Remodeling of skeletal muscle myosin metabolic states in hibernating mammals.

Hibernation is a period of metabolic suppression utilized by many small and large mammal species to survive during winter periods. As the underlying cellular and molecular mechanisms remain incompletely understood, our study aimed to determine whether skeletal muscle myosin and its metabolic efficiency undergo alterations during hibernation to optimize energy utilization. We isolated muscle fibers from small hibernators, Ictidomys tridecemlineatus and Eliomys quercinus and larger hibernators, Ursus arctos and Ursus americanus. We then conducted loaded Mant-ATP chase experiments alongside X-ray diffraction to measure resting myosin dynamics and its ATP demand. In parallel, we performed multiple proteomics analyses. Our results showed a preservation of myosin structure in U. arctos and U. americanus during hibernation, whilst in I. tridecemlineatus and E. quercinus, changes in myosin metabolic states during torpor unexpectedly led to higher levels in energy expenditure of type II, fast-twitch muscle fibers at ambient lab temperatures (20 °C). Upon repeating loaded Mant-ATP chase experiments at 8 °C (near the body temperature of torpid animals), we found that myosin ATP consumption in type II muscle fibers was reduced by 77-107% during torpor compared to active periods. Additionally, we observed Myh2 hyper-phosphorylation during torpor in I. tridecemilineatus, which was predicted to stabilize the myosin molecule. This may act as a potential molecular mechanism mitigating myosin-associated increases in skeletal muscle energy expenditure during periods of torpor in response to cold exposure. Altogether, we demonstrate that resting myosin is altered in hibernating mammals, contributing to significant changes to the ATP consumption of skeletal muscle. Additionally, we observe that it is further altered in response to cold exposure and highlight myosin as a potentially contributor to skeletal muscle non-shivering thermogenesis.

Many animals use hibernation as a tactic to survive harsh winters. During this dormant, inactive state, animals reduce or limit body processes, such as heart rate and body temperature, to minimise their energy use. To conserve energy during hibernation, animals can use different approaches. For example, garden dormice undergo periodic states of extremely low core temperatures (down to 4­8^oC); whereas Eurasian brown bears see milder temperature drops (down to 23­25^oC). An important organ that changes during hibernation is skeletal muscle. Skeletal muscle typically uses large amounts of energy, making up around 50% of body mass. To survive, hibernating animals must change how their skeletal muscle uses energy. Traditionally, active myosin ­ a protein found in muscles that helps muscles to contract ­ was thought to be responsible for most of the energy use by skeletal muscle. But, more recently, resting myosin has also been found to use energy when muscles are relaxed. Lewis et al. studied myosin and skeletal muscle energy use changes during hibernation and whether they could impact the metabolism of hibernating animals. Lewis et al. assessed myosin changes in muscle samples from squirrels, dormice and bears during hibernation and during activity. Experiments showed changes in resting myosin in squirrels and dormice (whose temperature drops to 4­8^oC during hibernation) but not in bears. Further analysis revealed that cooling samples from non-hibernating muscle to 4­8^oC increased energy use in resting myosin, thereby generating heat. However, no increase in energy use was found after cooling hibernating muscle samples to 4­8^oC. This suggest that resting myosin generates heat at cool temperatures ­ a mechanism that is switched off in hibernating animals to allow them to cool their body temperature. These findings reveal key insights into how animals conserve energy during hibernation. In addition, the results show that myosin regulates energy use in skeletal muscles, which indicates myosin may be a potential drug target in metabolic diseases, such as obesity.

Remodelling of Skeletal Muscle Myosin Metabolic States in Hibernating Mammals.

Hibernation is a period of metabolic suppression utilized by many small and large mammal species to survive during winter periods. As the underlying cellular and molecular mechanisms remain incompletely understood, our study aimed to determine whether skeletal muscle myosin and its metabolic efficiency undergo alterations during hibernation to optimize energy utilization. We isolated muscle fibers from small hibernators, Ictidomys tridecemlineatus and Eliomys quercinus and larger hibernators, Ursus arctos and Ursus americanus. We then conducted loaded Mant-ATP chase experiments alongside X-ray diffraction to measure resting myosin dynamics and its ATP demand. In parallel, we performed multiple proteomics analyses. Our results showed a preservation of myosin structure in U. arctos and U. americanus during hibernation, whilst in I. tridecemlineatus and E. quercinus, changes in myosin metabolic states during torpor unexpectedly led to higher levels in energy expenditure of type II, fast-twitch muscle fibers at ambient lab temperatures (20°C). Upon repeating loaded Mant-ATP chase experiments at 8°C (near the body temperature of torpid animals), we found that myosin ATP consumption in type II muscle fibers was reduced by 77-107% during torpor compared to active periods. Additionally, we observed Myh2 hyper-phosphorylation during torpor in I. tridecemilineatus, which was predicted to stabilize the myosin molecule. This may act as a potential molecular mechanism mitigating myosin-associated increases in skeletal muscle energy expenditure during periods of torpor in response to cold exposure. Altogether, we demonstrate that resting myosin is altered in hibernating mammals, contributing to significant changes to the ATP consumption of skeletal muscle. Additionally, we observe that it is further altered in response to cold exposure and highlight myosin as a potentially contributor to skeletal muscle non-shivering thermogenesis.

Differences in auditory associative memory between younger adults and older adults.

Aging impairs visual associative memories. Up to date, little is known about whether aging impairs auditory associative memories. Using the head-related-transfer function to induce perceived spatial locations of auditory phonemes, this study used an audiospatial paired-associates-learning (PAL) paradigm to assess the auditory associative memory for phoneme-location pairs in both younger and older adults. Both aging groups completed the PAL task with various levels of difficulty, which were defined by the number of items to be remembered. The results showed that compared with younger participants' performance, older participants passed fewer stages and had lower capacity of auditory associative memory. For maintaining a single audiospatial pair, no significant behavioral differences between the two aging grous werefound. However, when multiple sound-location pairs were required to be remembered, older adults made more errors and demonstrated a lower working memory capacity than younger adults. Our study indicates aging impairs audiospatial associative learning and memory.

Impaired interaural correlation processing in people with schizophrenia.

Detection of transient changes in interaural correlation is based on the temporal precision of the central representations of acoustic signals. Whether schizophrenia impairs the temporal precision in the interaural correlation process is not clear. In both participants with schizophrenia and matched healthy-control participants, this study examined the detection of a break in interaural correlation (BIC, a change in interaural correlation from 1 to 0 and back to 1), including the longest interaural delay at which a BIC was just audible, representing the temporal extent of the primitive auditory memory (PAM). Moreover, BIC-induced electroencephalograms (EEGs) and the relationships between the early binaural psychoacoustic processing and higher cognitive functions, which were assessed by the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), were examined. The results showed that compared to healthy controls, participants with schizophrenia exhibited poorer BIC detection, PAM and RBANS score. Both the BIC-detection accuracy and the PAM extent were correlated with the RBANS score. Moreover, participants with schizophrenia showed weaker BIC-induced N1-P2 amplitude which was correlated with both theta-band power and inter-trial phase coherence. These results suggested that schizophrenia impairs the temporal precision of the central representations of acoustic signals, affecting both interaural correlation processing and higher-order cognitions.

Development of Mandarin Chinese Vowel Perception in Young Children With Normal Hearing and Cochlear Implants.

Purpose Depicting the development pattern of vowel perception for children with normal hearing (NH) and cochlear implants (CIs) would be useful for clinicians and school teachers to monitor children's auditory rehabilitation. The study was to investigate the development of Mandarin Chinese vowel perception for Mandarin Chinese native-speaking children with the ages of 4-6 years. Method Vowel identification of children with NH and CIs were tested. All children with CIs received CIs before the age of 4 years. In a picture identification task with Mandarin Chinese speech stimuli, listeners identified the target consonant-vowel word among two to four contrastive words that differed only in vowels. Each target word represented a concrete object and was spoken by a young female native Mandarin Chinese talker. The target words included 16 monophthongs, 22 diphthongs, and nine triphthongs. Results Children with NH showed significantly better identification of monophthongs and diphthongs than children with CIs at the age of 6 years, whereas the two groups had comparable performance at age of 4 and 5 years. Children with NH significantly outperformed children with CIs for triphthong identification across all three age groups. For children with NH, a rapid development of perception of all three types of vowels occurred between age 4 and 5 years with a rapid development only for monophthong perception between age 5 and 6 years. For children with CIs, a rapid development of both diphthong and triphthong perception occurred between 4 and 5 years old, but not monophthong, with no significant development between 5 and 6 years old for all three types of vowels. Overall, Mandarin-speaking children with NH achieved their ceiling performance in vowel perception before or at the age of 6 years, whereas children with CIs may need more time to reach the typical level of their peers with NH. Conclusions The development of Mandarin vowel perception for Mandarin-native children differed between preschool-age children with NH and CIs, likely due to the deficits of spectral processing for children with CIs. The results would be a supplement to the development of speech recognition in Mandarin-native children with NH and CIs.

Phosphoproteomics Identifies Significant Biomarkers Associated with the Proliferation and Metastasis of Prostate Cancer.

The spider peptide toxins HNTX-III and JZTX-I are a specific inhibitor and activator of TTX-S VGSCs, respectively. They play important roles in regulating MAT-LyLu cell metastasis in prostate cancer. In order to identify key biomarkers involved in the regulation of MAT-LyLu cell metastasis, iTRAQ-based quantitative phosphoproteomics analysis was performed on cells treated with HNTX-III, JZTX-I and blank. A total of 554 unique phosphorylated proteins and 1779 distinct phosphorylated proteins were identified, while 55 and 36 phosphorylated proteins were identified as differentially expressed proteins in HNTX-III and JZTX-I treated groups compared with control groups. Multiple bioinformatics analysis based on quantitative phosphoproteomics data suggested that the differentially expressed phosphorylated proteins and peptides were significantly associated with the migration and invasion of prostate tumors. Specifically, the toxins HNTX-III and JZTX-I have opposite effects on tumor formation and metastasis by regulating the expression and phosphorylation level of causal proteins. Herein, we highlighted three key proteins EEF2, U2AF2 and FLNC which were down-regulated in HNTX-III treated cells and up-regulated in JZTX-I treated cells. They played significant roles in cancer related physiological and pathological processes. The differentially expressed phosphorylated proteins identified in this study may serve as potential biomarkers for precision medicine for prostate cancer in the near future.

A "Brick" Mass Spectrometer with Photoionization for Direct Analysis of Trace Volatile Compounds.

With high portability and favorable performance, miniature mass spectrometers have become one of the most attractive tools for on-site analysis of trace volatile compounds. Based on the "Brick" mass spectrometer (BMS) developed previously, a hand-held BMS integrated with a photoionization source (PI-BMS) was developed in this study for volatile compound analysis. With compact dimensions of 30 cm × 18.5 cm × 27.6 cm (length × width × height), the PI-BMS was equipped with a 10.6 eV UV lamp and capable of generating molecular ions. The capabilities of qualitative and quantitative analyses for different volatile samples were demonstrated and characterized. Under optimized conditions, high detection sensitivity in open air was obtained for the PI-BMS with a limit of detection (LOD) of ∼10 ppbv. As demonstrations of mixture analysis, four different fresh fruits were directly analyzed using PI-BMS, observing characteristic mass spectra for each type of fruit.

The mediating effect of perceived social support on the relationship between mindfulness and burnout in special education teachers.

This study aimed to explore the mediating effect of perceived social support on the relationship between mindfulness and burnout in Chinese special education teachers. Three hundred and seven teachers completed the Five-Facet Mindfulness Questionnaire, Multi-dimensional Scale of Perceived Social Support Scale, and Teacher Burnout Inventory. The results showed that burnout was negatively correlated with mindfulness and perceived social support, while perceived social support was positively correlated with mindfulness. Moreover, perceived social support partially mediated the effect of mindfulness on special education teachers' burnout. These results suggest that the use of mindfulness combined with perceived social support may be beneficial for preventing and mitigating burnout among special education teachers.

Mechanistic insights into Nav1.7-dependent regulation of rat prostate cancer cell invasiveness revealed by toxin probes and proteomic analysis.

Voltage-gated sodium channels are involved in tumor metastasis, as potentiating or attenuating their activities affects the migration and invasion process of tumor cells. In the present study, we tested the effect of two peptide toxins, JZTX-I and HNTX-III which function as Nav1.7 activator and inhibitor, respectively, on the migration and invasion ability of prostate cancer (PCa) cell line Mat-LyLu. These two peptides showed opposite effects, and subsequently a comparative proteomic analysis characterized 64 differentially expressed membrane proteins from the JZTX-I- and HNTX-III-treated groups. Among these, 15 proteins were down-regulated and 49 proteins were up-regulated in the HNTX-III group. Bioinformatic analysis showed eight proteins are cytoskeleton proteins or related regulators, which might play important roles in the metastasis of Mat-LyLu cells. The altered expressions of four of these proteins, fascin, muskelin, annexin A2, and cofilin-1, were validated by western blot analysis. Further function network analysis of these proteins revealed that the Rho family GTPases RhoA and Rac1 might be of particular importance for the rat PCa cell invasion. Pharmacological data revealed that JZTX-I and HNTX-III could modulate the Rho signaling pathway in a Nav1.7-dependent manner. In summary, this study suggests that the Nav1.7-dependent regulation of Rho GTPase activity plays a vital role in Mat-LyLu cell migration and invasion and provides new insights into the treatment of PCa.

Naja atra venom peptide reduces pain by selectively blocking the voltage-gated sodium channel Nav1.8.

The voltage-gated sodium channel Nav1.8 is preferentially expressed in peripheral nociceptive neurons and contributes to inflammatory and neuropathic pain. Therefore, Nav1.8 has emerged as one of the most promising analgesic targets for pain relief. Using large-scale screening of various animal-derived toxins and venoms for Nav1.8 inhibitors, here we identified µ-EPTX-Na1a, a 62-residue three-finger peptide from the venom of the Chinese cobra (Naja atra), as a potent inhibitor of Nav1.8, exhibiting high selectivity over other voltage-gated sodium channel subtypes. Using whole-cell voltage-clamp recordings, we observed that purified µ-EPTX-Na1a blocked the Nav1.8 current. This blockade was associated with a depolarizing shift of activation and repolarizing shift of inactivation, a mechanism distinct from that of any other gating modifier toxin identified to date. In rodent models of inflammatory and neuropathic pain, µ-EPTX-Na1a alleviated nociceptive behaviors more potently than did morphine, indicating that µ-EPTX-Na1a has a potent analgesic effect. µ-EPTX-Na1a displayed no evident cytotoxicity and cardiotoxicity and produced no obvious adverse responses in mice even at a dose 30-fold higher than that producing a significant analgesic effect. Our study establishes µ-EPTX-Na1a as a promising lead for the development of Nav1.8-targeting analgesics to manage pain.

Both Val158Met Polymorphism of Catechol-O-Methyltransferase Gene and Menstrual Cycle Affect Prepulse Inhibition but Not Attentional Modulation of Prepulse Inhibition in Younger-Adult Females.

Prepulse inhibition (PPI) can be modulated by both the Val158Met (rs4680) polymorphism of the Catechol-O-Methyltransferase (COMT) gene and the menstrual-cycle-related hormone fluctuations, each of which affects the subcortical/cortical dopamine metabolism. PPI can also be modulated by attention. The attentional modulation of PPI (AMPPI) is sensitive to psychoses. Whether the Val158Met polymorphism affects the AMPPI in female adults at different menstrual-cycle phases is unknown. This study examined whether AMPPI and/or PPI are affected by the Val158Met polymorphism in 177 younger-adult females whose menstrual cycles were mutually different across the menstruation, proliferative, or secretory phases. The AMPPI was evaluated by comparing PPI under the condition of the auditory precedence-effect-induced perceptual spatial separation between the prepulse stimulus and a masking noise (PPIPSS) against that under the condition of the precedence-effect-induced perceptual spatial co-location (PPIPSC). The results showed that both the menstrual cycle and the COMT Val158Met polymorphism affected both PPIPSC and PPIPSS, but not the AMPPI (difference between PPIPSS and PPIPSC). Moreover, throughout the menstrual cycle, both PPIPSC and PPIPSS decreased monotonously in Val/Val-carrier participants. However, the decreasing pattern was not overserved in either Met/Met-carrier or Met/Val-carrier participants. Thus, in healthy younger-adult females, PPIPSC and PPIPSS, but not the AMPPI, is vulnerable to changes of ovarian hormones, and the COMT Val158Met polymorphism also has a modulating effect on this menstrual-cycle-dependent PPI variation. In contrast, the AMPPI seems to be more steadily trait-based, less vulnerable to ovarian hormone fluctuations, and may be useful in assisting the diagnosis of schizophrenia in female adults.

Auditory spatial attention modulates the unmasking effect of perceptual separation in a "cocktail party" environment.

The perceptual separation between a signal speech and a competing speech (masker), induced by the precedence effect, plays an important role in releasing the signal speech from the masker, especially in a reverberant environment. The perceptual-separation-induced unmasking effect has been suggested to involve multiple cognitive processes, such as selective attention. However, whether listeners' spatial attention modulate the perceptual-separation-induced unmasking effect is not clear. The present study investigated how perceptual separation and auditory spatial attention interact with each other to facilitate speech perception under a simulated noisy and reverberant environment by analyzing the cortical auditory evoked potentials to the signal speech. The results showed that the N1 wave was significantly enhanced by perceptual separation between the signal and masker regardless of whether the participants' spatial attention was directed to the signal or not. However, the P2 wave was significantly enhanced by perceptual separation only when the participants attended to the signal speech. The results indicate that the perceptual-separation-induced facilitation of P2 needs more attentional resource than that of N1. The results also showed that the signal speech caused an enhanced N1 in the contralateral hemisphere regardless of whether participants' attention was directed to the signal or not. In contrast, the signal speech caused an enhanced P2 in the contralateral hemisphere only when the participant attended to the signal. The results indicate that the hemispheric distribution of N1 is mainly affected by the perceptual features of the acoustic stimuli, while that of P2 is affected by the listeners' attentional status.

A preliminary study on time-compressed speech recognition in noise among teenage students who use personal listening devices.

OBJECTIVE: To compare speech perception obtained with different time compression rates in teenagers that do or do not use personal listening devices (PLDs). DESIGN: Teenagers in a high school were recruited to complete questionnaires reporting their recreational noise exposure using PLDs. The dose of individual recreational noise exposure was calculated. The individuals with the most and least doses of recreational noise were selected and grouped into PLD users and non-PLD users. Normal rate and time-compressed (60% and 70%) speech recognition in quiet and noisy conditions was measured. STUDY SAMPLE: PLD user and non-PLD user group each included 20 participants. RESULTS: ANOVA analysis showed that the effect of group, background, compression rate, and interactions between any two factors are significant. Post hoc analysis showed that the speech recognition scores with normal rate in quiet and noise and those obtained from time-compressed speech in the quiet condition were not significantly different between PLD users and non-PLD users. However, differences in the time-compressed speech recognition scores (60% and 70%) in noisy conditions between the two groups were statistically significant. CONCLUSIONS: The fast-speed speech recognition in noise decreased significantly in PLD users compared with that in non-PLD users selected by extreme entertainment exposure.

Speaking rhythmically improves speech recognition under "cocktail-party" conditions.

This study examines whether speech rhythm affects speech recognition under "cocktail-party" conditions. Against a two-talker masker, but not a speech-spectrum noise masker, recognition of the last (third) keyword in a normal rhythmic sentence was significantly better than that of the first keyword. However, this word-position-related speech-recognition improvement disappeared for rhythmically hybrid target sentences that were constructed by grouping parts from different sentences with different artificially modulated rhythms (rates) (fast, normal, or slow). Thus, the normal rhythm with a constant rate plays a role in improving speech recognition against informational speech masking, probably through a build-up of temporal prediction for target words.

Neural correlates of perceptual separation-induced enhancement of prepulse inhibition of startle in humans.

Prepulse inhibition (PPI) is the suppression of the startle reflex when the intense startling stimulus is shortly preceded by a weaker non-startling stimulus (prepulse). In rats, the auditory precedence-effect-induced perceived spatial separation between the fear-conditioned prepulse and a noise masker facilitates selective attention to the prepulse and enhances PPI. However, whether the perceptual separation between the prepulse and a noise masker can also enhance PPI in humans remains unclear. Also, the relationship between the PPI enhancement and the change in early cortical representations of prepulse signals is unclear. This study for the first time reveals that in a sound-attenuated laboratory environment, relative to the listening condition with perceptual co-location between the prepulse stimulus and a noise-masking stimulus, the perceptual separation between the two stimuli significantly enhances the group-mean PPI. More importantly, the early cortical responses (N1/P2 complex) to the prepulse stimulus are also enhanced by the perceptual separation in most listeners, and the perceptual-separation-induced enhancement of the N1 component is positively correlated with the perceptual-separation-induced PPI enhancement. Thus, the perceptual separation enhances PPI through facilitating selective attention to the prepulse, leading to an enhancement of the early cortical representation of the prepulse signal in temporal auditory cortical fields.

Mental imagery of face enhances face-sensitive event-related potentials to ambiguous visual stimuli.

Visual mental imagery forms mental representations of visual objects when correspondent stimuli are absent and shares some characters with visual perception. Both the vertex-positive-potential (VPP) and N170 components of event-related potentials (ERPs) to visual stimuli have a remarkable preference to faces. This study investigated whether visual mental imagery modulates the face-sensitive VPP and/or N170 components. The results showed that with significantly larger amplitudes under the face-imagery condition than the house-imagery condition, the VPP and P2 responses, but not the N170 component, were elicited by phase-randomized ambiguous stimuli. Thus, the brain substrates underlying VPP are not completely identical to those underlying N170, and the VPP/P2 manifestation of the category selectivity in imagery probably reflects an integration of top-down mental imagery signals (from the prefrontal cortex) and bottom-up perception signals (from the early visual cortex) in the occipito-temporal cortex where VPP and P2 originate.

A novel tarantula toxin stabilizes the deactivated voltage sensor of bacterial sodium channel.

Voltage-gated sodium channels (NaVs) are activated by transiting the voltage sensor from the deactivated to the activated state. The crystal structures of several bacterial NaVs have captured the voltage sensor module (VSM) in an activated state, but structure of the deactivated voltage sensor remains elusive. In this study, we sought to identify peptide toxins stabilizing the deactivated VSM of bacterial NaVs. We screened fractions from several venoms and characterized a cystine knot toxin called JZTx-27 from the venom of tarantula Chilobrachys jingzhao as a high-affinity antagonist of the prokaryotic NaVs NsVBa (nonselective voltage-gated Bacillus alcalophilus) and NaChBac (bacterial sodium channel from Bacillus halodurans) (IC50 = 112 nM and 30 nM, respectively). JZTx-27 was more efficacious at weaker depolarizing voltages and significantly slowed the activation but accelerated the deactivation of NsVBa, whereas the local anesthetic drug lidocaine was shown to antagonize NsVBa without affecting channel gating. Mutation analysis confirmed that JZTx-27 bound to S3-4 linker of NsVBa, with F98 being the critical residue in determining toxin affinity. All electrophysiological data and in silico analysis suggested that JZTx-27 trapped VSM of NsVBa in one of the deactivated states. In mammalian NaVs, JZTx-27 preferably inhibited the inactivation of NaV1.5 by targeting the fourth transmembrane domain. To our knowledge, this is the first report of peptide antagonist for prokaryotic NaVs. More important, we proposed that JZTx-27 stabilized the NsVBa VSM in the deactivated state and may be used as a probe to determine the structure of the deactivated VSM of NaVs.-Tang, C., Zhou, X., Nguyen, P. T., Zhang, Y., Hu, Z., Zhang, C., Yarov-Yarovoy, V., DeCaen, P. G., Liang, S., Liu, Z. A novel tarantula toxin stabilizes the deactivated voltage sensor of bacterial sodium channel.

Attentional modulation of informational masking on early cortical representations of speech signals.

To recognize speech in a noisy auditory scene, listeners need to perceptually segregate the target talker's voice from other competing sounds (stream segregation). A number of studies have suggested that the attentional demands placed on listeners increase as the acoustic properties and informational content of the competing sounds become more similar to that of the target voice. Hence we would expect attentional demands to be considerably greater when speech is masked by speech than when it is masked by steady-state noise. To investigate the role of attentional mechanisms in the unmasking of speech sounds, event-related potentials (ERPs) were recorded to a syllable masked by noise or competing speech under both active (the participant was asked to respond when the syllable was presented) or passive (no response was required) listening conditions. The results showed that the long-latency auditory response to a syllable (/bi/), presented at different signal-to-masker ratios (SMRs), was similar in both passive and active listening conditions, when the masker was a steady-state noise. In contrast, a switch from the passive listening condition to the active one, when the masker was two-talker speech, significantly enhanced the ERPs to the syllable. These results support the hypothesis that the need to engage attentional mechanisms in aid of scene analysis increases as the similarity (both acoustic and informational) between the target speech and the competing background sounds increases.

Synergetic action of domain II and IV underlies persistent current generation in Nav1.3 as revealed by a tarantula toxin.

The persistent current (INaP) through voltage-gated sodium channels enhances neuronal excitability by causing prolonged depolarization of membranes. Nav1.3 intrinsically generates a small INaP, although the mechanism underlying its generation remains unclear. In this study, the involvement of the four domains of Nav1.3 in INaP generation was investigated using the tarantula toxin α-hexatoxin-MrVII (RTX-VII). RTX-VII activated Nav1.3 and induced a large INaP. A pre-activated state binding model was proposed to explain the kinetics of toxin-channel interaction. Of the four domains of Nav1.3, both domain II and IV might play important roles in the toxin-induced INaP. Domain IV constructed the binding site for RTX-VII, while domain II might not participate in interacting with RTX-VII but could determine the efficacy of RTX-VII. Our results based on the use of RTX-VII as a probe suggest that domain II and IV cooperatively contribute to the generation of INaP in Nav1.3.