicited by CO 2 exposure in mice. • Hypercapnia activates the LC-NA neurons, with males presenting a heightened level of activation. • Mutant males lacking or with reduced LC-NA synthesis showed hypoventilation. • Mutant males lacking LC-NA systhesis had a lower respiratory frequency, while mutant females showed a higher tidal volume under CO 2. • Mice lacking LC noradrenaline had a blunted jumping response and an increased freezing duration compared to the other groups. [ABSTRACT FROM AUTHOR]

A context can be conceptualized as a stable arrangement of elements or as the sum of single elements. Both configural and elemental representations play a role in associative processes. This study aimed to explore the respective contributions of these two representations of a context in the acquisition of conditioned anxiety in humans. Virtual reality (VR) can be an ecologically valid tool to investigate context-related mechanisms, yet the influence of the sense of presence within the virtual environment remains unclear. Forty-eight healthy individuals participated in a VR-based context conditioning wherein electric shocks (unconditioned stimulus, US) were unpredictably delivered in one virtual office (CTX+), but not in the other (CTX-). During the test phase, nine elements from each context were presented singularly. We found a cluster of participants, who exhibited heightened anticipation of the US for anxiety-related elements as compared to the other group. In contrast to their clear elemental representation, these individuals showed diminished discriminative responses between the two context's configurations. Discriminative responses to the contexts were boosted in those individuals, who had a weaker elemental representation. Importantly, the individual sense of presence significantly influenced the conditioned responses. These findings align with the dual-representation view of context and provide insights into the role of presence in eliciting (conditioned) anxiety responses. [ABSTRACT FROM AUTHOR]

• The preliminary background discharge in the IEC chamber has a significant impact on the device operation modes. • The preionization voltage positive polarity for pulse IEC device ensures the stable volume glow discharge combustion with a constant discharge current. • A pre-discharge current for pulse IEC chamber causes the main discharge current amplitude to increase several times. • Pulse IEC device neutron parameters could be estimated from the discharge power pulse. • Pulse IEC device can achieve neutron (2.5 MeV) fluxes of 106 neutrons/s at a frequency of 100 Hz. The paper discusses the operation features of the inertial electrostatic plasma confinement (IEC) devices in the pulsed high voltage mode. The pulse operation mode offers significant advantages in IEC devices, which are associated with high discharge currents that are inaccessible for continuous operating modes. However, the implementation of such operating modes is associated with a number of physical limitations and technical difficulties. A stand with an IEC chamber powered by a high-voltage pulse transformer and a unit for gas preliminary ionization in the IEC chamber has been developed. In the chamber, ions are accelerated from a background glow discharge. A study of the burning background discharge in the IEC chamber, background discharge current I pre influence on the duration of current and voltage pulses of the main discharge and the delay between them was carried out. The results of the neutron yield measuring in an IEC chamber operating in pulsed mode are presented at a charging voltage up to 105 kV, a discharge current amplitude of several tens of amperes, a preionization current of 8 mA, and a pulse repetition rate from single to 300 Hz. A stable neutron flux with an energy of 2.5 MeV at a level of 106 neutrons/s was experimentally obtained. [ABSTRACT FROM AUTHOR]

[Display omitted] • Amygdala glutamatergic neurons suppress auditory neurotransmission in vitro. • Amygdala glutamatergic neurons likely act on GlyT2+ neurons not auditory afferents. • Activation of brainstem GlyT2+ neurons is sufficient to induce acoustic PPI in vivo. • The contribution of brainstem GlyT2+ neurons to acoustic PPI decreases with aging. Prepulse inhibition (PPI) of the auditory startle response, a key measure of sensorimotor gating, diminishes with age and is impaired in various neurological conditions. While PPI deficits are often associated with cognitive impairments, their reversal is routinely used in experimental systems for antipsychotic drug screening. Yet, the cellular and circuit-level mechanisms of PPI remain unclear, even under non-pathological conditions. We recently showed that brainstem neurons located in the caudal pontine reticular nucleus (PnC) expressing the glycine transporter type 2 (GlyT2±) receive inputs from the central nucleus of the amygdala (CeA) and contribute to PPI but via an uncharted pathway. Here, using tract-tracing, immunohistochemistry and in vitro optogenetic manipulations coupled to field electrophysiological recordings, we reveal the neuroanatomical distribution of GlyT2± PnC neurons and PnC-projecting CeA glutamatergic neurons and we provide mechanistic insights on how these glutamatergic inputs suppress auditory neurotransmission in PnC sections. Additionally, in vivo experiments using GlyT2-Cre mice confirm that optogenetic activation of GlyT2± PnC neurons enhances PPI and is sufficient to induce PPI in young mice, emphasizing their role. However, in older mice, PPI decline is not further influenced by inhibiting GlyT2± neurons. This study highlights the importance of GlyT2± PnC neurons in PPI and underscores their diminished activity in age-related PPI decline. [ABSTRACT FROM AUTHOR]

Cisplatin is an effective chemotherapy agent against various solid malignancies; however, it is associated with irreversible bilateral sensorineural hearing loss, emphasizing the need for drug development to prevent this complication, with the current options being very limited. Rho-associated coiled-coil-containing protein kinase (ROCK) is a serine-threonine protein kinase involved in various cellular processes, including apoptosis regulation. In this study, we used a transgenic zebrafish model (Brn3C: EGFP) in which hair cells within neuromasts are observed in green under fluorescent microscopy without the need for staining. Zebrafish larvae were exposed to cisplatin alone or in combination with various concentrations of Y-27632, a potent ROCK inhibitor. Hair cell counts, apoptosis assessments using the terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling assay, FM1-43FX labeling assay and behavioral analyses (startle response and rheotaxis) were performed to evaluate the protective effects of Y-27632 against cisplatin-induced ototoxicity. Cisplatin treatment reduced the number of hair cells in neuromasts, induced apoptosis, and impaired zebrafish larval behaviors. Y-27632 demonstrated a dose-dependent protective effect against cisplatin-induced hair cell loss and apoptosis. These findings suggest that Y-27632, as a ROCK inhibitor, mitigates cisplatin-induced hair cell loss and associated ototoxicity in zebrafish. [Display omitted] • Y-27632 protects zebrafish hair cells from cisplatin damage. • Y-27632 prevents cisplatin-induced apoptosis in hair cells. • Y-27632 shows potential in preserving behavioral responses. [ABSTRACT FROM AUTHOR]

Protein lysine modifications (PLMs) are hotspots of post-translational modifications and are involved in many diseases; however, their role in human sperm remains obscure. This study examined the presence and functional roles of a classical PLM (lysine acetylation, Kac) and three novel PLMs (lysine malonylation, Kmal; lysine succinylation, Ksucc; lysine crotonylation, Kcr) in human sperm. Immunoblotting and immunofluorescence assays revealed modified proteins (15–150 kDa) in the tails of human sperm. An immunoaffinity approach coupled with liquid chromatography/tandem mass spectrometry revealed 1423 Kac sites in 680 proteins, 196 Kmal sites in 118 proteins, 788 Ksucc sites in 251 proteins, and 1836 Kcr sites in 645 proteins. These modified proteins participate in a variety of biological processes and metabolic pathways. Crosstalk analysis demonstrated that proteins involved in the sperm energy pathways of glycolysis, oxidative phosphorylation, the citrate cycle, fatty acid oxidation, and ketone body metabolism were modified by at least one of these modifications. In addition, these modifications were found in 62 male fertility-related proteins that weave a protein-protein interaction network associated with asthenoteratozoospermia, asthenozoospermia, globozoospermia, spermatogenic failure, hypogonadotropic hypogonadism, and polycystic kidney disease. Our findings shed light on the functional role of PLMs in male reproduction. Protein lysine modifications (PLMs) are hotspots of posttranslational modifications and are involved in many diseases. This study revealed the presence of a classical PLM (lysine acetylation) and three novel PLMs (lysine malonylation, lysine succinylation, and lysine crotonylation) in human sperm tails. The modified proteins participate in a variety of biological processes and metabolic pathways. In addition, these modifications were found in 62 male infertility-associated proteins and could serve as potential diagnostic markers and therapeutic targets for male infertility. [Display omitted] • Lysine acetylation, malonylation, succinylation, and crotonylation were detected in human sperm tails. • The modified proteins participate in a variety of biological processes and metabolic pathways. • Crosstalk analysis showed the enrichment of modified proteins in sperm energy pathways. • The 62 modified male fertility-related proteins constitute a PPI network of male infertility. [ABSTRACT FROM AUTHOR]

Although observational fear learning has been implicated in the development of phobic-related fears, studies investigating observational learning of fear of bodily symptoms remain scarce. Therefore, the aim of the present study was to investigate whether fear in response to bodily symptoms can be acquired simply by observing a fearful reaction to provocation of aversive bodily symptoms in others. Forty healthy participants underwent an observational fear conditioning paradigm consisting of two phases. In the first phase, participants observed a demonstrator reacting to an aversive bodily symptom provocation (unconditioned stimulus or US, i.e., labored breathing) paired with one conditioned stimulus (CS+) but not with the other one (CS-, both CSs were geometric symbols presented on a screen the demonstrator was watching). In the second phase, participants were directly presented with the same conditioned stimuli, but in the absence of the US. Our results revealed enhanced conditioned fear responses in the beginning of the second phase to the CS + as compared to CS-, as indexed by greater skin conductance and subjective fear responses, as well as greater potentiation of startle eyeblink responses to the CS + as compared to the ITI. Taken together, these findings implicate that fear of bodily symptoms can be learned through observation of others, that is, without first-hand experience of bodily threat. • This study investigates whether fear is acquired by observing others' reactions to aversive bodily symptoms (i.e., restricted breathing). • Participants displayed greater physiological and subjective fear responses to threat conditioned cue after observational learning. • Fear of bodily symptoms can be learned through observation, even without first-hand experience of aversive bodily symptoms. • Observational fear learning of interoceptive threat contributes to etiology of panic and somatic symptom disorders. [ABSTRACT FROM AUTHOR]

• Conducting ex vivo chemical composition analysis of Xintongtai granule using UPLC-Q-TOF-MS/MS technology, we achieved high-resolution and high-sensitivity component detection. This has provided an advanced tool for in-depth research on traditional Chinese medicine formulations. • Successful attribution and analysis of the chemical composition of Xintongtai granule revealed their complex pharmacologically active components, laying the foundation for a deeper understanding of the mechanisms underlying traditional Chinese medicine in the treatment of atherosclerosis. • Through the study of medicated serum, the successful identification of the bloodstream components of Xintongtai Granule has been achieved, providing crucial clues for a deeper understanding of the metabolism and distribution of traditional Chinese medicine in the body. • Building upon the bloodstream components, a network pharmacology study was conducted, revealing the multi-level regulatory mechanisms of Xintongtai Granule on atherosclerosis. This provides profound theoretical support for the development of traditional Chinese medicine in the treatment of cardiovascular diseases. A serum medicinal chemistry analysis was performed to investigate the pharmacological basis of Xintongtai granule and to predict the potential mechanism of anti-atherosclerotic action based on the blood components. UPLC-Q-TOF-MS/MS was used to analyze the in vitro chemical composition and in vivo blood components of Xintongtai granule, and to detect the blood drug concentration. The PPI network was constructed by collecting blood components and disease targets through the network pharmacology method, and the key targets were subjected to GO and KEGG functional enrichment analyses, so as to construct the topology network of drug-component-target-disease, and to validate the network by molecular docking. The UPLC-Q-TOF-MS/MS analysis identified 69 chemical components in Xintongtai granule, including 19 prototype circulating components and 9 metabolites in the bloodstream. Network pharmacology analysis revealed 115 intersecting targets for the circulating components, from which 10 core targets were selected. GO and KEGG analyses unveiled associated signaling pathways and biological processes. The construction of a topology network and preliminary molecular docking provided insights into its mechanism of action. The mechanism underlying the anti- atherosclerosis effect of Xintongtai granule may be associated with the intervention of active components such as Cryptotanshinone, Kaempferitrin, and Puerarin in pathways targeting CXCL8, STAT3, TNF, and other related targets. [ABSTRACT FROM AUTHOR]

The chorion is the first protective barrier set to prevent numerous pollutants from damaging the developing embryo. However, depending on their size, some nanoplastics (NPs) can pass through this barrier and reach the embryo, while all microplastics (MPs) remain on the outside. This study brings a straight approach to compare MPs and NPs, and assess their direct and indirect effects on zebrafish embryos and larvae. Zebrafish eggs were exposed before 2 h post fertilization (hpf) to polystyrene MPs (5 μm) and NPs (250 nm) at a concentration of 1000 μg/L until 96 hpf. Physiotoxicity and neurotoxicity were assessed prior and post-hatching through several biomarkers. Response to hypoxia (upregulation of hif-1aa and hif-1ab) were found in embryos exposed to MPs, and partly found in those exposed to NPs. Embryos exposed to NPs showed significant tachycardia, reduced O 2 consumption and increased apoptosis in the eyes, whereas MPs affected the expressions of all genes related to the neurodevelopment of embryos (elavl3, pax2a, pax6a, act1b). Post-hatching, physiological responses were muted. MPs and NPs exposures ended by evaluating larval behaviours during dark-and-light cycles. Both sizes of plastic particles negatively affected the visual motor response (VMR) and vibrational startle response (VSR). Thigmotaxis levels were significantly increased by NPs whereas MPs showed anxiolytic properties. This study shows that both MPs and NPs affect the physiology and neurodevelopment of zebrafish at different levels, before and after hatching. [Display omitted] • Nm nanoplastics (NPs) can pass through the pores of the zebrafish chorion. • Microplastics (MPs) induce greater hypoxia than NPs in the embryos. • NPs disrupt the physiology of embryos. • Gene expressions linked to neurological development are up-regulated by MPs. • NPs and MPs modify larval behaviour in different ways. [ABSTRACT FROM AUTHOR]

Constant change in global climate has become the most important limiting factor to crop productivity. Asymmetrical precipitations are causing recurrent flood events around the world. Submergence is one of the most detrimental abiotic stresses for sustainable rice production in the rainfed ecosystems of Southeast Asia. Therefore, the development of submergence-tolerant rice is an essential requirement to encounter food security. Submergence tolerance in rice is governed by the major quantitative trait locus (QTL) designated as Submergence1 (Sub1) near the centromere of chromosome 9. The introduction of the Sub1 in high-yielding rice varieties producing near-isogenic lines (NILs) has shown extreme submergence tolerance. The present study aimed to understand the responses of rice genotype IR64 and its Sub1 NIL IR64 Sub1 following one week of complete submergence treatment. Submergence imposed severe nitro-oxidative stress in both the rice genotypes, consequently disrupting the cellular redox homeostasis. In this study, IR64 exhibited higher NADPH oxidase activity accompanied by increased reactive oxygen species, reactive nitrogen species, and malondialdehyde buildups and cell death under submergence. Higher accumulations of 1-Aminocyclopropane-1-carboxylic acid, gibberellic acid, and Indole-3-acetic acid were also observed in IR64 which accelerated the plant growth and root cortical aerenchyma development following submergence. In contrast, IR64 Sub1 had enhanced submergence tolerance associated with an improved antioxidant defense system with sustainable morpho-physiological activities and restricted root aerenchyma formation. The comprehensive analyses of the responses of rice genotypes with contrasting submergence tolerance may demonstrate the intricacies of rice under complete submergence and may potentially contribute to improving stress resilience by advancing our understanding of the mechanisms of submergence tolerance in rice. [Display omitted] • IAA induces lateral root formation in rice under submergence • ROS and RNS cause lysigenous aerenchyma formation in root cortex of rice • Submergence decreases ABA level, causing GA-mediated escape response in rice shoot • Enhanced antioxidant levels dampen nitro-oxidative damage during de-submergence [ABSTRACT FROM AUTHOR]

The success of cancer treatment relies on the composition of the tumour microenvironment which is comprised of tumour cells, blood vessels, stromal cells, immune cells, and extracellular matrix components. Barriers to effective cancer treatment need to be overcome, and the acidic microenvironment of the tumour provides a key target for treatment. This review intends to provide an overview of the effects that low extracellular pH has on components of the tumour microenvironment and how they contribute to immune escape. Further, potential therapeutic targets will be discussed. [ABSTRACT FROM AUTHOR]

As SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) continues to inflict chaos globally, a new variant officially known as B.1.1.529 was reported in South Africa and was found to harbor 30 mutations in the spike protein. It is too early to speculate on transmission and hospitalizations. Hence, more analyses are required, particularly to connect the genomic patterns to the phenotypic attributes to reveal the binding differences and antibody response for this variant, which can then be used for therapeutic interventions. Given the urgency of the required analysis and data on the B.1.1.529 variant, we have performed a detailed investigation to provide an understanding of the impact of these novel mutations on the structure, function, and binding of RBD to hACE2 and mAb to the NTD of the spike protein. The differences in the binding pattern between the wild type and B.1.1.529 variant complexes revealed that the key substitutions Asn417, Ser446, Arg493, and Arg498 in the B.1.1.529 RBD caused additional interactions with hACE2 and the loss of key residues in the B.1.1.529 NTD resulted in decreased interactions with three CDR regions (1–3) in the mAb. Further investigation revealed that B.1.1.529 displayed a stable dynamic that follows a global stability trend. In addition, the dissociation constant (K D), hydrogen bonding analysis, and binding free energy calculations further validated the findings. Hydrogen bonding analysis demonstrated that significant hydrogen bonding reprogramming took place, which revealed key differences in the binding. The total binding free energy using MM/GBSA and MM/PBSA further validated the docking results and demonstrated significant variations in the binding. This study is the first to provide a basis for the higher infectivity of the new SARS-CoV-2 variants and provides a strong impetus for the development of novel drugs against them. [ABSTRACT FROM AUTHOR]

Latah is a culture-specific syndrome characterized by exaggerated startle response, echolalia, palilalia, echopraxia, coprolalia, forced obedience and involuntary vocalization in response to startle. Latah is stimulus-induced and is associated with behavior and psychiatric features. The aim of this review is to provide a comprehensive description on latah from a regional perspective based on previous literature and clinical experiences and highlight the clinical characteristics of latah from a movement disorders perspective. The pathophysiology of latah is complex and poorly understood although psychological stressors have been implicated. In view of the distressing psychosocial impact of latah, this neuropsychiatric startle syndrome warrants further studies to understand the pathophysiology and identify the appropriate treatments. [ABSTRACT FROM AUTHOR]

This study simulates the hydrothermal conditions that existed on carbonaceous chondrite planetesimals in the early solar system. Our experiments are relevant to alteration conditions that existed on the CV parent body and the late stage oxidizing alteration of the CM chondrites. We conducted 11 alteration experiments using chips of the CO3 chondrite Kainsaz. Water was added to each chip and sealed in separate Teflon reaction vessels for 175 days. Samples were altered at different initial water-to-rock ratios (W/R: 0.2–0.8) and temperatures (50 °C and 150 °C). Isotopically doped 17O-rich heavy water (δ17O: +64.5‰) was used in five runs. All samples experienced pronounced alteration under a partially open system environment where gases were able to escape the reaction vessels. The style of alteration (Fe-alkali metasomatism) is similar in all cases. The principal alteration minerals formed are Fe-oxyhydroxides (goethite) and Fe-oxides (magnetite), with smaller quantities of Fe-sulphides. Minor phases formed include fayalite, sulphates (gypsum and Fe-sulphate) and calcite. Nanophase, poorly crystalline phyllosilicates formed in the high-temperature samples but are absent from the low-temperature experiments. In all instances, Mg-rich chondrule silicates remained chemically unaltered although some grains suffered hydrothermal fracture. Chondrule mesostases remained largely unaffected. By contrast, kamacite readily dissolved, acting as a source of Fe and Ni for the fluid phase. A new generation of nanophase Fe-sulphides formed within the matrix, while pre-existing pyrrhotite group sulphides experienced Ni enrichment (<3 at%). In the high temperature samples these sulphides were also partially oxidized, lowering their (Fe + Ni)/S ratio. High-Ni sulphides (pyrrhotite with Ni > 10 at%) were formed in the 150 °C samples, most likely by sulphidation of taenite. Matrix alteration cemented grains together, reducing porosity. The fine-grained matrix shows highly variable degrees of alteration, with minimally altered matrix in direct contact with regions of heavily altered matrix. Chondrule fine-grained rims (FGRs) were preferentially altered. These textures imply that the unaltered matrix readily reacted with the fluid phase, resulting in an efficient depletion of dissolved ions (Fe2+ and S2-), limiting reactivity until further primary phases were dissolved. At larger length-scales the distribution of heavily altered matrix reveals the presence of large ∼100 µm wide channels that meander through the specimens. Their textures resemble features seen in some CM chondrites and the ungrouped CO-like chondrite MIL 07687. We suggest that alteration fronts developed by sustained rapid reaction of matrix with dissolved cations in solution. Our observations provide a mechanism for the establishment and maintenance of geochemical microenvironments on chondritic asteroids. The effects of open system loss notwithstanding, our experiments demonstrate that more advanced alteration is correlated with higher initial W/R ratios. The use of 17O-rich doped water allowed the isotopic effects of aqueous alteration to be observed. Bulk rock compositions evolved towards the initial water composition, reflecting the incorporation of heavy O into hydrated minerals. Additionally, altered samples shifted in δ18O space, reflecting the competing effects of water–mineral fractionation and mass fractionation due to the preferential escape of isotopically light water. [ABSTRACT FROM AUTHOR]

• Evolutionary functions of play. • Neuroanatomical underpinning of play. • Role of the Parafascicular nucleus in play. • Functional circuits of play. • Gating, set-shifting and prepulse inhibition and its role in Play. Play has been recognized as a complex and diverse set of behaviors that has been difficult to define. Play can range from rough and tumble play among rats to a human child playing a computer game. Play has been understood to exist in multiple forms such as social, object, and locomotor (Burghardt, 2005). In this article we review the literatures on the neural basis of social play, on heart rate variability, on behavioral switching and set-shifting, on prepulse inhibition of the acoustic startle reflex, and on learning at the level of the basal ganglia. Each of these neuronal pathways, aside from heart rate variability, is rooted in the parafascicular nucleus of the thalamus, an important neural substrate for social play. We argue that social play optimally balances a number of opposing neural pathways by engaging systems involved in safety versus danger (heart rate variability), automatized reactions versus learned reactions to new stimuli (behavioral switching and set-shifting), and gating relevant versus less relevant stimuli (prepulse inhibition of the acoustic startle reflex). The idea that play, in addition to its role in interpersonal adaptation to social life, may have a central role in optimizing flexibility and creativity in individual response to novelty has been explored by previous authors (Huizinga, 1955 ; Spinka et al., 2001; Pellegrini et al., 2007; Pellis and Pellis, 2017). In this paper we explore the possible underlying neural basis for this function of play, having to do with balancing various neural networks, and in doing so propose an expanded understanding of the nature and function of social play. [ABSTRACT FROM AUTHOR]

The present study aims at comparing the effects of two subtypes of cognitive reappraisal (i.e., stimulus-focused vs. goal-based reappraisal) to reduce anticipatory anxiety of pain. Affective ratings, startle reflex, and autonomic measures (electrodermal and heart rate changes) were used as a measure of emotion regulation success. A total of 86 undergraduate students completed an anticipatory task in which they had to regulate their negative emotions or react naturally when faced with the possibility of receiving a painful thermal stimulus. Participants were randomly assigned to two experimental groups to compare the stimulus-focused and goal-based strategies explored here. Our results revealed enhanced self-reported anxiety, electrodermal activity and eyeblink response when participants tried to voluntarily down-regulate their negative emotions, compared to the control instruction. Differences between both cognitive reappraisal groups were not found. These unexpected findings suggest that brief reappraisal instructions may not necessarily be favorable for regulating emotions during anticipation of aversive events. Moreover, these results are further explained in terms of the pain expectation, the painful stimuli modality, and emotion regulation instructions. • Pain anticipation task with instructed emotion regulation (ER) for threatening trials. • No differences between stimulus-focused and goal-based reappraisal were found. • Down-regulation was associated to higher anxiety levels during threat of pain vs. control condition. • Reappraising the threat was associated to higher electrodermal activity and eyeblink responses. • Brief ER instructions might not be efficient to reduce anticipatory anxiety to pain. [ABSTRACT FROM AUTHOR]

Diagnostic criteria of subacute sclerosing panencephalitis (SSPE) include myoclonus, a well-recognized clinical feature. Here, we studied the electrophysiological features of myoclonus with regards to disease staging in SSPE patients. We included 10 patients diagnosed with SSPE between 2010 and 2018, along with 21 healthy subjects. All participants had detailed electrophysiological evaluation including polymyographic analysis, blink reflex after trigeminal stimulation, auditory startle response, startle response after somatosensory stimuli, F-waves, and long-loop reflexes. Clinical findings were retrieved from the medical records. Patients were categorized into Gascon stage 2B (n = 5, 50%), 2A (n = 2, 20%), 3B (n = 2, 20%) and 4A (n = 1, 10%) at the time of electrophysiological evaluation. Two patients had cortical myoclonus, four had possible cortico-subcortical myoclonus, and four had brainstem myoclonus. Patients were categorized into Gascon stages 2a and 2b had possible cortico-subcortical myoclonus (85.7%). However, none of the patients with stage 3b or 4a had possible cortico-subcortical subtype but all had the brainstem subtype. Association was seen between subtypes of myoclonus and clinical staging in SSPE. This suggests that myoclonus in SSPE may primarily involve the cortex and cortico-subcortical structures such as the thalamus at earlier stages of disease, and then involve more caudal structures as the disease progresses. [ABSTRACT FROM AUTHOR]

• Validity of auditory prepulse inhibition paradigm was examined. • Responses to prepulse and test stimulus are evaluated. • P50, N100, and P200 components of the change-related response were used. • Results showed good reproducibility of the response and suppression. Prepulse inhibition (PPI) is a neurological phenomenon in which a weak initial stimulus reduces the level of responses to a subsequent stronger stimulus. Although acoustic startle reflexes are usually used for PPI examinations, recent studies have observed similar phenomena with event-related cortical potentials. In the present study, test-retest reliability of PPI measured using auditory change-related cortical responses was assessed in 35 healthy adults. Four sound stimuli were randomly presented at an even probability; Standard, Test alone, Prepulse alone, and Test + Prepulse. The Standard stimulus was a train of 25-ms tone pulses at 70 dB for 650 ms, while for Test alone and Prepulse alone, the sound pressure was increased to 80 dB at 350 ms and 73 dB at 300 ms, respectively. Measurements were performed twice with at least 7 days separation, and validity was evaluated using intra-class correlation (ICC) for latency, amplitude, and suppression rate of the P50, N100, and P200 components. The results showed high ICC values for the latency and amplitude of nearly all components, except for response to Prepulse alone (0.3–0.6). Furthermore, ICC for suppression rate was greater than 0.5 for the peak-to-peak amplitude. Good reproducibility for N100 and P200 components was obtained with this method. The present results support the PPI paradigm as a reliable tool for clinical measurements of inhibitory functions. [ABSTRACT FROM AUTHOR]

Background: The auditory startle reflex (ASR) is enlarged in patients with functional movement disorders (FMD).Objectives: To study whether the ASR relates to symptom reduction in FMD patients, who participated in a placebo controlled double blind treatment trial with Botulinum Neurotoxin (BoNT).Methods: Response to treatment in the BoNT study was assessed using the Clinical Global Impression - Improvement scale (CGI-I). The electromyography (EMG) muscle activity of 7 muscles following 110 dB tones was measured in 14 FMD patients before and after one-year treatment and compared to 11 matched controls. The early and a late (behaviorally affected) component of the ASR and the sympathetic skin response (SSR) were assessed.Results: 10 of 14 patients (71.4%) showed symptom improvement, which was believed to be mainly caused by placebo effects. The early total response probability of the ASR at baseline tended to be larger in patients compared to controls (p = 0.08), but normalized at follow-up (p = 0.84). The late total response probability was larger in patients vs. controls at baseline (p < 0.05), a trend that still was present at follow-up (p = 0.08). The SSR was higher in patients vs. controls at baseline (p < 0.01), and normalized at follow-up (p = 0.71).Conclusions: On a group level 71.4% of the patients showed clinical symptom improvement after treatment. The early part of the ASR, most likely reflecting anxiety and hyperarousal, normalized in line with the clinical improvement. Interestingly, the augmented late component of the ASR remained enlarged suggesting persistent altered behavioral processing in functional patients despite motor improvement. [ABSTRACT FROM AUTHOR]

With the increasing use of triazole fungicides in agriculture, triazole pesticides have aroused great concern about their toxicity and ecological risk. The current study investigated the impairments of embryonic exposure to fenbuconazole (FBZ) on cardiac transgenerational toxicity and related mechanisms. The fertilized eggs were exposed to 5, 50 and 500 ng/L FBZ for 72 h, and the larvae were then raised to adulthood in clean water. The adult fish were mated with unexposed fish to produce maternal and paternal F1 and F2 embryos, respectively. The results showed that increased arrhythmia were observed in F0, F1 and F2 larvae. Transcriptome sequencing indicated that the pathway of adrenergic signaling in cardiomyocytes was enriched in F0 and F2 larvae. In both F0 and F1 adult zebrafish hearts, ADRB2 protein expression decreased, and transcription of genes related to cardiac development and Ca2+ homeostasis was downregulated. These alterations might cause cardiac developmental defects. Significantly decreased protein levels of H3K9Ac and H3K14Ac might be linked with the downregulation in transcription of cardiac development genes. Protein‒protein interaction analysis exhibited that the pathway affecting the heart was well inherited in the paternal line. These results provide new ideas for the analysis and prevention of congenital heart disease. [Display omitted] • Embryonic exposure to FBZ caused cardiac defects which continued to F2 zebrafish. • RNA-seq enriched main action pathway the adrenergic signaling in cardiomyocytes. • The expression of ADRB2 protein and key genes were reduced in F0 and F1 adult hearts. • PPI analysis showed that the action molecules were well inherited in the paternal line. • Alterations in histone acetylation levels were persisted in adult zebrafish hearts. Capsule: Cardiac defects caused by embryonic exposure to FBZ were persisted to F2 larvae, the underlying mechanisms might be related to persistent alterations in histone acetylation levels. [ABSTRACT FROM AUTHOR]

• A large-scale blood transcriptome profiling dataset was constructed. • Our study noted NK cells and type I interferon signaling pathway changes in IgAN. • Five key genes were significantly associated with clinical parameters and prognosis. • Predicted therapeutic drugs may offer promising treatment strategies. IgA nephropathy (IgAN) is the most prevalent form of glomerulonephritis. Unfortunately, molecular biomarkers for IgAN derived from omics studies are still lacking. This research aims to identify critical genes associated with IgAN through large-scale blood transcriptome analysis. We constructed novel blood transcriptome profiles from peripheral blood mononuclear cells (PBMCs) of 53 Chinese IgAN patients and 28 healthy individuals. Our analysis included GO, KEGG, and GSEA for biological pathways. We analyzed immune cell profiles with CIBERSORT and constructed PPI networks with STRING, visualized in Cytoscape. Key differentially expressed genes (DEGs) were identified using CytoHubba and MCODE. We assessed the correlation between gene expressions and clinical data to evaluate clinical significance and identified hub genes through machine learning, validated with an open-access dataset. Potential drugs were explored using the CMap database. We identified 333 DEGs between IgAN patients and healthy controls, mainly related to immune response and inflammation. Key pathways included NK cell mediated cytotoxicity, complement and coagulation cascades, antigen processing, and B cell receptor signaling. Cytoscape revealed 16 clinically significant genes (including KIR2DL1 , KIR2DL3 , VISIG4 , C1QB , and C1QC , associated with sub-phenotype and prognosis). Machine learning identified two hub genes (KLRC1 and C1QB) for a diagnostic model of IgAN with 0.92 accuracy, validated at 1.00 against the GSE125818 dataset. Sirolimus, calcifediol, and efaproxiral were suggested as potential therapeutic agents. Key DEGs, particularly VISIG4 , KLRC1 , and C1QB , emerge as potential specific markers for IgAN, paving the way for future targeted personalized treatment options. [ABSTRACT FROM AUTHOR]