Pathologically Activated Neuroprotection via Uncompetitive Blockade of \u3cem\u3eN\u3c/em\u3e-Methyl-d-aspartate Receptors with Fast Off-rate by Novel Multifunctional Dimer Bis(propyl)-cognitin

Uncompetitive N-methyl-d-aspartate (NMDA) receptor antagonists with fast off-rate (UFO) may represent promising drug candidates for various neurodegenerative disorders. In this study, we report that bis(propyl)-cognitin, a novel dimeric acetylcholinesterase inhibitor and γ-aminobutyric acid subtype A receptor antagonist, is such an antagonist of NMDA receptors. In cultured rat hippocampal neurons, we demonstrated that bis(propyl)-cognitin voltage-dependently, selectively, and moderately inhibited NMDA-activated currents. The inhibitory effects of bis(propyl)-cognitin increased with the rise in NMDA and glycine concentrations. Kinetics analysis showed that the inhibition was of fast onset and offset with an off-rate time constant of 1.9 s. Molecular docking simulations showed moderate hydrophobic interaction between bis(propyl)-cognitin and the MK-801 binding region in the ion channel pore of the NMDA receptor. Bis(propyl)-cognitin was further found to compete with [3H]MK-801 with a Ki value of 0.27 μm, and the mutation of NR1(N616R) significantly reduced its inhibitory potency. Under glutamate-mediated pathological conditions, bis(propyl)-cognitin, in contrast to bis(heptyl)-cognitin, prevented excitotoxicity with increasing effectiveness against escalating levels of glutamate and much more effectively protected against middle cerebral artery occlusion-induced brain damage than did memantine. More interestingly, under NMDA receptor-mediated physiological conditions, bis(propyl)-cognitin enhanced long-term potentiation in hippocampal slices, whereas MK-801 reduced and memantine did not alter this process. These results suggest that bis(propyl)-cognitin is a UFO antagonist of NMDA receptors with moderate affinity, which may provide a pathologically activated therapy for various neurodegenerative disorders associated with NMDA receptor dysregulation

The Present-Day Mass Function of Star Clusters in the Solar Neighborhood

This work analyses the present-day mass function (PDMF) of 93~star clusters utilizing Gaia DR3 data, with membership determined by the StarGo machine learning algorithm. The impact of unresolved binary systems on mass estimation is rigorously assessed, adopting three mass ratio profiles for correction. The PDMF is characterized by the power-law index, $\alpha$, derived through a robust maximum likelihood method that avoids biases associated with data binning. The value of $\alpha$ for stars between the completeness limited mass of Gaia with a mean 0.3 $M_\odot$ for our cluster samples and 2 $M_\odot$, exhibits stability for clusters younger than 200 Myr, decreasing for older clusters, particularly when considering stars within the half-mass radius. The PDMF of these star clusters is consistent with a dynamically evolved Kroupa IMF via the loss of low-mass stars. Cluster morphology shows a correlation with $\alpha$, as $\alpha$ values exhibit a decreasing trend from filamentary to tidal-tail clusters, mirroring the sequence of increasing cluster age. The dependence of $\alpha$ on total cluster mass is weak, with a subtle increase for higher-mass clusters, especially outside the half-mass radius. We do not observe a correlation between $\alpha$ and the mean metallicity of the clusters. Younger clusters have lower metallicity compared to their older counterparts, which indicates that the older clusters might have migrated to the solar neighbourhood from the inner disk. A comparison with numerical models incorporating a black hole population suggests the need for observations of distant, older, massive open clusters to determine whether or not they contain black holes.Comment: 19 pages, 10 figures, accepted to Ap

Functional miR-142a-3p induces apoptosis and macrophage polarization by targeting tnfaip2 and glut3 in grass carp (Ctenopharyngodon idella)

In the process of microbial invasion, the inflammation reaction is induced to eliminate the pathogen. However, un-controlled or un-resolved inflammation can lead to tissue damage and death of the host. MicroRNAs (miRNAs) are the signaling regulators that prevent the uncontrolled progress of an inflammatory response. Our previous work strongly indicated that miR-142a-3p is related to the immune regulation in grass carp. In the present study, we found that the expression of miR-142a-3p was down-regulated after infection by Aeromonas hydrophila. tnfaip2 and glut3 were confirmed as be the target genes of miR-142a-3p, which were confirmed by expression correlation analysis, gene overexpression, and dual luciferase reporter assay. The miR-142a-3p can reduce cell viability and stimulate cell apoptosis by targeting tnfaip2 and glut3. In addition, miR-142a-3p also regulates macrophage polarization induced by A. hydrophila. Our results suggest that miR-142a-3p has multiple functions in host antibacterial immune response. Our research provides further understanding of the molecular mechanisms between miRNAs and their target genes, and provides a new insights for the development of pro-resolution strategies for the treatment of complex inflammatory diseases in fish.31802285, CARROS-45-03info:eu-repo/semantics/publishedVersio

Up-regulation of DDIT4 predicts poor prognosis in acute myeloid leukaemia

The mammalian target of rapamycin (mTOR) inhibitor, DNA damage inducible transcript 4 (DDIT4), has inducible expression in response to various cellular stresses. In multiple malignancies, studies have shown that DDIT4 participates in tumorigenesis and impacts patient survival. We aimed to study the prognostic value of DDIT4 in acute myeloid leukaemia (AML), which is currently unclear. Firstly, The Cancer Genome Atlas was screened for AML patients with complete clinical characteristics and DDIT4 expression data. A total of 155 patients were included and stratified according to the treatment modality and the median DDIT4 expression levels. High DDIT4 expressers had shorter overall survival (OS) and event-free survival (EFS) than the low expressers among the chemotherapy-only group (all P <.001); EFS and OS were similar in the high and low DDIT4 expressers of the allogeneic haematopoietic stem cell transplantation (allo-HSCT) group. Furthermore, in the DDIT4(high) group, patients treated with allo-HSCT had longer EFS and OS than those who received chemotherapy alone (all P <.01). In the DDIT4(low) group, OS and EFS were similar in different treatment groups. Secondly, we analysed two other cytogenetically normal AML (CN-AML) cohorts derived from the Gene Expression Omnibus database, which confirmed that high DDIT4 expression was associated with poorer survival. Gene Ontology (GO) enrichment analysis showed that the genes related to DDIT4 expression were mainly concentrated in the acute and chronic myeloid leukaemia signalling pathways. Collectively, our study indicates that high DDIT4 expression may serve as a poor prognostic factor for AML, but its prognostic effects could be outweighed by allo-HSCT

Overexpression of PDK2 and PDK3 reflects poor prognosis in acute myeloid leukemia

Acute myeloid leukemia (AML) is a hematological malignancy characterized by the proliferation of immature myeloid cells, with impaired differentiation and maturation. Pyruvate dehydrogenase kinase (PDK) is a pyruvate dehydrogenase complex (PDC) phosphatase inhibitor that enhances cell glycolysis and facilitates tumor cell proliferation. Inhibition of its activity can induce apoptosis of tumor cells. Currently, little is known about the role of PDKs in AML. Therefore, we screened The Cancer Genome Atlas (TCGA) database for de novo AML patients with complete clinical information and PDK family expression data, and 84 patients were included for the study. These patients did not undergo allogeneic hematopoietic stem cell transplantation (allo-HSCT). Univariate analysis showed that high expression of PDK2 was associated with shorter EFS (P = 0.047), and high expression of PDK3 was associated with shorter OS (P = 0.026). In multivariate analysis, high expression of PDK3 was an independent risk factor for EFS and OS (P 0.05). Our results indicated that high expressions of PDK2 and PDK3, especially the latter, were poor prognostic factors of AML, and the effect could be overcome by allo-HSCT

Binary Star Evolution in Different Environments: Filamentary, Fractal, Halo and Tidal-tail Clusters

Using membership of 85 open clusters from previous studies (Pang et al. 2021a,b, 2022b; Li et al. 2021) based on Gaia DR3 data, we identify binary candidates in the color-magnitude diagram, for systems with mass ratio q > 0.4. The binary fraction is corrected for incompleteness at different distances due to the Gaia angular resolution limit. We find a decreasing binary fraction with increasing cluster age, with substantial scatter. For clusters with a total mass > 200$M_\odot$, the binary fraction is independent of cluster mass. The binary fraction depends strongly on stellar density. Among four types of cluster environments, the lowest-density filamentary and fractal stellar groups have the highest mean binary fraction: 23.6% and 23.2%, respectively. The mean binary fraction in tidal-tail clusters is 20.8%, and is lowest in the densest halo-type clusters: 14.8%. We find clear evidence of early disruptions of binary stars in the cluster sample. The radial binary fraction depends strongly on the cluster-centric distance across all four types of environments, with the smallest binary fraction within the half-mass radius $r_h$, and increasing towards a few $r_h$. Only hints of mass segregation is found in the target clusters. The observed amount of mass segregation is not significant to generate a global effect inside the target clusters. We evaluate the bias of unresolved binary systems (assuming a primary mass of 1$M_\odot$) in 1D tangential velocity, which is 0.1-1$\,\rm km\,s^{-1}$. Further studies are required to characterize the internal star cluster kinematics using Gaia proper motions