Effects of intermittent theta-burst transcranial magnetic stimulation on post-traumatic stress disorder symptoms: A randomized controlled trial.

Post-traumatic stress disorder (PTSD) is a prevalent and debilitating illness, which can be alleviated by transcranial magnetic stimulation (TMS). Intermittent theta burst stimulation (iTBS), a newer form of repetitive transcranial magnetic stimulation (rTMS), offers the advantage of shorter treatment sessions compared to the standard 10 Hz rTMS treatment. In order to compare the two forms of TMS, we enrolled 75 participants aged between 18 and 55 years who presented with (PCL-C) scale score of at least 50. Participants were randomly assigned to groups in a ratio of 1:1:1, receiving either 10 Hz rTMS, iTBS, or sham-controlled iTBS. Participants in the two treatment groups underwent 15 therapies which consisted of 1800 pulses and targeted the right dorsolateral prefrontal cortex (DLPFC). The main outcomes included changes in scores on the PCL-C and the Post-Traumatic Growth Inventory (PTGI). After intervention, the PCL-C and PTGI scores in iTBS and rTMS groups were significantly different from those in sham-controlled iTBS group. No significant differences in PCL-C and PTGI were found between the two active treatment groups. ITBS, with a shorter treatment duration, can effectively improve the symptoms of PTSD, with no significant difference in effect from that of rTMS. Future studies need to further elucidate the mechanisms, optimize the parameters and investigate the therapeutic potential and efficacy of iTBS in PTSD.

Consensus on the pharmacological treatment of acute stress disorder in Chinese pilots: a Delphi study.

BACKGROUND: Appropriate medication is very important for pilots with acute stress disorder. Improper medication can not only affect the physical and mental health of the pilots but can also endanger flight safety. Hence, we aimed to quickly and effectively relieve symptoms and restore cognitive function by forming a consensus of Chinese experts on the pharmacological treatment of acute stress disorder in pilots using the Delphi method. METHODS: Relevant literature was searched to enumerate the current status of pharmacological treatment of acute stress disorder in pilots, followed by two rounds of expert consultation and discussion according to the listed status of the survey using the Delphi method. A descriptive statistical method was used to analyze the basic information, authority coefficients, concentration of opinions, and survey items of the experts to develop a consensus on the pharmacological treatment of acute stress disorder in pilots. RESULTS: A total of 16 experts in psychiatry, pharmacology, and aerospace medicine from different provinces and cities across China were invited for consultation. The recovery rate of the two rounds of consultation was 100%, and the expert authority coefficients were 0.897 and 0.906, respectively. Kendall's coefficient of concordance of indicators at all levels was 0.564-0.594 (p < 0.01). Based on the number of votes received, alprazolam tablets (16), eszopiclone tablets (15), and lorazepam tablets (14) were recommended for the treatment of excitatory psychomotor symptoms of acute stress disorder; paroxetine tablets (15) and sertraline tablets (15) were available for psychomotor depressive symptoms; olanzapine tablets (15), olanzapine orally disintegrating tablets (14), and quetiapine fumarate tablets (14) were selected for psychotic symptoms. CONCLUSIONS: This study formed a consensus on rapid and effective pharmacological treatment for different symptoms of acute stress disorder pilots, which provides a reference for clinical treatment.

A multi-attack intrusion detection model based on Mosaic coded convolutional neural network and centralized encoding.

With the development of the Internet of Vehicles (IoV), attacks to the vehicle-mounted control area network (CAN) have seriously jeopardized the security of automobiles. As an important security measure, intrusion detection technologies have aroused great interest in researchers and many detection methods have also been proposed based on the vehicle's CAN bus. However, many studies only considered one type of attack at a time but in real environments there may contain a variety of attack types simultaneously. In view of the deficiency in the current methods, this paper proposed a method to detect multi-intrusions at one time based on a Mosaic coded convolutional neural network (CNN) and a centralized coding method. A Mosaic-like data block was created to convert the one-dimensional CAN ID into a two-dimensional data grid for the CNN to effectively extract the data characteristics and maintain the time characteristics between the CAN IDs. Four types of attacks and all combinations of them were used to train and test our model. Finally, a centralized coding method was used to increase the discrimination capability of the model. Experimental results showed that this single model could successfully detect any combinations of the intrusion types with very high and stable performance.

Multi-attack and multi-classification intrusion detection for vehicle-mounted networks based on mosaic-coded convolutional neural network.

With the development of Internet of vehicles, the information exchange between vehicles and the outside world results in a higher risk of external network attacks to the vehicles. The attack modes to the most widely used vehicle-mounted CAN bus are complex and diverse, but most of the intrusion detection approaches proposed by now can only detect one type of attack at a time. Aiming at detecting multi-types of attacks using a single model, we proposed a detection method based on the Mosaic-coded convolution neural network for intrusions containing various combinations of attacks with multi-classification capability. A Mosaic-like two-dimensional data grid was created from the one-dimensional CAN ID for the CNN to effectively extract the data features and maintain the time connections between the CAN IDs. Four types of attacks and all possible combinations of them were used to train and test our model. The autoencoder was also used to reduce the dimensionality of the data so as to cut down the model's complexity. Experimental results showed that the proposed method was effective in detecting all types of attack combinations with high and stable multi-classification ability.

Network structure of PTSD symptoms in Chinese male firefighters.

The network perspective of mental disorder offers a novel way of understanding the psychopathology of post-traumatic stress disorder (PTSD). In this framework, PTSD may arise from direct interactions between its symptoms. In the present study, we used the Post-Traumatic Stress Disorder Checklist-civilian Version (PCL-C) to investigate the network structure of PTSD symptoms in 994 Chinese male firefighters. We also calculated the micro (i.e., edges weight and node expected influence) and middle (i.e., community) indicators of the final network. Nine strongest edges existed in the final network were from the same dimension of PCL-C, like "avoidance of thoughts" and "avoidance of reminders". Symptoms "emotional reactivity", "avoidance of reminders" and "exaggerated startle response" had the highest expected influence. As for the results of community detection, the spinglass and walktrap algorithm detected the same three communities which are slightly different from the original dimensions of PCL-C (i.e., symptoms "avoidance of thoughts", "avoidance of reminders" and "trauma-related amnesia" of avoidance dimension of PCL-C were added to the intrusion dimension of PCL-C). The present study explored the network structure of PTSD symptoms in Chinese male firefighters and provided several implications for clinical prevention and intervention to address the mental health needs in this special group.

The relations among worry, meta-worry, intolerance of uncertainty and attentional bias for threat in men at high risk for generalized anxiety disorder: a network analysis.

BACKGROUND: Improving the psychotherapies for generalized anxiety disorder (GAD) is dependent on a deeper understanding of the relations between GAD and its associated cognitive factors. In the present study, we investigate how the core feature of GAD (i.e., worry) and its associated cognitive factors, such as meta-worry, intolerance of uncertainty, and attention bias towards threat, relate to each other in men at high risk for GAD. METHODS: We used network analysis to explore the relations among these variables in a cross-sectional sample of 122 men at high risk for generalized anxiety disorder. Specifically, we computed the expected influence and predictability of each variable. RESULTS: In the final network, we found that worry and meta-worry had the highest expected influence and predictability. In contrast, attention bias towards threat showed the lowest expected influence and predictability. The estimates of the expected influence of the nodes were stable (correlation stability coefficient = 0.52). CONCLUSIONS: The present study is the first to investigate the relations among worry, meta-worry, intolerance of uncertainty, and attention bias towards threat in men at high risk for generalized anxiety disorder. These findings indicate that worry and meta-worry may play important roles in the present network. The implications for clinical interventions and future studies are discussed.

PbGA2ox8 induces vascular-related anthocyanin accumulation and contributes to red stripe formation on pear fruit.

Fruit with stripes, which are generally longitudinal, can occur naturally, but the bioprocesses underlying this phenomenon are unclear. Previously, we observed an atypical anthocyanin distribution that caused red-striped fruit on the spontaneous pear bud sport "Red Zaosu" (Pyrus bretschneideri Rehd.). In this study, comparative transcriptome analysis of the sport and wild-type "Zaosu" revealed that this atypical anthocyanin accumulation was tightly correlated with abnormal overexpression of the gene-encoding gibberellin (GA) 2-beta-dioxygenase 8, PbGA2ox8. Consistently, decreased methylation was also observed in the promoter region of PbGA2ox8 from "Red Zaosu" compared with "Zaosu". Moreover, the GA levels in "Red Zaosu" seedlings were lower than those in "Zaosu" seedlings, and the application of exogenous GA4 reduced abnormal anthocyanin accumulation in "Red Zaosu". Transient overexpression of PbGA2ox8 reduced the GA4 level and caused anthocyanin accumulation in pear fruit skin. Moreover, the presence of red stripes indicated anthocyanin accumulation in the hypanthial epidermal layer near vascular branches (VBs) in "Red Zaosu". Transient overexpression of PbGA2ox8 resulting from vacuum infiltration induced anthocyanin accumulation preferentially in calcium-enriched areas near the vascular bundles in pear leaves. We propose a fruit-striping mechanism, in which the abnormal overexpression of PbGA2ox8 in "Red Zaosu" induces the formation of a longitudinal array of anthocyanin stripes near vascular bundles in fruit.

The implicit beliefs and implicit behavioral tendencies towards smoking-related cues among Chinese male smokers and non-smokers.

BACKGROUND: The dual-process theory is central to several models of addiction, implying the importance of automatic processes in the maintenance and development of addiction. Implicit beliefs are traces of previous experience which relate to the representation in cognition. Implicit behavioral tendencies are traces of previous experience which relate to the representation in behavioral tendencies. In this study, we aim to provide behavioral evidence for implicit beliefs and implicit behavioral tendencies towards smoking-related cues among Chinese male smokers and non-smokers. We also examine the relationships among implicit beliefs, implicit behavioral tendencies and smoking behaviors of smokers. METHODS: In order to achieve these goals, we used an implicit association test (IAT) to measure implicit beliefs and implicit behavioral tendencies simultaneously. Thirty-nine smokers and twenty-five non-smokers were tested, using smoking-related words and images, as well as neutral words and images as stimuli. RESULTS: Our analysis shows significant differences in smokers' and non-smokers' implicit beliefs and behavioral tendencies (t62 = 3.494, p < 0.001; t62 = 5.034, p < 0.001). In the group of smokers, implicit beliefs and implicit behavioral tendencies were positively correlated with each other (r = 0.460, p < 0.01). In addition, smokers' scores for implicit behavioral tendencies are negatively correlated with the number of cigarettes smoked per day (r = - 0.51, p < 0.001). CONCLUSIONS: This study suggests that implicit beliefs and behavioral tendencies toward smoking-related cues vary significantly between Chinese male smokers and non-smokers. In addition, there is a positive correlation between implicit beliefs and behavioral tendencies within smokers. It also shows for the first time that the implicit behavioral tendencies are related to smoking behaviors. Our results may be considered as references for smoking cessation interventions focused on changes at the implicit level, and they provide a new perspective for measuring different dimensions of implicit attitudes by an IAT. This finding might promote the development of the network theory of implicit attitudes.

BBX16, a B-box protein, positively regulates light-induced anthocyanin accumulation by activating MYB10 in red pear.

The red coloration of pear (Pyrus pyrifolia) results from anthocyanin accumulation in the fruit peel. Light is required for anthocyanin biosynthesis in pear. A pear homolog of Arabidopsis thaliana BBX22, PpBBX16, was differentially expressed after fruits were removed from bags and may be involved in anthocyanin biosynthesis. Here, the expression and function of PpBBX16 were analysed. PpBBX16's expression was highly induced by white-light irradiation, as was anthocyanin accumulation. PpBBX16's ectopic expression in Arabidopsis increased anthocyanin biosynthesis in the hypocotyls and tops of flower stalks. PpBBX16 was localized in the nucleus and showed trans-activity in yeast cells. Although PpBBX16 could not directly bind to the promoter of PpMYB10 or PpCHS in yeast one-hybrid assays, the complex of PpBBX16/PpHY5 strongly trans-activated anthocyanin pathway genes in tobacco. PpBBX16's overexpression in pear calli enhanced the red coloration during light treatments. Additionally, PpBBX16's transient overexpression in pear peel increased anthocyanin accumulation, while virus-induced gene silencing of PpBBX16 decreased anthocyanin accumulation. The expression patterns of pear BBX family members were analysed, and six additional BBX genes, which were differentially expressed during light-induced anthocyanin biosynthesis, were identified. Thus, PpBBX16 is a positive regulator of light-induced anthocyanin accumulation, but it could not directly induce the expression of the anthocyanin biosynthesis-related genes by itself but needed PpHY5 to gain full function. Our work uncovered regulatory modes for PpBBX16 and suggested the potential functions of other pear BBX genes in the regulation of anthocyanin accumulation, thereby providing target genes for further studies on anthocyanin biosynthesis.

Weakly-coupled 4-mode step-index FMF and demonstration of IM/DD MDM transmission.

Weakly coupled-mode division multiplexing (MDM) over few-mode fibers (FMF) for short-reach transmission has attracted great interest, which can avoid multiple-input-multiple-output digital signal processing (MIMO-DSP) by greatly suppressing modal crosstalk. In this paper, step-index FMF supporting 4 linearity polarization (LP) modes for MIMO-free transmission is designed and fabricated for the first time, to our knowledge. Modal crosstalk of the fiber is suppressed by increasing the mode effective refractive index differences. The same fabrication method as standard single-mode fiber is adopted so that it is practical and cost-effective. The mode multiplexer/demultiplexer (MUX/DEMUX) consists of cascaded mode-selective couplers (MSCs), which are designed and fabricated by tapering the proposed FMF with single-mode fiber (SMF). The mode MUX and DEMUX achieve very low modal crosstalk not only for the multiplexing/demultiplexing but also for the coupling to/from the FMF. Based on the fabricated FMF and mode MUX/DEMUX, we successfully demonstrate the first simultaneous 4-modes (LP01, LP11, LP21 & LP31) 10-km FMF transmission with 10-Gb/s intensity modulation and MIMO-free direct detection (IM/DD). The modal crosstalk of the whole transmission link is successfully suppressed to less than -16.5 dB. The experimental results indicate that FMF with simple step-index structure supporting 4 weakly-coupled modes is feasible.

Wavelength-interleaved MDM-WDM transmission over weakly-coupled FMF.

Recently mode-division-multiplexing (MDM) has been widely investigated to enhance fiber optics capacity, in which modes or mode groups in few-mode fiber (FMF) or multi-mode fiber (MMF) are exploited as different spatial channels for data transmission. For short-reach applications, significantly reducing inter-spatial-channel crosstalk to avoid coherent detection and multiple-input-multiple-output (MIMO) equalization is preferred. Currently most studies focus on the design of weakly-coupled FMFs and mode (de)multiplexers. Alternatively, in this work, a wavelength-interleaved (WI) scheme is proposed to mitigate inter-spatial-channel crosstalk by optimizing the design of direct detection (DD) MDM and wavelength-division-multiplexing (WDM) system. In weakly-coupled MDM systems, crosstalk mainly comes from the adjacent spatial channels, and the signal-to-crosstalk beat interference (SCBI) constitutes main crosstalk impairment after square-law detection. The WI scheme interleaves the WDM grids in adjacent spatial channels by half WDM channel spacing and uses an electrical low-pass filtering (ELPF) to remove out-of-band SCBI. The effectiveness of SCBI suppression is theoretically analyzed. The feasibility of WI scheme is experimentally verified by 3-mode 3-wavelength MDM-WDM transmission over 500-m OM3 MMF. Enabled by WI scheme, record 120-km 10G-per-channel MDM-WDM transmission over 2-mode FMF without MIMO equalization is successfully demonstrated. The WI scheme is promising to enhance the performance of short reach or even metro MDM optics.

Cost effective wavelength reused MDM system for bidirectional mobile fronthaul.

In this paper, we propose a cost-effective wavelength-reused mode-division-multiplexing (MDM) system for high speed symmetrical bidirectional mobile fronthaul application. At the base band unit (BBU) pool, one of the spatial modes is used to transmit signal carrier while the others are used for downstream (DS) signal channels. At the remote radio unit (RRU) side, the signal carrier is split and reused as modulation carrier for all the upstream (US) signal channels after mode demultiplexing. Thanks to the low mode crosstalk characteristic of the mode multiplexer/demultiplexer (MUX/DEMUX) and few-mode fiber (FMF), the signal carrier and each signal channel can be effectively separated. The spectral efficiency (SE) is significantly enhanced when multiple spatial channels are used. Compared with other wavelength reused scheme in which the downstream and upstream be modulated in orthogonal dimension, the modulation format of both directions are independent in the proposed wavelength reused MDM system. Therefore, it can easily achieve symmetrical bidirectional transmission without residual re-modulation crosstalk. The proposed scheme is scalable to multi-wavelength application when wavelength MUX/DEMUX is utilized. With the proposed scheme, we demonstrate a proof of concept intensity modulated 4 × 25-Gb/s 16-QAM orthogonal frequency division multiplexing (OFDM) transmission over 10-km FMF using low modal-crosstalk two-mode FMF and MUX/DEMUX with error free operation. The downstream receiver sensitivity is -21 dBm while the upstream receiver sensitivity is -18 dBm for bidirectional transmission. Due to the Rayleigh backscattering and other spurious reflections, the upstream suffers 2 dB power penalty compared with unidirectional transmission without downstream. To mitigate bidirectional transmission impairments, we propose a simple and effective method to suppress Rayleigh backscattering by shifting the downstream subcarrier frequency. A receiver sensitivity improvement of up to 2.5 dB is achieved for upstream with different downstream power.

Demonstration of all-optical MDM/WDM switching for short-reach networks.

Mode division multiplexing (MDM) has been widely investigated in optical transmission systems and networks to improve network capacity. However, the MDM receiver is always expensive and complex because coherent detection and multiplex-input-and-multiplex-output (MIMO) digital signal processing (DSP) are required to demultiplex each spatial mode. In this paper, we investigate the application of MDM in short-reach scenarios such as datacenter networking. Two-dimensional MDM and wavelength division multiplexing node structure based on low modal-crosstalk few-mode fiber (FMF) and components is proposed, in which signal in each mode or wavelength can be independently switched. We experimentally demonstrate independent adding, dropping and switching functionalities with two linearly polarized modes and four wavelength channels over a total 11.8-km 2-mode low modal-crosstalk FMFs. The structure is simple without coherent detection or MIMO DSP. Only slight penalties of receiver sensitivity are observed for all switching operations. The influence of modal-crosstalk accumulation for cascaded switching nodes is also investigated.

Quantification of MDL-induced signal degradation in MIMO-OFDM mode-division multiplexing systems.

Mode-division multiplexing (MDM) transmission over few-mode optical fiber has emerged as a promising technology to enhance transmission capacity, in which multiple-input-multiple-output (MIMO) digital signal processing (DSP) after coherent detection is used to demultiplex the signals. Compared with conventional single-mode systems, MIMO-MDM systems suffer non-recoverable signal degradation induced by mode-dependent loss (MDL). In this paper, the MDL-induced signal degradation in orthogonal-frequency-division-multiplexing (OFDM) MDM systems is theoretically quantified in terms of mode-average error vector magnitude (EVM) through frequency domain norm analysis. A novel scalar MDL metric is proposed considering the probability distribution of the practical MDM input signals, and a closed-form expression for EVM measured after zero-force (ZF) MIMO equalization is derived. Simulation results show that the EVM estimations utilizing the novel MDL metric remain unbiased for unrepeated links. For a 6 × 100 km 20-mode MDM transmission system, the estimation accuracy is improved by more than 90% compared with that utilizing traditional condition number (CN) based MDL metric. The proposed MDL metric can be used to predict the MDL-induced SNR penalty in a theoretical manner, which will be beneficial for the design of practical MIMO-MDM systems.

Novel MDM-PON scheme utilizing self-homodyne detection for high-speed/capacity access networks.

In this paper, we propose a cost-effective, energy-saving mode-division-multiplexing passive optical network (MDM-PON) scheme utilizing self-homodyne detection for high-speed/capacity access network based on low modal-crosstalk few-mode fiber (FMF) and all-fiber mode multiplexer/demultiplexer (MUX/DEMUX). In the proposed scheme, one of the spatial modes is used to transmit a portion of signal carrier (namely pilot-tone) as the local oscillator (LO), while the others are used for signal-bearing channels. At the receiver, the pilot-tone and the signal can be separated without strong crosstalk and sent to the receiver for coherent detection. The spectral efficiency (SE) is significantly enhanced when multiple spatial channels are used. Meanwhile, the self-homodyne detection scheme can effectively suppress laser phase noise, which relaxes the requirement for the lasers line-width at the optical line terminal or optical network units (OLT/ONUs). The digital signal processing (DSP) at the receiver is also simplified since it removes the need for frequency offset compensation and complex phase correction, which reduces the computational complexity and energy consumption. Polarization division multiplexing (PDM) that offers doubled SE is also supported by the scheme. The proposed scheme is scalable to multi-wavelength application when wavelength MUX/DEMUX is utilized. Utilizing the proposed scheme, we demonstrate a proof of concept 4 × 40-Gb/s orthogonal frequency division multiplexing (OFDM) transmission over 55-km FMF using low modal-crosstalk two-mode FMF and MUX/DEMUX with error free operation. Compared with back to back case, less than 1-dB Q-factor penalty is observed after 55-km FMF of the four channels. Signal power and pilot-tone power are also optimized to achieve the optimal transmission performance.

Experimental demonstration of EON node supporting reconfigurable optical superchannel multicasting.

Elastic optical networks (EON) based on optical superchannel enables higher spectral flexibility, in which the network nodes should provide multiple all-optical functionalities to manipulate bandwidth-variable data traffic. In this paper, we propose and demonstrate an EON node structure supporting reconfigurable optical superchannel multicasting. The node structure incorporates a shared multicasting module, which performs reconfigurable selection of target incoming/outgoing superchannels/replicas and leverages a group of nonlinear devices to satisfy multiple multicast requests. Moreover, an optical comb is utilized to efficiently provide and manage all pump resources for multicasting with potential cost reduction and phase noise inhibition. Based on the node structure, we experimentally demonstrate polarization division multiplexing (PDM) superchannel multicasting scenarios with different replica amount, input/output locations, and modulation formats. Less than 0.7 dB optical signal-to-noise ratio (OSNR) penalties are demonstrated in multiple multicasting scenarios.

Pre- and postsynaptic modulations of hypoglossal motoneurons by α-adrenoceptor activation in wild-type and Mecp2(-/Y) mice.

Hypoglossal motoneurons (HNs) control tongue movement and play a role in maintenance of upper airway patency. Defects in these neurons may contribute to the development of sleep apnea and other cranial motor disorders including Rett syndrome (RTT). HNs are modulated by norepinephrine (NE) through α-adrenoceptors. Although postsynaptic mechanisms are known to play a role in this effect, how NE modulates the synaptic transmissions of HNs remains poorly understood. More importantly, the NE system is defective in RTT, while how the defect affects HNs is unknown. Believing that information of NE modulation of HNs may help the understanding of RTT and the design of new therapeutical interventions to motor defects in the disease, we performed these studies in which glycinergic inhibitory postsynaptic currents and intrinsic membrane properties were examined in wild-type and Mecp2(-/Y) mice, a mouse of model of RTT. We found that activation of α1-adrenoceptor facilitated glycinergic synaptic transmission and excited HNs. These effects were mediated by both pre- and postsynaptic mechanisms. The latter effect involved an inhibition of barium-sensitive G protein-dependent K(+) currents. The pre- and postsynaptic modulations of the HNs by α1-adrenoceptors were not only retained in Mecp2-null mice but also markedly enhanced, which appears to be a compensatory mechanism for the deficiencies in NE and GABAergic synaptic transmission. The existence of the endogenous compensatory mechanism is an encouraging finding, as it may allow therapeutical modalities to alleviate motoneuronal defects in RTT.

The disruption of central CO2 chemosensitivity in a mouse model of Rett syndrome.

People with Rett syndrome (RTT) have breathing instability in addition to other neuropathological manifestations. The breathing disturbances contribute to the high incidence of unexplained death and abnormal brain development. However, the cellular mechanisms underlying the breathing abnormalities remain unclear. To test the hypothesis that the central CO(2) chemoreception in these people is disrupted, we studied the CO(2) chemosensitivity in a mouse model of RTT. The Mecp2-null mice showed a selective loss of their respiratory response to 1-3% CO(2) (mild hypercapnia), whereas they displayed more regular breathing in response to 6-9% CO(2) (severe hypercapnia). The defect was alleviated with the NE uptake blocker desipramine (10 mg·kg(-1)·day(-1) ip, for 5-7 days). Consistent with the in vivo observations, in vitro studies in brain slices indicated that CO(2) chemosensitivity of locus coeruleus (LC) neurons was impaired in Mecp2-null mice. Two major neuronal pH-sensitive Kir currents that resembled homomeric Kir4.1 and heteromeric Ki4.1/Kir5.1 channels were identified in the LC neurons. The screening of Kir channels with real-time PCR indicated the overexpression of Kir4.1 in the LC region of Mecp2-null mice. In a heterologous expression system, an overexpression of Kir4.1 resulted in a reduction in the pH sensitivity of the heteromeric Kir4.1-Kir5.1 channels. Given that Kir4.1 and Kir5.1 subunits are also expressed in brain stem respiration-related areas, the Kir4.1 overexpression may not allow CO(2) to be detected until hypercapnia becomes severe, leading to periodical hyper- and hypoventilation in Mecp2-null mice and, perhaps, in people with RTT as well.

Oxidative stress inhibits vascular K(ATP) channels by S-glutathionylation.

The K(ATP) channel is an important player in vascular tone regulation. Its opening and closure lead to vasodilation and vasoconstriction, respectively. Such functions may be disrupted in oxidative stress seen in a variety of cardiovascular diseases, while the underlying mechanism remains unclear. Here, we demonstrated that S-glutathionylation was a modulation mechanism underlying oxidant-mediated vascular K(ATP) channel regulation. An exposure of isolated mesenteric rings to hydrogen peroxide (H(2)O(2)) impaired the K(ATP) channel-mediated vascular dilation. In whole-cell recordings and inside-out patches, H(2)O(2) or diamide caused a strong inhibition of the vascular K(ATP) channel (Kir6.1/SUR2B) in the presence, but not in the absence, of glutathione (GSH). Similar channel inhibition was seen with oxidized glutathione (GSSG) and thiol-modulating reagents. The oxidant-mediated channel inhibition was reversed by the reducing agent dithiothreitol (DTT) and the specific deglutathionylation reagent glutaredoxin-1 (Grx1). Consistent with S-glutathionylation, streptavidin pull-down assays with biotinylated glutathione ethyl ester (BioGEE) showed incorporation of GSH to the Kir6.1 subunit in the presence of H(2)O(2). These results suggest that S-glutathionylation is an important mechanism for the vascular K(ATP) channel modulation in oxidative stress.

Intrinsic membrane properties of locus coeruleus neurons in Mecp2-null mice.

Rett syndrome caused by mutations in methyl-CpG-binding protein 2 (Mecp2) gene shows abnormalities in autonomic functions in which brain stem norepinephrinergic systems play an important role. Here we present systematic comparisons of intrinsic membrane properties of locus coeruleus (LC) neurons between Mecp2(-/Y) and wild-type (WT) mice. Whole cell current clamp was performed in brain slices of 3- to 4-wk-old mice. Mecp2(-/Y) neurons showed stronger inward rectification and had shorter time constant than WT cells. The former was likely due to overexpression of inward rectifier K(+) (K(ir))4.1 channel, and the latter was attributable to the smaller cell surface area. The action potential duration was prolonged in Mecp2(-/Y) cells with an extended rise time. This was associated with a significant reduction in the voltage-activated Na(+) current density. After action potentials, >60% Mecp2(-/Y) neurons displayed fast and medium afterhyperpolarizations (fAHP and mAHP), while nearly 90% WT neurons showed only mAHP. The mAHP amplitude was smaller in Mecp2(-/Y) neurons. The firing frequency was higher in neurons with mAHP, and the frequency variation was greater in cells with both fAHP and mAHP in Mecp2(-/Y) mice. Small but significant differences in spike frequency adaptation and delayed excitation were found in Mecp2(-/Y) neurons. These results indicate that there are several electrophysiological abnormalities in LC neurons of Mecp2(-/Y) mice, which may contribute to the dysfunction of the norepinephrine system in Rett syndrome.