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Cephalotocin is a bioactivity-regulating peptide expressed in octopus (

Although the pathological contributions of reactive astrocytes have been implicated in Alzheimer's disease (AD), their in vivo functions remain elusive due to the lack of appropriate experimental models and precise molecular mechanisms. Here, we show the importance of astrocytic reactivity on the pathogenesis of AD using GiD, a newly developed animal model of reactive astrocytes, where the reactivity of astrocytes can be manipulated as mild (GiDm) or severe (GiDs). Mechanistically, excessive hydrogen peroxide (H2O2) originated from monoamine oxidase B in severe reactive astrocytes causes glial activation, tauopathy, neuronal death, brain atrophy, cognitive impairment and eventual death, which are significantly prevented by AAD-2004, a potent H2O2 scavenger. These H2O2--induced pathological features of AD in GiDs are consistently recapitulated in a three-dimensional culture AD model, virus-infected APP/PS1 mice and the brains of patients with AD. Our study identifies H2O2 from severe but not mild reactive astrocytes as a key determinant of neurodegeneration in AD.

The study aimed to understand the delirium experience of intensive care unit (ICU) patients.We performed a qualitative study using Colaizzi's phenomenological method. Eleven patients, who experienced delirium according to the Confusion Assessment Method for ICU, participated after transferring to general wards from the ICU. Individual in-depth semi-structured interviews ranging from 30 minutes to 2 hours in length were conducted between November 2018 and August 2019.Nine themes and four theme clusters emerged. The four theme clusters were: 1) "Overwhelmed by fear," which describes the experience of a patient close to death and the feeling of difficulty in understanding disorganized thinking; 2) "Anxious about not understanding the situation," which means that patients' sense of time and space were disordered in the ICU; 3) "Being deserted," which indicates the feeling of being separated from others and yourself; and 4) "Resistance to protect my dignity," which indicates that the dignity and autonomy of an individual in the patient's position at the ICU, are ignored.Nursing interventions are needed that would enable patients to maintain orientation and self-esteem in the ICU. In addition, healthcare providers need to provide information about the unfamiliar environment in the ICU in advance.

Background The shuttles hoppfish (mudskipper), Periophthalmus modestus, is one of the mudskippers, which are the largest group of amphibious teleost fishes, which are uniquely adapted to live on mudflats. Because mudskippers can survive on land for extended periods by breathing through their skin and through the lining of the mouth and throat, they were evaluated as a model for the evolutionary sea-land transition of Devonian protoamphibians, ancestors of all present tetrapods. Results A total of 39.6, 80.2, 52.9, and 33.3 Gb of Illumina, Pacific Biosciences, 10X linked, and Hi-C data, respectively, was assembled into 1,419 scaffolds with an N50 length of 33 Mb and BUSCO score of 96.6%. The assembly covered 117% of the estimated genome size (729 Mb) and included 23 pseudo-chromosomes anchored by a Hi-C contact map, which corresponded to the top 23 longest scaffolds above 20 Mb and close to the estimated one. Of the genome, 43.8% were various repetitive elements such as DNAs, tandem repeats, long interspersed nuclear elements, and simple repeats. Ab initio and homology-based gene prediction identified 30,505 genes, of which 94% had homology to the 14 Actinopterygii transcriptomes and 89% and 85% to Pfam familes and InterPro domains, respectively. Comparative genomics with 15 Actinopterygii species identified 59,448 gene families of which 12% were only in P. modestus. Conclusions We present the high quality of the first genome assembly and gene annotation of the shuttles hoppfish. It will provide a valuable resource for further studies on sea-land transition, bimodal respiration, nitrogen excretion, osmoregulation, thermoregulation, vision, and mechanoreception.

Parupeneus barberinus is a tropical/subtropical reef-dwelling marine fish belonging to the family Mullidae. Herein, we report the first sequencing and assembly of the complete mitochondrial genome of P. barberinus. The complete mitochondrial genome is 16,560 bp long and has the typical vertebrate mitochondrial gene arrangement, consisting of 13 protein-coding genes, 22 tRNA genes, two rRNA genes, and a control region. Phylogenetic analysis using mitochondrial genomes of 18 species showed that P. barberinus is clustered with P. multifasciatus and P. chrysopleuron and rooted with other Mullidae species. This mitochondrial genome provides potentially important resources for addressing taxonomic issues and studying molecular evolution.

Cephalopods have the most advanced nervous systems and intelligent behavior among all invertebrates. Their brains provide comparative insights for understanding the molecular and functional origins of the human brain. Although brain maps that contain information on the organization of each subregion are necessary for a study on the brain, no whole brain atlas for adult cephalopods has been constructed to date. Here, we obtained sagittal and coronal sections covering the entire brain of adult Octopus minor (Sasaki), which belongs to the genus with the most species in the class Cephalopoda and is commercially available in East Asia throughout the year. Sections were stained using Hematoxylin and Eosin (H&E) to visualize the cellular nuclei and subregions. H&E images of the serial sections were obtained at 30~70-µm intervals for the sagittal plain and at 40~80-µm intervals for the coronal plain. Setting the midline point of the posterior end as the fiducial point, we also established the distance coordinates of each image. We found that the brain had the typical brain structure of the Octopodiformes. A number of subregions were discriminated by a Hematoxylin-positive layer, the thickness and neuronal distribution pattern of which varied markedly depending upon the region. We identified more than 70 sub-regions based on delineations of representative H&E images. This is the first brain atlas, not only for an Octopodiformes species but also among adult cephalopods, and we anticipate that this atlas will provide a valuable resource for comparative neuroscience research., Graphical Abstract

The complete mitochondrial genome was determined for the flying gurnard Dactylopterus volitans belonging to the family Dactylopteridae. The total length of the D. volitans mitochondrial genome is 1...

The complete mitochondrial genome was determined for the Robust tonguefish Cynoglossus robustus belonging to the family Cynoglossidae. The length of the complete mitochondrial genome is 16,720 bp, consisting of 13 protein-coding genes, 22 tRNA genes, two rRNA genes, and a control region. Rearrangements of the tRNAGln and a control region gene were found and tRNAGln is translocated from the light to the heavy strand. Phylogenetic analysis using mitochondrial genomes of 12 species showed that C. robustus formed a well-supported monophyletic group with other Cynoglossus species.

Although the pathological contributions of reactive astrocytes have been implicated in Alzheimer's disease (AD), their in vivo functions remain elusive due to the lack of appropriate experimental models and precise molecular mechanisms. Here, we show the importance of astrocytic reactivity on the pathogenesis of AD using GiD, a newly developed animal model of reactive astrocytes, where the reactivity of astrocytes can be manipulated as mild (GiDm) or severe (GiDs). Mechanistically, excessive hydrogen peroxide (H

Current pharmacological treatments for Parkinson's disease (PD) are focused on symptomatic relief, but not on disease modification, based on the strong belief that PD is caused by irreversible dopaminergic neuronal death. Thus, the concept of the presence of dormant dopaminergic neurons and its possibility as the disease-modifying therapeutic target against PD have not been explored. Here we show that optogenetic activation of substantia nigra pars compacta (SNpc) neurons alleviates parkinsonism in acute PD animal models by recovering tyrosine hydroxylase (TH) from the TH-negative dormant dopaminergic neurons, some of which still express DOPA decarboxylase (DDC). The TH loss depends on reduced dopaminergic neuronal firing under aberrant tonic inhibition, which is attributed to excessive astrocytic GABA. Blocking the astrocytic GABA synthesis recapitulates the therapeutic effect of optogenetic activation. Consistently, SNpc of postmortem PD patients shows a significant population of TH-negative/DDC-positive dormant neurons surrounded by numerous GABA-positive astrocytes. We propose that disinhibiting dormant dopaminergic neurons by blocking excessive astrocytic GABA could be an effective therapeutic strategy against PD.

KDS2010, a MAO-B inhibitor, shows a long-lasting effect in alleviating memory impairment in an Alzheimer’s disease mouse model., Monoamine oxidase–B (MAO-B) has recently emerged as a potential therapeutic target for Alzheimer’s disease (AD) because of its association with aberrant γ-aminobutyric acid (GABA) production in reactive astrocytes. Although short-term treatment with irreversible MAO-B inhibitors, such as selegiline, improves cognitive deficits in AD patients, long-term treatments have shown disappointing results. We show that prolonged treatment with selegiline fails to reduce aberrant astrocytic GABA levels and rescue memory impairment in APP/PS1 mice, an animal model of AD, because of increased activity in compensatory genes for a GABA-synthesizing enzyme, diamine oxidase (DAO). We have developed a potent, highly selective, and reversible MAO-B inhibitor, KDS2010 (IC50 = 7.6 nM; 12,500-fold selectivity over MAO-A), which overcomes the disadvantages of the irreversible MAO-B inhibitor. Long-term treatment with KDS2010 does not induce compensatory mechanisms, thereby significantly attenuating increased astrocytic GABA levels and astrogliosis, enhancing synaptic transmission, and rescuing learning and memory impairments in APP/PS1 mice.

The complete mitochondrial genome was determined for the Cynoglossus interruptus belonging to the family Cynoglossidae. The length of the complete mitochondrial genome is 17,262 bp, consisting of 13 protein-coding genes, 22 tRNA genes, two rRNA genes, and a control region. The gene rearrangement related to tRNAGln and a control region gene were found, forming the gene order of CR-Ile-Gln-Met. Phylogenetic analysis using mitochondrial genomes of 12 species showed that C. interruptus formed a well-supported monophyletic group with other Cynoglossus species.

Stethojulis strigiventer is a tropical reef-associated marine fish belonging to the family Labridae. Herein, we report the first sequencing and assembly of the complete mitochondrial genome of S. s...

The complete mitochondrial genome was determined for the shuttles hoppfish Periophthalmus modestus belonging to the family Oxudercidae. The length of the complete mitochondrial genome is 16,510 bp ...

Pristicon trimaculatus is a tropical reef-associated marine fish belonging to the family Apogonidae. Herein, we report the first sequencing and assembly of the complete mitochondrial genome of P. t...

GABA is the major inhibitory transmitter in the brain and is released not only from a subset of neurons but also from glia. Although neuronal GABA is well known to be synthesized by glutamic acid decarboxylase (GAD), the source of glial GABA is unknown. After estimating the concentration of GABA in Bergmann glia to be around 5-10 mM by immunogold electron microscopy, we demonstrate that GABA production in glia requires MAOB, a key enzyme in the putrescine degradation pathway. In cultured cerebellar glia, both Ca(2+)-induced and tonic GABA release are significantly reduced by both gene silencing of MAOB and the MAOB inhibitor selegiline. In the cerebellum and striatum of adult mice, general gene silencing, knock out of MAOB or selegiline treatment resulted in elimination of tonic GABA currents recorded from granule neurons and medium spiny neurons. Glial-specific rescue of MAOB resulted in complete rescue of tonic GABA currents. Our results identify MAOB as a key synthesizing enzyme of glial GABA, which is released via bestrophin 1 (Best1) channel to mediate tonic inhibition in the brain.

In Alzheimer's disease (AD), memory impairment is the most prominent feature that afflicts patients and their families. Although reactive astrocytes have been observed around amyloid plaques since the disease was first described, their role in memory impairment has been poorly understood. Here, we show that reactive astrocytes aberrantly and abundantly produce the inhibitory gliotransmitter GABA by monoamine oxidase-B (Maob) and abnormally release GABA through the bestrophin 1 channel. In the dentate gyrus of mouse models of AD, the released GABA reduces spike probability of granule cells by acting on presynaptic GABA receptors. Suppressing GABA production or release from reactive astrocytes fully restores the impaired spike probability, synaptic plasticity, and learning and memory in the mice. In the postmortem brain of individuals with AD, astrocytic GABA and MAOB are significantly upregulated. We propose that selective inhibition of astrocytic GABA synthesis or release may serve as an effective therapeutic strategy for treating memory impairment in AD.

Alzheimer's disease (AD) is characterized by the transition of amyloid-β (Aβ) monomers into toxic oligomers and plaques. Given that Aβ abnormality typically precedes the development of clinical symptoms, an agent capable of disaggregating existing Aβ aggregates may be advantageous. Here we report that a small molecule, 4-(2-hydroxyethyl)-1-piperazinepropanesulphonic acid (EPPS), binds to Aβ aggregates and converts them into monomers. The oral administration of EPPS substantially reduces hippocampus-dependent behavioural deficits, brain Aβ oligomer and plaque deposits, glial γ-aminobutyric acid (GABA) release and brain inflammation in an Aβ-overexpressing, APP/PS1 transgenic mouse model when initiated after the development of severe AD-like phenotypes. The ability of EPPS to rescue Aβ aggregation and behavioural deficits provides strong support for the view that the accumulation of Aβ is an important mechanism underlying AD.

Alzheimer's disease (AD) is characterized by the transition of amyloid-β (Aβ) monomers into toxic oligomers and plaques. Given that Aβ abnormality typically precedes the development of clinical symptoms, an agent capable of disaggregating existing Aβ aggregates may be advantageous. Here we report that a small molecule, 4-(2-hydroxyethyl)-1-piperazinepropanesulphonic acid (EPPS), binds to Aβ aggregates and converts them into monomers. The oral administration of EPPS substantially reduces hippocampus-dependent behavioural deficits, brain Aβ oligomer and plaque deposits, glial γ-aminobutyric acid (GABA) release and brain inflammation in an Aβ-overexpressing, APP/PS1 transgenic mouse model when initiated after the development of severe AD-like phenotypes. The ability of EPPS to rescue Aβ aggregation and behavioural deficits provides strong support for the view that the accumulation of Aβ is an important mechanism underlying AD., Amyloid-beta deposits are a pathological hallmark of Alzheimer's disease, and have previously been targeted in immunisation therapies. Here, the authors show that oral administration of the small molecule EPPS reduces Aß plaque and oligomer load in APP/PS1 mice and improves learning and memory performance.

Parupeneus barberinus is a tropical/subtropical reef-dwelling marine fish belonging to the family Mullidae. Herein, we report the first sequencing and assembly of the complete mitochondrial genome ...

Hypoxic damage to the prefrontal cortex (PFC) has been implicated in the frontal lobe dysfunction found in various neuropsychiatric disorders. The underlying subcortical mechanisms, however, have not been well explored. In this study, we induced a PFC-specific hypoxia-like damage by cobalt-wire implantation to demonstrate that the role of the mediodorsal thalamus (MD) is critical for the development of frontal lobe dysfunction, including frontal lobe-specific seizures and abnormal hyperactivity. Before the onset of these abnormalities, the cross talk between the MD and PFC nuclei at theta frequencies was enhanced. During the theta frequency interactions, burst spikes, known to depend on T-type Ca2+channels, were increased in MD neurons.In vivoknockout or knockdown of the T-type Ca2+channel gene (CaV3.1) in the MD substantially reduced the theta frequency MD–PFC cross talk, frontal lobe-specific seizures, and locomotor hyperactivity in this model. These results suggest a two-step model of prefrontal dysfunction in which the response to a hypoxic lesion in the PFC results in abnormal thalamocortical feedback driven by thalamic T-type Ca2+channels, which, in turn, leads to the onset of neurological and behavioral abnormalities. This study provides valuable insights into preventing the development of neuropsychiatric disorders arising from irreversible PFC damage.

The rhythmic motor pathway activation by pacemaker neurons or circuits in the brain has been proposed as the mechanism for the timing of motor coordination, and the abnormal potentiation of this mechanism may lead to a pathological tremor. Here, we show that the potentiation of Ca V 3.1 T-type Ca 2+ channels in the inferior olive contributes to the onset of the tremor in a pharmacological model of essential tremor. After administration of harmaline, 4- to 10-Hz synchronous neuronal activities arose from the IO and then propagated to cerebellar motor circuits in wild-type mice, but those rhythmic activities were absent in mice lacking Ca V 3.1 gene. Intracellular recordings in brain-stem slices revealed that the Ca V 3.1-deficient inferior olive neurons lacked the subthreshold oscillation of membrane potentials and failed to trigger 4- to 10-Hz rhythmic burst discharges in the presence of harmaline. In addition, the selective knockdown of Ca V 3.1 gene in the inferior olive by sh RNA efficiently suppressed the harmaline-induced tremor in wild-type mice. A mathematical model constructed based on data obtained from patch-clamping experiments indicated that harmaline could efficiently potentiate Ca V 3.1 channels by changing voltage-dependent responsiveness in the hyperpolarizing direction. Thus, Ca V 3.1 is a molecular pacemaker substrate for intrinsic neuronal oscillations of inferior olive neurons, and the potentiation of this mechanism can be considered as a pathological cause of essential tremor.

Chronic uncontrollable stress has been shown to produce various physiological alterations and impair mnemonic functions in the rodent hippocampus. Impacts on neuronal activities, however, have not been well investigated. The present study examined dorsal CA1 place cells to elucidate the computational changes associated with chronic stress effects on cognitive behaviors. After administering chronic restraint stress (CRS; 6 hours/day for ≥21 consecutive days) to adult male mice, several hippocampal characteristics were examined; i.e., spatial learning, in vitro synaptic plasticity, in vivo place cell recording and western blot analysis to determine protein levels related to learning and memory. Behaviorally, CRS significantly impeded spatial learning but enhanced non-spatial cue learning on the Morris water maze. Physiologically, CRS reduced long-term potentiation (LTP) of Schaffer collateral/commisural-CA1 pathway, phospho-αCaMKII (alpha Ca2+/calmodulin-dependent protein kinase II) level in the hippocampus and stability of spatial representation and the mean firing rates (FRs) of place cells. Moreover, the local cue-dependency of place fields was increased and the intra-burst interval (IntraBI) between consecutive spikes within a burst was prolonged following CRS. These results extend the previous findings of stress impairing LTP and spatial learning to CRS modifying physical properties of spiking in place cells that contribute to changes in navigation and synaptic plasticity.

Basal ganglia (BG) circuits orchestrate complex motor behaviors predominantly via inhibitory synaptic outputs. Although these inhibitory BG outputs are known to reduce the excitability of postsynaptic target neurons, precisely how this change impairs motor performance remains poorly understood. Here, we show that optogenetic photostimulation of inhibitory BG inputs from the globus pallidus induces a surge of action potentials in the ventrolateral thalamic (VL) neurons and muscle contractions during the post-inhibitory period. Reduction of the neuronal population with this post-inhibitory rebound firing by knockout of T-type Ca2+ channels or photoinhibition abolishes multiple motor responses induced by the inhibitory BG input. In a low dopamine state, the number of VL neurons showing post-inhibitory firing increases, while reducing the number of active VL neurons via photoinhibition of BG input, effectively prevents Parkinson disease (PD)-like motor symptoms. Thus, BG inhibitory input generates excitatory motor signals in the thalamus and, in excess, promotes PD-like motor abnormalities. VIDEO ABSTRACT.

Background Glutamate is the major neurotransmitter that mediates a principal form of excitatory synaptic transmission in the brain. From the presynaptic terminals of neurons, glutamate is released upon exocytosis of the glutamate-packaged vesicles. In recent years, astrocytes are also known to release glutamate via various routes to modulate synaptic transmission. In particular, we have characterized a glutamate-permeable Ca2+-activated anion channel encoded by Bestrophin 1 gene (Best1) that is responsible for Ca2+-dependent, channel-mediated glutamate release in astrocyte. Best1 channel contains a large pore that is readily permeable to large molecules such as glutamate and GABA. In those studies we obtained permeability ratio of glutamate to Cl- in heterologously expressed mouse Best1 in HEK293T cells and in endogenously expressed mouse Best1 in cultured astrocytes. However, up to now, glutamate permeability of the native Best1 channel in vivo has not been reported. Findings In whole-cell recordings of CA1 hippocampal astrocytes, we found that opening of Best1 channel upon activation of a Gq-coupled GPCR, protease-activated receptor 1 (PAR1) generated the anion current carried by glutamate via Ca2+ increase. This Ca2+-evoked glutamate-mediated anion current was unaffected by pretreatment of the inhibitors for a gap junction hemi-channel or Ca2+-activated K+ conductance. This astrocytic anion conductance carried by glutamate was mediated by Best1 channel expression in CA1 hippocampal astrocytes, because Best1 knock-down by shRNA expression eliminated astrocytic glutamate conductance by PAR-1 activation. However, we found that these astrocytes showed a deviation in reversal potential of Best1-mediated current from the predicted value. By performing dual patch recording, we concluded that the deviation of reversal potential is due to incomplete space clamping arising from extremely leaky membrane (input resistance ranging 1–3 MΩ), very low length constant of astrocytic processes, and the localization of Best1 channel in distal microdomains near synapses. Based on the relative shift of reversal potentials by ion substitutions, we estimated the permeability ratio of glutamate and Cl- (Pglutamate/PCl) as 0.53. Conclusions Our study shows that Best1, located at the microdomains near the synaptic junctions, has a significantly high permeability to glutamate in vivo, serving as the prominent glutamate-releasing channel in astrocytes, mediating the release of various gliotransmitters in the brain, and playing an important role in modulating synaptic transmission.

In Parkinson's disease, the motor impairments are mainly caused by the death of dopaminergic neurons. Among the enzymes which are involved in the biosynthesis and catabolism of dopamine, monoamine oxidase B (MAO-B) has been a therapeutic target of Parkinson's disease. However, due to the undesirable adverse effects, development of alternative MAO-B inhibitors with greater optimal therapeutic potential towards Parkinson's disease is urgently required. In this study, we designed and synthesized the oxazolopyridine and thiazolopyridine derivatives, and biologically evaluated their inhibitory activities against MAO-B. Structure-activity relationship study revealed that the piperidino group was the best choice for the R(1) amino substituent to the oxazolopyridine core structure and the activities of the oxazolopyridines with various phenyl rings were between 267.1 and 889.5nM in IC50 values. Interestingly, by replacement of the core structure from oxazolopyrine to thiazolopyridine, the activities were significantly improved and the compound 1n with the thiazolopyridine core structure showed the most potent activity with the IC50 value of 26.5nM. Molecular docking study showed that van der Waals interaction in the human MAO-B active site could explain the enhanced inhibitory activities of thiazolopyridine derivatives.

A tonic form of synaptic inhibition occurs in discrete regions of the central nervous system and has an important role in controlling neuronal excitability. Recently, we reported that GABA present in astrocyte is the major source of tonic inhibition in cerebellum and that GABA is released through Bestrophin-1 channel by direct permeation. In this study, we screened for the presence of astrocytic GABA in various brain regions such as hippocampus, thalamus, hypothalamus and cerebellum using immunohistochemistry. We found that astrocytic GABA was present in the regions that were reported to show tonic inhibition. Because the existence of tonic inhibition in hippocampal CA1 is somewhat controversial, we compared the amount of astrocytic GABA and tonic inhibition between the hippocampal CA1 pyramidal cell layer and the cerebellar granule cell layer. Unlike cerebellar glial cells, hippocampal astrocytes did not contain GABA. The tonic inhibition was also much lower in the pyramidal neurons of hippocampal CA1 compared to the granule cells of cerebellum. Nevertheless, most of the hippocampal astrocytes expressed Bestrophin-1 channel. These data indicate that the absence of astrocytic GABA results in a low level of tonic inhibition in hippocampal CA1 region.

Poly(vinylidene fluoride) (PVdF) fine fiber of 200–300 nm in diameter was prepared through the electrospinning process. Dehydrofluorination of PVdF-based fibers for making infusible fiber was carried out using DBU, and the infusible PVdF-based nanofibers were then carbonized at 900–1800°C. The structural properties and morphologies of the resulting carbon nanofibers were investigated using XRD, Raman IR, SEM, TEM, and surface area & pore analysis. The PVdF-based carbon nanofibers had rough surfaces composed of 20-to 30-nm granular carbons, indicating their high surface area in the range of 400–970 m2/g. They showed amorphous structures. In the case of the highly ehydrofluorinated PVdF fiber, the resulting carbon fiber had a smoother surface, with d002 = 0.34–0.36 nm, and a very low surface area of 16–33 m2/g. The hydrogen storage capacities of the above carbon nano-fibers were measured, using the gravimetric method, by magnetic suspension balance (MSB), at room temperature and at 100 bars. The storage data were obtained after the buoyancy correction. The PVdF-based microporous carbon nanofibers showed a hydrogen storage capacity of 0.04–0.4 wt%. The hydrogen storage capacity depended on the dehydrofluorination of the PVdF nanofiber precursor, and on the carbonization temperatures.