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Whether it is for military or civilian use, quadrotor UAV has always been one of research central issues. Most of the current quadrotor drones are manually operated and use GPS signals for navigation, which not only limits the operating range of the drone but also consumes a lot of manpower and material resources. This research mainly studies the method of realizing autonomous flight and conflict avoidance of quadrotor UAV by using multisensor system and deep learning method in extreme flight conditions through track prediction. The convolutional neural network method is used to extract the image information collected by the UAV sensor system. And it uses the cyclic neural network to extract the time feature of the information collected by the UAV sensor. The research results show that the track prediction method based on the deep learning method has higher flight accuracy for quadrotor UAVs. The yaw error of the spatial position is only 2.82%, and the maximum error of the time characteristic error tolerance is only 0.77%.

TFG-related axonal Charcot-Marie-Tooth (CMT) disease is a late-onset, autosomal dominant, hereditary motor, and sensory neuropathy characterized by slowly progressive weakness and atrophy of the distal muscles. The objective of this study was to determine the common pathogenic mechanism of TFG-related CMT type 2 (CMT2) caused by different mutations and establish a direct association between TFG haploinsufficiency and neurodegeneration.Three individuals carrying the TFG p.G269V mutation but with varying disease durations were studied. The effect of the p.G269V mutation was confirmed by analyzing protein samples extracted from the blood of two individuals. The functional consequences of both CMT2 mutant gene products were evaluated in vitro. The effect of TFG deficiency in the nervous system was examined using zebrafish models and cultured mouse neurons.Overexpression of p.G269V TFG failed to enhance soluble TFG levels by generating insoluble TFG aggregates. TFG deficiency disrupted neurite outgrowth and induced neuronal apoptosis both in vivo and in vitro and further impaired locomotor capacity in zebrafish, which was consistent with the phenotype in patients. Wnt signaling was activated as a protective factor in response to TFG deficiency.CMT2-related TFG mutation induces TFG haploinsufficiency within cells and drives disease by causing progressive neurite degeneration.

Transition metal sulfides are considered as one of the most potential anode materials in sodium-ion batteries due to their high capacity, low cost, and rich resources. Among plenty of options, molybdenum sulfide (MoS2) has been the focus of research due to the graphene-like layered structure and unique electrochemical properties. Importantly, an abnormal capacity increase phenomenon was observed in the MoS2 anode of sodium-ion batteries, but the mechanisms involved are still unclear. In this study, by analyzing the composition and structure of the material after a different number of cycles, we confirmed that the (002) plane shows a significant expansion of the interlayer spacing after the sodium ion insertion process and a phase transformation from the hexagonal phase MoS2 (2H-MoS2) to the trigonal phase MoS2 (1T-MoS2). Moreover, the ratio of 1T-MoS2 presented an increasing trend during cycling. The dual-phase co-existence leads to enhanced electrical conductivity, higher Na affinity, and higher Na+ mobility, thus increasing the capacity. Our work provides a new perspective on the anomalous electrochemical behavior of sulfide anodes during long-term cycling.

In the event-driven wireless sensor networks (EWSNs), the event of interests occurs irregularly and at random in the network. Then, sensor nodes near the event sense the event and send out data packets of the event. Next, router nodes (RNs) forward those packets to the sink node (SN) by multi-hop communications. Compromised RNs would become malicious and launch selective forwarding attacks by dropping part of or all the packets from other nodes. On the other hand, a harsh environment makes the channel poor, so the routing nodes under a harsh environment have low packet forwarding rates because they sometimes have to give up forwarding the current packets after many tries to forward them due to poor channel. If the malicious nodes’ forwarding rates become close to those of nodes under a harsh environment, the schemes based on packet forwarding rates for detecting selective forwarding attack may fail because they cannot differentiate the low data packet forwarding rates resulting from the malicious behaviors or harsh environment. To solve this problem, we provide a combined scheme for detecting selective forwarding attack in wireless sensor networks (WSNs) under harsh environments. This scheme employs a data clustering algorithm (DCA) to screen the malicious nodes out by clustering their cumulative forwarding rates (CFRs) and designs a voting decision method to protect the nodes under a harsh environment from being judged as malicious nodes. The simulation results show that our scheme has a low false detection rate (FDR) of 1% and a low missed detection rate (MDR) of 5% respectively with negligible energy consumption in WSNs under a local variable harsh environment.

Perinatal exposure to nicotine produces ventilatory and chemoreflex deficits in neonatal mammals. Medullary 5-HT neurons are putative central chemoreceptors that innervate respiratory nuclei and promote ventilation, receive cholinergic input and express nicotinic acetylcholine receptors (nAChRs). Perforated patch clamp recordings were made from cultured 5-HT neurons dissociated from the medullary raphé of 0–3 day old ePet-EYFP mice. The effect of exposure to low (6 mg kg(−1)day(−1)) or high (60 mg kg(−1)day(−1)) doses of nicotine in utero (prenatal), in culture (postnatal), or both and the effect of acute nicotine exposure (10 μM), were examined on baseline firing rate (FR at 5% CO(2), pH = 7.4) and the change in FR with acidosis (9% CO(2), pH 7.2) in young (12– 21 days in vitro, DIV) and older (≥ 22 DIV) acidosis stimulated 5-HT neurons. Nicotine exposed neurons exhibited ~67% of the response to acidosis recorded in neurons given vehicle (p=0.005), with older neurons exposed to high dose prenatal and postnatal nicotine, exhibiting only 28% of that recorded in the vehicle neurons (p

Deployed in a harsh or hostile environment and running in an unattended state, wireless sensor networks (WSNs) are vulnerable to many attacks. The selective forwarding attack is one most difficult to be detected, and trust-based detection methods often fail especially under the poor wireless channels. Based on nodes’ cumulative forwarding rates ( CFRs ) and cumulative transmission rates ( CTRs ), we propose a clustering scheme in clustered WSNs to divide the nodes into three types: malicious, suspicious, and regular nodes. To defend selective forwarding attacks of malicious nodes, our scheme isolates them from the network. For suspicious nodes, our scheme uses the non-cooperative game with incomplete information to force them to promote forwarding rates. In the game, the reward and punishment mechanism reduces the attackers’ expected revenues and trust values. And the suspicious nodes, screened out by our clustering method, will be forced to forward packets to elude our detecting scheme. The Nash equilibrium of the game between regular nodes and suspicious nodes is proved to exist here. Simulation results show that our scheme can promote network throughput largely, and our dynamic-time behavior monitoring scheme can gain a longer network lifetime than that of the full-time behavior monitoring scheme.

International audience; Objective. Alterations in the methylation state of pseudogenes may serve as clinically useful biomarkers of glioblastomas (GBMs) that do not have glioma-CpG island methylator phenotype (G-CIMP).Methods. Non-G-CIMP GBM datasets were included for evaluation, and a RISK-score signature was determined from the methylation state of pseudogene loci. Both bioinformatic and experimental analyses were performed for biological validation.Results. By integrating clinical information with DNA methylation microarray data, we screened a panel of eight CpGs from discovery cohorts of non-G-CIMP GBMs. Each CpG could accurately and independently predict the prognosis of patients under a treatment regime that combined radiotherapy (RT) and temozolomide (TMZ). The 8-CpG signature appeared to show opposite prognostic correlations between patients treated with RT/TMZ and those treated with RT monotherapy. The analyses further indicated that this signature had predictive value for TMZ efficacy because different survival benefits between RT/TMZ and RT therapies were observed in each risk subgroup. The incorporation of other risk factors, such as age and O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status, with our pseudogene methylation signature could provide precise risk classification. In vitro experimental data revealed that two locus-specific pseudogenes (ZNF767P and CLEC4GP1) may modulate TMZ resistance via distinct mechanisms in GBM cells.Conclusion. The biologically and clinically relevant RISK-score signature, based on pseudogene methylation loci, may offer information for predicting TMZ responses of non-G-CIMP GBMs, that is independent from, but complementary to, MGMT-based approaches.

Background: Vector control has been a key strategy in malaria prevention and elimination for decades. However, insecticide resistance is becoming a serious threat to vector control. Anopheles sinensis is one of the important transmission vectors for malaria in Guizhou Province, China. However, little is known on insecticide resistance status and related mechanism. In this study, the diversity and frequency of the major insecticide resistance associated genes such as voltage-gated sodium channel (vgsc) and acetylcholinesterase-1 ( ace-1 ) genes that encoded the target proteins of Pyrethroids and OPs were investigated in field populations.Methods: Adult mosquitoes were collected from 12 sampling sites across Guizhou by lamp trapping. Female An. sinensis were identified by morphological and molecular identification. Genomic DNA was extracted to amplify vgsc and ace-1 gene fragments. PCR products were sequenced bi-directly. Mutations of vgsc gene at locus 1014 and that of ace-1 at locus 119 were analyzed using MEGA 7.1 software, and the frequencies of mutations were calculated respectively.Results: 5 kdr mutation alleles at the locus 1014 of vgsc gene as a result of three amino acid replacements ( namely 1014F/C/S) in 548 samples of 12 An. sinensis populations. The total frequency of kdr mutation alleles was 27.4%, of which the TTT/C (F) allele had a highest mutation frequency of 22.5%. The top three mutation genotypes were from XiShui, TongZhi and DeJiang populations collected in north Guizhou. There were three alleles at locus 119 in ace-1 gene with 49.47% of GGC/G, 0.17% of GGT/G and 50.36% of AGC/S. The 100% frequency of mutation genotypes (GS, SS) was found in CeHeng, LuoDian and SanDu populations gathered in southwest Guizhou.Conclusion: A diverse genetic mutations of vgsc and ace-1 genes are found in An. sinensis in Guizhou. There are a significant geographical heterogeneities of allele frequency among different populations in Guizhou. A high frequency of kdr mutation (>44 %) in north Guizhou. The 119S mutation of ace-1 gene is present at a high frequency in most An. sinensis populations in Guizhou, especially in the previously highly endemic malaria regions. These findings suggest continued monitoring of the genotypic diversity of insecticides resistance genes may assist to formulate a region-customized resistance management strategies.

Background Dysregulation and dysfunction of DNA damage response (DDR) have prognostic and predictive implications for glioblastomas (GBMs) without glioma-CpGs island methylator phenotype (G-CIMP); mathematical modeling based on DNA methylation abnormality in DDR genes may serve as clinically useful biomarkers. Methods Independent cohorts of non-G-CIMP GBMs and IDH wild type (wt) lower-grade gliomas (LGGs) from local and public databases were included for discovery and validation of a multimarker signature, combined using a RISK score model. Different bioinformatic and functional experiments were performed for biological validation. Results By analyzing DNA methylation microarray data of DDR genes, we totally identified five CpGs, each of which was significantly correlated with overall survival (OS) of non-G-CIMP GBMs, independent of age, treatments and the O-6-methylguanine-DNA methyltransferase (MGMT) methylation status. A RISK score signature of the 5 CpGs was constructed and validated to powerfully and independently prognosticate prognosis in non-G-CIMP GBMs. It also showed good discriminating value in stratified cohorts by patient age and MGMT methylation status. Bioinformatic analysis revealed a close correlation of the DDR epigenetic signature to distinct immunophenotypes of non-G-CIMP GBMs. Functional studies showed that NSUN5, epigenetically regulated by one identified CpGs, exhibited tumor-suppressor characteristics but may have immunosuppressive implications and confer TMZ resistance to GBM cells. Conclusions The epigenetic signature of DDR genes might be of promising value for refining current prognostic classification of non-G-CIMP GBMs, and its potential links to distinct immunophenotypes make it a promising biomarker candidate in the coming era of cancer immunotherapy.

Transition metal sulfides are considered as one of the most potential anode materials in sodium-ion batteries due to their high capacity, low cost, and rich resources. Among plenty of options, molybdenum sulfide (MoS

Acetylcholinesterase is the primary target of organophosphates (OPs) and carbamates in insects. As gene mutation has been verified as an important mechanism of insecticide resistance in insects, in this study, we investigated the status of OPs resistance and the polymorphism of ace gene (that encodes acetylcholinesterase) in housefly (Musca domestica L) field populations in Guizhou Province, China. Bioassays showed that the houseflies had 142.16–303.54-fold resistance to dichlorvos (DDVP) and 122.13–363.98-fold resistance to temephos. Molecular analysis revealed resistance-causing mutations of ace gene at loci of 260, 342 and 407 in the housefly populations, with a total frequency of 55%, 100% and 94%, respectively. In addition, 11 combinations of ace mutation were observed across the detected populations. The most frequently detected combination was L/V+A/V+Y, followed by L+A+Y and L/V+A+Y. No significant relationship was found between single mutation/combination mutations and DDVP resistance. These results indicate that the OPs resistance is prevalent among the housefly populations in Guizhou Province, with a similar pattern of allele mutation of ace across China. The target resistance can not fully account for the resistance of houseflies to OPs in Guizhou.

The BBSome, a complex of eight Bardet-Biedl syndrome (BBS) proteins involved in cilia function, has emerged as an important regulator of energy balance, but the underlying cellular and molecular mechanisms are not fully understood. Here, we show that the control of energy homeostasis by the anorexigenic proopiomelanocortin (POMC) neurons and orexigenic agouti-related peptide (AgRP) neurons require intact BBSome. Targeted disruption of the BBSome by Bbs1 gene deletion in POMC or AgRP neurons increases body weight and adiposity. We demonstrate that obesity in mice lacking the Bbs1 gene in POMC neurons is associated with hyperphagia. Mechanistically, we present evidence implicating the BBSome in the trafficking of G protein–coupled neuropeptide Y Y2 receptor (NPY2R) and serotonin 5-hydroxytryptamine (HT)2C receptor (5-HT2CR) to cilia and plasma membrane, respectively. Consistent with this, loss of the BBSome reduced cell surface expression of the 5-HT2CR, interfered with serotonin-evoked increase in intracellular calcium and membrane potential, and blunted the anorectic and weight-reducing responses evoked by the 5-HT2cR agonist, lorcaserin. Finally, we show that disruption of the BBSome causes the 5-HT2CR to be stalled in the late endosome. Our results demonstrate the significance of the hypothalamic BBSome for the control of energy balance through regulation of trafficking of important metabolic receptors.

The Hycleus cichorii and Hycleus phaleratus are two species of medicinal meloids widely distributed in southwest of China. We sequenced an annotated the complete mitochondrial genomes of H. cichorii and H. phaleratus, and the mitogenomes are 15,847 and 16,004 bp in length, respectively. Every mitochondrial genome encodes 13 proteins, 2 ribosomal RNAs, 22 tRNAs, and a control region with the identical arrangement to other beetles. The preliminary phylogenetic analysis with mitochondrial genomes of nine meloid species further confirmed the status of these two species.

Background Ambiguous or atypical phenotypes can make a definite diagnosis of primary immunodeficiency diseases based on biochemical indices alone challenging. Further, mortality in early life because of infections in patients with these conditions supports the use of genetic tests to facilitate rapid and accurate diagnoses. Methods Genetic and clinical analyses of three unrelated Chinese children with clinical manifestations of recurrent infections, who were considered to have primary immunodeficiency diseases, were conducted. Patient clinical features and serum immunological indices were recorded. Next‐generation sequencing was used to screen for suspected pathogenic variants. Family co‐segregation and in silico analysis were conducted to evaluate the pathogenicity of identified variants, following the American College of Medical Genetics and Genomics guidance. Results All three patients were found to have predominant antibody defects. Sequencing analysis revealed that one had two compound heterozygous variants, c.255C>A and c.295C>T, in the autosomal gene, activation‐induced cytidine deaminase (AICDA). The other two patients were each hemizygous for the variants c.1185G>A and c.82C>T in the Bruton's tyrosine kinase (BTK) gene on the X chromosome. In silico analysis revealed that identified substituted amino acids were highly conserved and predicted to cause structural and functional damage to the proteins. Conclusion Four pathogenic variants in AICDA and BTK were confirmed to cause different forms of hyper‐IgM syndrome type 2 (HIGM2) and X‐linked agammaglobulinemia (XLA); two were novel mutations that have never been reported previously. This is the first report of HIGM2 caused by AICDA deficiency in a patient from the Chinese mainland., In this paper, comprehensive clinical characteristics of the PIDDs patients are recorded, which will give more evidence for the diagnosis of the two diseases. Two novel mutations have never been reported before were identified, which will enrich the worldwide spectrum of HIGM2 and XLA. Moreover, this is the first report of HIGM2 caused by AICDA deficiency in the Chinese mainland cohorts, which will set a good example for similar cases in the future.

In cluster-based wireless sensor networks, cluster heads (CHs) gather and fuse data packets from sensor nodes, then, they forward fused packets to the sink node (SN). This helps wireless sensor networks balance energy effectively and efficiently to prolong their lifetime. However, cluster-based WSNs are vulnerable to selective forwarding attacks. Compromised CHs would become malicious and launch selective forwarding attacks in which they drop part of or all the packets from other nodes. In this paper, a data clustering algorithm (DCA) for detecting a selective forwarding attack (DCA-SF) is proposed. It can capture and isolate malicious CHs that have launched selective forwarding attacks by clustering their cumulative forwarding rates (CFRs). The DCA-SF algorithm has been strengthened by changing the DCA parameters (Eps, Minpts) adaptively. The simulation results show that the DCA-SF has a low missed detection rate of 1.04% and a false detection rate of 0.42% respectively with low energy consumption.

Background: Commonly known as blister beetles or Spanish fly, there are more than 1,500 species in the Meloidae family (Coleoptera:Tenebrionoidea) that produce the potent defensive blistering agent cantharidin, which has recently been exploited for cancer therapy. Hycleus cichorii and Hycleus phaleratus are exploited as traditional Chinese medicine over 2,000 years due to their ability to biosynthesize cantharidin. These blister beetles share highly similar environments and ecological niches. To understand the role of the chemosensory system in speciation and evolution in the beetles, we identified the chemosensory gene families in whole genome of both blister beetle comprehensively. Results: We identified 29 OBPs, 10 CSPs, 116 ORs, 80 GRs, and 35 IRs in H. phaleratus and 30 OBPs, 10 CSPs, 191 ORs, 92 GRs and 42 IRs in H. cichorii. The 7 groups of beetles’ ORs were recovered, but a new pattern of ORs in Coleoptera were surfaced, due to lack of whole OR repertoire for comparison to T. castaneum before. The OR number is varied, identified in H. cichorii 64% more than that in H. phaleratus (191 VS 116), which maybe an evolution event between these blister beetle’s speciation. A major Hycleus-specific expansion clade of bitter GRs is evident based on our phylogenetic tree, in which, clustered more than 50% Hycleus-bitter GRs. All the ten clade of beetles’ antennal IR identified in both Hycleus beetles. Interestingly, IR75 and IR41a were obviously expensed compare to other insects. Conclusions: The GR and IR expansion events may promote Hycleus genus evolution. Our data will provide a basis for future species protection and speciation focusing on the blister beetle.

CYP4B1 belongs to the mammalian CYP4 enzyme family and is predominantly expressed in the lungs of humans. It is responsible for the oxidative metabolism of a wide range of endogenous compounds and xenobiotics. In this study, using data from The Cancer Genome Atlas (TCGA) project and the Gene Expression Omnibus (GEO) database, a secondary analysis was performed to explore the expression profile of CYP4B1, as well as its prognostic value in patients with lung adenocarcinoma (LUAD). Based on the obtained results, a significantly decreased CYP4B1 expression was discovered in patients with LUAD when compared with their normal counterparts (pp = 0.0041), history of pharmaceutical (p = 0.0127) and radiation (p = 0.0340) therapy, mutations in KRAS/EGFR/ALK (p = 0.0239), and living status of dead (p = 0.0026). Survival analysis indicated that the low CYP4B1 expression was an independent prognostic indicator of shorter survival in terms of overall survival (OS) and recurrence-free survival (RFS) in patients with LUAD. The copy number alterations (CNAs) and sites of cg23440155 and cg23414387 hypermethylation might contribute to the decreased CYP4B1 expression. Gene set enrichment analysis (GSEA) suggested that CYP4B1 might act as an oncogene in LUAD by preventing biological metabolism pathways of exogenous and endogenous compounds and enhancing DNA replication and cell cycle activities. In conclusion, CYP4B1 expression may serve as a valuable independent prognostic biomarker and a potential therapeutic target in patients with LUAD.

With the popularity of wireless sensor networks (WSNs), it is high time to solve the tough problem of isolated nodes. To avoid isolated clusters effectively, we proposed Diffusion Clustering Routing Protocol (DCRP). In this scheme, clusters are diffusing outward from the base station (BS) hop by hop. BS and the one-depth sensor nodes form the first cluster and then new cluster heads (CHs) are selected from the member nodes of existing clusters. Moreover, the optimal CHs equation (1) consist of three factors of the number of neighbor nodes, depth and residual energy. DCRP realizes the communication between neighbour CHs without the help of relay nodes and makes energy consumption equilibrate among CHs during data transmission, prolonging the lifespan of WSNs with low transmission delay. Table 1 shows that DCRP extends the lifespan of WSNs by 65%, 16% and 10% respectively compared with DEBR, EEUC and MOCH.

Mobile wireless sensor network (MWSN) has the features of self-organization, multiple-hop and limited energy resources. It is vulnerable to a wide set of security attacks, including those targeting the routing protocol functionality. In this paper, the existing security problems and solutions in MWSN are summarized, and then a trust management system based on neighbor monitoring is proposed. In the trust management system, the trust value is calculated by the neighbor monitoring mechanism, and the direct trust value and the indirect trust value are combined to establish the distributed trust model to detect the malicious nodes. The consistency check algorithm is capable of defending against the attacks on the trust model. In addition, because of the limited energy of the sensor nodes, the energy-balanced algorithm is introduced to prolong the lifespan of MWSN. The residual energy and energy density are considered in the routing decision. Finally, the simulation experiments show that the proposed algorithm can detect the malicious nodes effectively and achieve the energy-balanced goal to prolong the lifespan of MWSN.

Lhermitte-Duclos disease (LDD) is a rare, non-cancerous entity characterized by enlarged, abnormally developed cerebellar folia containing dysplastic cells. Symptomatic LDD is commonly observed in adults (adult-onset LDD, aLDD) as an isolated condition or associated with Cowden's disease (CD). The present study aimed to investigate the magnetic resonance imaging (MRI) characteristics and the underlying pathological findings in 7 cases of aLDD, with emphasis on the association with CD and the need for active cancer surveillance once the diagnosis of LDD is confirmed. The MRI findings along with the clinical and histopathological data collected from 7 patients with aLDD were retrospectively reviewed. The diagnosis of CD was based on a range of clinical characteristics, according to the International Cowden Consortium Criteria. A thorough review of the published data was conducted and our results indicated that all 7 cases shared similar MRI characteristics, whether the aLDD was sporadic (2 cases) or associated with CD (5 cases), including a highly typical non-enhancing striated MRI appearance of thickened folia, consisting of alternating bands on T1- and T2-weighted images. On gross examination, the involved cerebellar folia were distorted and enlarged, whereas the histopathological examination revealed that the molecular layer was widened and occupied by abnormal ganglion cells. Moreover, a reduction in the number or absence of the Purkinje cells and hypertrophy of the granular cell layer were observed. Our findings were consistent with the diagnosis of LDD. Variable levels of vacuolization of the white matter and the molecular layer were observed in all the cases. Notably, CD34 immunohistochemical analysis revealed the presence of angiogenesis within the lesions. aLDD associated with CD exhibited no pathological or immunohistochemical characteristics that were distinct from those of isolated aLDD. Of the 7 cases of aLDD, 5 presented with symptoms suggestive of CD, which is a syndrome associated with a high risk of multiple benign and malignant neoplasms. In conclusion, aLDD exhibits characteristic MRI and histopathological findings and displays a strong association with CD. Therefore, we recommend that the MRI diagnosis of aLDD triggers active cancer surveillance and preventive care.

The security problems of wireless sensor networks (WSN) have attracted people’s wide attention. In this paper, after we have summarized the existing security problems and solutions in WSN, we find that the insider attack to WSN is hard to solve. Insider attack is different from outsider attack, because it can’t be solved by the traditional encryption and message authentication. Therefore, a reliable secure routing protocol should be proposed in order to defense the insider attack. In this paper, we focus on insider selective forwarding attack. The existing detection mechanisms, such as watchdog, multipath retreat, neighbor-based monitoring and so on, have both advantages and disadvantages. According to their characteristics, we proposed a secure routing protocol based on monitor node and trust mechanism. The reputation value is made up with packet forwarding rate and node’s residual energy. So this detection and routing mechanism is universal because it can take account of both the safety and lifetime of network. Finally, we use OPNET simulation to verify the performance of our algorithm.

Inhibitory 5-HT1areceptors are located on serotonin (5-HT) neurons (autoreceptors) as well as neurons of the respiratory network (heteroreceptors). Thus, effects on breathing of 5-HT1aagonists, such as (R)-(+)-8-hydroxy-2-(di-N-propylamino) tetralin (8-OH-DPAT), could either be due to decreased firing of 5-HT neurons or direct effects on the respiratory network. Mice in which the transcription factor LMX1B is genetically deleted selectively inPet1-1-expressing cells (Lmx1bf/f/p) essentially have complete absence of central 5-HT neurons, providing a unique opportunity to separate the effect of activation of downstream 5-HT1aheteroreceptors from that of autoreceptors. We used rhythmically active medullary slices from wild-type (WT) andLmx1bf/f/pneonatal mice to differentiate autoreceptor versus heteroreceptor effects of 8-OH-DPAT on hypoglossal nerve respiratory output. 8-OH-DPAT transiently increased respiratory burst frequency inLmx1bf/f/ppreparations, but not in WT slices. This excitation was abolished when synaptic inhibition was blocked by GABAergic/glycinergic receptor antagonists. Conversely, after 10 min of application, frequency inLmx1bf/f/pslices was not different from baseline, whereas it was significantly depressed in WT slices. In WT micein vivo, subcutaneous injection of 8-OH-DPAT produced similar biphasic respiratory effects as inLmx1bf/f/pmice. We conclude that 5-HT1areceptor agonists have two competing effects: rapid stimulation of breathing due to excitation of the respiratory network, and delayed inhibition of breathing due to autoreceptor inhibition of 5-HT neurons. The former effect is presumably due to inhibition of inhibitory interneurons embedded in the respiratory network.

Subacute and chronic changes in tonic GABAergic inhibition occur in human and experimental epilepsy. Less is known about how tonic inhibition is modulated over shorter time frames (seconds). We measured endogenous tonic GABA currents from cultured rat hippocampal neurons to evaluate how they are affected by 1) transient increases in extracellular GABA concentration ([GABA]), 2) transient postsynaptic depolarization, and 3) depolarization of presynaptic cells. Transient increases in [GABA] (1 μM) reduced tonic currents; this reduction resulted from GABA-induced shifts in the reversal potential for GABA currents ( EGABA). Transient depolarization of postsynaptic neurons reversed the effects of exogenous GABA and potentiated tonic currents. The voltage-dependent potentiation of tonic GABA currents was independent of EGABA shifts and represented postdepolarization potentiation (PDP), an intrinsic GABAA receptor property (Ransom CB, Wu Y, Richerson GB. J Neurosci 30: 7672–7684, 2010). Inhibition of vesicular GABA release with concanamycin A (ConA) did not affect tonic currents. In ConA-treated cells, transient application of 12 mM K+ to depolarize presynaptic neurons and glia produced a persistent increase in tonic current amplitude. The K+-induced increase in tonic current was reversibly inhibited by SKF89976a (40 μM), indicating that this was caused by nonvesicular GABA release from GABA transporter type 1 (GAT1). Nonvesicular GABA release due to GAT1 reversal also occurred in acute hippocampal brain slices. Our results indicate that tonic GABA currents are rapidly regulated by GABA-induced changes in intracellular Cl− concentration, PDP of extrasynaptic GABAA receptors, and nonvesicular GABA release. These mechanisms may influence tonic inhibition during seizures when neurons are robustly depolarized and extracellular GABA and K+ concentrations are elevated.