Abolished ketamine effects on the spontaneous excitatory postsynaptic current of medial prefrontal cortex neurons in GluN2D knockout mice

Abstract Ketamine, a non-competitive antagonist of the N-methyl-d-aspartate receptor (NMDAR), generates a rapidly-acting antidepressant effect. It exerts psychomimetic effects, yet demands a further investigation of its mechanism. Previous research showed that ketamine did no longer promote hyperlocomotion in GluN2D knockout (KO) mice, which is a subunit of NMDAR. In the present study, we tested whether GluN2D-containing NMDARs participate in the physiological changes in the medial prefrontal cortex (mPFC) triggered by ketamine. Sub-anesthetic dose of ketamine (25mg/kg) elevated the frequency of spontaneous excitatory postsynaptic currents (sEPSC) in wild-type (WT) mice, but not in GluN2D KO mice, 1h after the injection. The amplitude of sEPSC and paired-pulse ratio (PPR) were unaltered by ketamine in both WT and GluN2D KO mice. These findings suggest that GluN2D-containing NMDARs might play a role in the ketamine-mediated changes in glutamatergic neurons in mPFC and, presumably, in ketamine-induced hyperlocomotion

Are the long-term survival, proliferation, and differentiation of transplanted cells desirable in clinical application for spinal cord injury?

Cell transplantation studies of spinal cord injury have a premise that the transplants should be integrated in the host spinal cord tissue, differentiate into neural cells, and re-establish neural circuits, leading to the improvement of locomotor functions. However, the long-term survival, extensive proliferation, and/or differentiation of transplanted cells are not necessarily desirable clinically, and may, on the contrary, cause serious problems regarding the safety of transplants. The excessive proliferation, migration, and/or differentiation of transplanted cells may deteriorate the histological as well as functional organization of the host spinal cord. The present communication will discuss the feasibility of using three kinds of cell as transplants, including bone marrow-derived cells (BMDCs), Schwann cells, and neural stem/progenitor cells (NSPCs). BMDCs enhance tissue recovery and locomotor improvements; however, they disappear within 2-3 weeks after transplantation from the host spinal cord. This indicates that BMDCs do not serve as scaffolds for the growth of regenerating axons, but promote "endogenous" regenerating capacities of the host spinal cord, probably by secreting some trophic factors. This short-term survival of transplants, although appearing to be a disadvantage, guarantees the safety of cell transplantation. The transplantation of BMDCs is now at the Phase I/II stage of clinical application. Schwann cells have been studied extensively as a transplant material for spinal cord injury. Schwann cells survive long-term, and moderately proliferate and/or migrate in the spinal cord. It can be said that Schwann cells become well integrated in the host spinal cord. Therefore, they are regarded as a safe transplant. NSPCs proliferate, migrate, and differentiate extensively after transplantation in the host spinal cord. It is impossible at present to manipulate or control the proliferation/migration/differentiation of NPSCs to make them properly integrate in the host spinal cord. NSPCs are not considered safe for clinical application. BMDCs and Schwann cells are clinically relevant, while NS/PCs are clinically irrelevant

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Role of NMDA receptor GluN2D subunit in the antidepressant effects of enantiomers of ketamine

We investigated the rapid and sustained antidepressant effects of enantiomers of ketamine in N-methyl-d-aspartate (NMDA) receptor GluN2D subunit knockout (GluN2D-KO) mice. Intraperitoneal administration of ketamine or its enantiomers 10 min before the tail-suspension test exerted significant antidepressant effects on restraint stress-induced depression in both wildtype and GluN2D-KO mice. The antidepressant effects of (RS)-ketamine and (S)-ketamine were sustained 96 h after the injection in both wildtype and GluN2D-KO mice, but such sustained antidepressant effects of (R)-ketamine were only observed in wildtype mice. These data suggest that the GluN2D subunit is critical for the sustained antidepressant effects of (R)-ketamine

The Detection and Negative Reversion of Circulating Tumor Cells as Prognostic Biomarkers for Metastatic Castration-Resistant Prostate Cancer with Bone Metastases Treated by Enzalutamide

Enzalutamide is a second-generation androgen receptor inhibitor that increases overall survival (OS) rates in patients with metastatic castration-resistant prostate cancer (mCRPC). This study evaluates the efficacy of circulating tumor cell (CTC) status as a prognostic biomarker following enzalutamide administration. A retrospective subgroup analysis and prognostic survey were conducted on 43 patients with mCRPC and bone metastases treated in Juntendo University-affiliated hospitals from 2015 to 2022. Patients were treated with 160 mg enzalutamide daily. CTC analyses on blood samples were performed regularly before and every three months after treatment. The relationship between the patients’ clinical factors and the OS rate was analyzed using the log-rank test; the median OS was 37 months. Patients with no detected CTCs at baseline showed significantly longer OS than those with detectable CTCs at baseline. Furthermore, patients demonstrating negative reversion of CTCs during enzalutamide treatment had significantly longer OS than patients with CTC-positivity. Two biomarkers—higher hemoglobin at baseline and achieving negative reversion of CTCs—were significantly associated with prolonged OS. This study suggests that patients achieving CTC-negative reversion during treatment for mCRPC with bone metastases exhibit improved long-term OS. Chronological measurement of CTC status might be clinically useful in the treatment of mCRPC

Aromatic Macrocycle Containing Amine and Imine Groups: Intramolecular Charge-Transfer and Multiple Redox Behavior

A cyclic compound that has alternating diphenylamine and quinodiimine units was obtained by condensation of anthraquinone with bis­(4-aminophenyl)­amine (aniline dimer) in 20% yield. The resulting macrocycle has an absorption of 462 nm, which is assigned to charge transfer transitions between electron-rich diphenylamine units and electron-poor anthraquinone diimine units. Cyclic voltammetry in acidic MeCN shows redox of anthraquinone diimine units (<i>E</i>_1/2 = 0.03 V vs Ag/Ag⁺) and of oxidation of amino groups of higher potentials (0.60 and 0.77 V)

Aromatic Macrocycle Containing Amine and Imine Groups: Intramolecular Charge-Transfer and Multiple Redox Behavior

A cyclic compound that has alternating diphenylamine and quinodiimine units was obtained by condensation of anthraquinone with bis­(4-aminophenyl)­amine (aniline dimer) in 20% yield. The resulting macrocycle has an absorption of 462 nm, which is assigned to charge transfer transitions between electron-rich diphenylamine units and electron-poor anthraquinone diimine units. Cyclic voltammetry in acidic MeCN shows redox of anthraquinone diimine units (<i>E</i>_1/2 = 0.03 V vs Ag/Ag⁺) and of oxidation of amino groups of higher potentials (0.60 and 0.77 V)

An intraplate slow earthquake observed by a dense GPS network in Hokkaido, northernmost Japan

An intraplate slow earthquake was detected in northernmost Hokkaido, Japan, by a dense network of the global navigation satellite system. Transient abnormal acceleration of <12 mm was observed during the period 2012 July to 2013 January (similar to 5.5 months) at several sites. The spatial displacement distribution suggests that a localized tectonic event caused localized deformation. Estimated fault parameter indicates very shallow-dip reverse faulting in the uppermost crust, with a total seismic moment of 1.75E + 17 N m (M-w 5.4). This fault geometry is probably consistent with detachment structure indicated by geological studies. A simultaneous earthquake swarm with the maximum magnitude M4.1 suggests a possibility that the slow slip triggered the seismic activity for unknown reasons. This slow earthquake is slower than its moment would indicate, with a duration-magnitude scaling relationship unlike either regular earthquakes or subduction slow slip events. This result indicates that even if the area is under different physical property from subduction zones, slow earthquake can occur by some causes. Slow earthquakes exist in remote regions away from subduction zones and might play an important role in strain release and tectonic activity