Ethanol enhances neurosteroidogenesis in hippocampal pyramidal neurons by paradoxical NMDA receptor activation

Using an antibody against 5α-reduced neurosteroids, predominantly allopregnanolone, we found that immunostaining in the CA1 region of rat hippocampal slices was confined to pyramidal neurons. This neurosteroid staining was increased following 15 min administration of 60 mm but not 20 mm ethanol, and the enhancement was blocked by finasteride and dutasteride, selective inhibitors of 5α-reductase, a key enzyme required for allopregnanolone synthesis. Consistent with a prior report indicating that N-methyl-D-aspartate (NMDA) receptor (NMDAR) activation can promote steroid production, we observed that D-2-amino-5-phosphonovalerate (APV), a competitive NMDAR antagonist, blocked the effects of 60 mm ethanol on staining. We previously reported that 60 mm ethanol inhibits the induction of long-term potentiation (LTP), a cellular model for memory formation, in the CA1 region. In the present study, LTP inhibition by 60 mm ethanol was also overcome by both the 5α-reductase inhibitors and by APV. Furthermore, the effects of ethanol on neurosteroid production and LTP were mimicked by a low concentration of NMDA (1 μm), and the ability of NMDA to inhibit LTP and to enhance neurosteroid staining was reversed by finasteride and dutasteride, as well as by APV. These results indicate that ethanol paradoxically enhances GABAergic neurosteroid production by activation of unblocked NMDARs and that acute LTP inhibition by ethanol represents a form of NMDAR-mediated metaplasticity

Respiration-dependent primary Na+ pump in halophilic marine bacterium, Alcaligenes strain 201

AbstractThe inverted membrane vesicles of marine bacterium Alcaligenes strain 201 generated inside positive membrane potential and accumulated Na+ on the energization with NADH. Both the generation of membrane potential and the accumulation of Na+ were resistant to a proton conductor, carbonyl cyanide m-chlorophenylhydrazone. Collapse of the membrane potential by valinomycin resulted in the stimulation of Na+ accumulation. It was concluded that Alcaligenes strain 201 possesses a respiratory Na+ pump which is analogous to that of Vibrio alginolyticus.Inverted vesicle; Na+ pump; Marine bacteria; Respiratory chai

Midazolam inhibits hippocampal long-term potentiation and learning through dual central and peripheral benzodiazepine receptor activation and neurosteroidogenesis

Benzodiazepines (BDZs) enhance GABA(A) receptor inhibition by direct actions on central BDZ receptors (CBRs). Although some BDZs also bind mitochondrial receptors [translocator protein (18 kDa) (TSPO)] and promote the synthesis of GABA-enhancing neurosteroids, the role of neurosteroids in the clinical effects of BDZs is unknown. In rat hippocampal slices, we compared midazolam, an anesthetic BDZ, with clonazepam, an anticonvulsant/anxiolytic BDZ that activates CBRs selectively. Midazolam, but not clonazepam, increased neurosteroid levels in CA1 pyramidal neurons without changing TSPO immunostaining. Midazolam, but not clonazepam, also augmented a form of spike inhibition after stimulation adjacent to the pyramidal cell layer and inhibited induction of long-term potentiation. These effects were prevented by finasteride, an inhibitor of neurosteroid synthesis, or 17PA [17-phenyl-(3α,5α)-androst-16-en-3-ol], a blocker of neurosteroid effects on GABA(A) receptors. Moreover, the synaptic effects were mimicked by a combination of clonazepam with FGIN (2-[2-(4-fluorophenyl)-1H-indol-3-yl]-N,N-dihexylacetamide), a selective TSPO agonist, or a combination of clonazepam with exogenous allopregnanolone. Consistent with these in vitro results, finasteride abolished the effects of midazolam on contextual fear learning when administrated 1 d before midazolam injection. Thus, dual activation of CBRs and TSPO appears to result in unique actions of clinically important BDZs. Furthermore, endogenous neurosteroids are shown to be important regulators of pyramidal neuron function and synaptic plasticity

Embedding a Differentiable Mel-cepstral Synthesis Filter to a Neural Speech Synthesis System

This paper integrates a classic mel-cepstral synthesis filter into a modern neural speech synthesis system towards end-to-end controllable speech synthesis. Since the mel-cepstral synthesis filter is explicitly embedded in neural waveform models in the proposed system, both voice characteristics and the pitch of synthesized speech are highly controlled via a frequency warping parameter and fundamental frequency, respectively. We implement the mel-cepstral synthesis filter as a differentiable and GPU-friendly module to enable the acoustic and waveform models in the proposed system to be simultaneously optimized in an end-to-end manner. Experiments show that the proposed system improves speech quality from a baseline system maintaining controllability. The core PyTorch modules used in the experiments will be publicly available on GitHub.Comment: Submitted to ICASSP 202

On Nietzsche’s Concept of ‘European Nihilism’

<div><p>Aplog-1 is a simplified analog of the tumor-promoting aplysiatoxin with anti-proliferative and cytotoxic activities against several cancer cell lines. Our recent findings have suggested that protein kinase Cδ (PKCδ) could be one of the target proteins of aplog-1. In this study, we synthesized amide-aplog-1 (<b>3</b>), in which the C-1 ester group was replaced with an amide group, to improve chemical stability <i>in vivo</i>. Unfortunately, <b>3</b> exhibited seventy-fold weaker binding affinity to the C1B domain of PKCδ than that of aplog-1, and negligible anti-proliferative and cytotoxic activities even at 10⁻⁴ M. A conformational analysis and density functional theory calculations indicated that the stable conformation of <b>3</b> differed from that of aplog-1. Since 27-methyl and 27-methoxy derivatives (<b>1</b>, <b>2</b>) without the ability to bind to PKC isozymes exhibited marked anti-proliferative and cytotoxic activities at 10⁻⁴ M, <b>3</b> may be an inactive control to identify the target proteins of aplogs.</p></div

Inter-individual Variations in Circadian Misalignment-induced Nafld Pathophysiology in Mice

Pathological consequences of circadian misalignment, such as shift work, show considerable individual differences, but the lack of mechanistic understanding hinders precision prevention to prevent and mitigate disease symptoms. Here, we employed an integrative approach involving physiological, transcriptional, and histological phenotypes to examine inter-individual differences in pre-symptomatic pathological progression, preceding irreversible disease onset, in wild-type mice exposed to chronic jet-lag (CJL). We observed that CJL markedly increased the prevalence of hepatic steatosis with pronounced inter-individual differences. Stratification of individual mice based on CJL-induced hepatic transcriptomic signature, validated by histopathological analysis, pinpoints dysregulation of lipid metabolism. Moreover, the period and power of intrinsic behavioral rhythms were found to significantly correlate with CJL-induced gene signatures. Together, our results suggest circadian rhythm robustness of the animals contributes to inter-individual variations in pathogenesis of circadian misalignment-induced diseases and raise the possibility that these physiological indicators may be available for predictive hallmarks of circadian rhythm disorders

Clinical statistical study of patients with jaw deformity in the Department of Orthodontics, Matsumoto Dental University Hospital

Clinical and statistical analyses were conducred of patients with jaw deformity who visited the Department of orthodontics, Matsumoto Dental University hospital. One hundred and two patients with jaw deformity were treated in the department from January 2003 to December 2012. (1) The total number of patients was 102; the male–female ratio was 1: 1.32. (2) Mandibular protrusion was the most frequent diagnosis, with 35 cases (34.3％), followed by mandibular protrusion + maxillary retrusion (16 cases, 15.7％), and mandibular protrusion + asymmetry (15 cases, 14.7％). (3) As for the tooth extraction sites for presurgical orthodontic treatment, although non–tooth extraction was the highest from 2003 to 200₇, maxillary first premolar tooth extraction was the highest from 2008 to 2012. (4) Sagittal split ramus osteotomy (SSRO) was the most commonly performed procedure (5₇.8％), followed by Le Fort I + SSRO (36.3％). Le Fort I + SSRO showed an increasing tendency