Differential Actions of Ethanol and Trichloroethanol at Sites in the M3 and M4 Domains of the NMDA Receptor GluN2A (NR2A) Subunit

Background and purpose:  Alcohol produces its behavioural effects in part due to inhibition of N-methyl-d-aspartate (NMDA) receptors in the CNS. Previous studies have identified amino acid residues in membrane-associated domains 3 (M3) and 4 (M4) of the NMDA receptor that influence ethanol sensitivity. In addition, in other alcohol-sensitive ion channels, sedative-hypnotic agents have in some cases been shown to act at sites distinct from the sites of ethanol action. In this study, we compared the influence of mutations at these sites on sensitivity to ethanol and trichloroethanol, a sedative-hypnotic agent that is a structural analogue of ethanol. Experimental approach:  We constructed panels of mutants at ethanol-sensitive positions in the GluN2A (NR2A) NMDA receptor subunit and transiently expressed these mutants in human embryonic kidney 293 cells. We used whole-cell patch-clamp recording to assess the actions of ethanol and trichloroethanol in these mutant NMDA receptors. Key results:  Ethanol sensitivity of mutants at GluN2A(Ala825) was not correlated with any physicochemical measures tested. Trichloroethanol sensitivity was altered in two of three ethanol-insensitive mutant GluN2A subunits: GluN2A(Phe637Trp) in M3 and GluN2A(Ala825Trp) in M4, but not GluN2A(Met823Trp). Trichloroethanol sensitivity decreased with increasing molecular volume at Phe637 or increasing hydrophobicity at Ala825 and was correlated with ethanol sensitivity at both sites. Conclusions and implications:  Evidence obtained to date is consistent with a role of GluN2A(Ala825) as a modulatory site for ethanol and trichloroethanol sensitivity, but not as a binding site. Trichloroethanol appears to inhibit the NMDA receptor in a manner similar, but not identical to, that of ethanol

CSMAAFL: Client Scheduling and Model Aggregation in Asynchronous Federated Learning

Asynchronous federated learning aims to solve the straggler problem in heterogeneous environments, i.e., clients have small computational capacities that could cause aggregation delay. The principle of asynchronous federated learning is to allow the server to aggregate the model once it receives an update from any client rather than waiting for updates from multiple clients or waiting a specified amount of time in the synchronous mode. Due to the asynchronous setting, the stale model problem could occur, where the slow clients could utilize an outdated local model for their local data training. Consequently, when these locally trained models are uploaded to the server, they may impede the convergence of the global training. Therefore, effective model aggregation strategies play a significant role in updating the global model. Besides, client scheduling is also critical when heterogeneous clients with diversified computing capacities are participating in the federated learning process. This work first investigates the impact of the convergence of asynchronous federated learning mode when adopting the aggregation coefficient in synchronous mode. The effective aggregation solutions that can achieve the same convergence result as in the synchronous mode are then proposed, followed by an improved aggregation method with client scheduling. The simulation results in various scenarios demonstrate that the proposed algorithm converges with a similar level of accuracy as the classical synchronous federated learning algorithm but effectively accelerates the learning process, especially in its early stage

Testing and Data Reduction of the Chinese Small Telescope Array (CSTAR) for Dome A, Antarctica

The Chinese Small Telescope ARray (hereinafter CSTAR) is the first Chinese astronomical instrument on the Antarctic ice cap. The low temperature and low pressure testing of the data acquisition system was carried out in a laboratory refrigerator and on the 4500m Pamirs high plateau, respectively. The results from the final four nights of test observations demonstrated that CSTAR was ready for operation at Dome A, Antarctica. In this paper we present a description of CSTAR and the performance derived from the test observations.Comment: Accepted Research in Astronomy and Astrophysics (RAA) 1 Latex file and 20 figure

Microbiology, ecology, and application of the nitrite-dependent anaerobic methane oxidation process

Nitrite-dependent anaerobic methane oxidation (n-damo), which couples the anaerobic oxidation of methane to denitrification, is a recently discovered process mediated by “Candidatus Methylomirabilis oxyfera.” M. oxyfera is affiliated with the “NC10” phylum, a phylum having no members in pure culture. Based on the isotopic labeling experiments, it is hypothesized that M. oxyfera has an unusual intra-aerobic pathway for the production of oxygen via the dismutation of nitric oxide into dinitrogen gas and oxygen. In addition, the bacterial species has a unique ultrastructure that is distinct from that of other previously described microorganisms. M. oxyfera-like sequences have been recovered from different natural habitats, suggesting that the n-damo process potentially contributes to global carbon and nitrogen cycles. The n-damo process is a process that can reduce the greenhouse effect, as methane is more effective in heat-trapping than carbon dioxide. The n-damo process, which uses methane instead of organic matter to drive denitrification, is also an economical nitrogen removal process because methane is a relatively inexpensive electron donor. This mini-review summarizes the peculiar microbiology of M. oxyfera and discusses the potential ecological importance and engineering application of the n-damo process

Interferon regulatory factor-1 together with reactive oxygen species promotes the acceleration of cell cycle progression by up-regulating the cyclin E and CDK2 genes during high glucose-induced proliferation of vascular smooth muscle cells

BACKGROUND: The high glucose-induced proliferation of vascular smooth muscle cells (VSMCs) plays an important role in the development of diabetic vascular diseases. In a previous study, we confirmed that Interferon regulatory factor-1 (Irf-1) is a positive regulator of the high glucose-induced proliferation of VSMCs. However, the mechanisms remain to be determined. METHODS: The levels of cyclin/CDK expression in two cell models involving Irf-1 knockdown and overexpression were quantified to explore the relationship between Irf-1 and its downstream effectors under normal or high glucose conditions. Subsequently, cells were treated with high glucose/NAC, normal glucose/H(2)O(2), high glucose/U0126 or normal glucose/H(2)O(2)/U0126 during an incubation period. Then proliferation, cyclin/CDK expression and cell cycle distribution assays were performed to determine whether ROS/Erk1/2 signaling pathway was involved in the Irf-1-induced regulation of VSMC growth under high glucose conditions. RESULTS: We found that Irf-1 overexpression led to down-regulation of cyclin D1/CDK4 and inhibited cell cycle progression in VSMCs under normal glucose conditions. In high glucose conditions, Irf-1 overexpression led to an up-regulation of cyclin E/CDK2 and an acceleration of cell cycle progression, whereas silencing of Irf-1 suppressed the expression of both proteins and inhibited the cell cycle during the high glucose-induced proliferation of VSMCs. Treatment of VSMCs with antioxidants prevented the Irf-1 overexpression-induced proliferation of VSMCs, the up-regulation of cyclin E/CDK2 and the acceleration of cell cycle progression in high glucose conditions. In contrast, under normal glucose conditions, H(2)O(2) stimulation and Irf-1 overexpression induced cell proliferation, up-regulated cyclin E/CDK2 expression and promoted cell cycle acceleration. In addition, overexpression of Irf-1 promoted the activation of Erk1/2 and when VSMCs overexpressing Irf-1 were treated with U0126, the specific Erk1/2 inhibitor abolished the proliferation of VSMCs, the up-regulation of cyclin E/CDK2 and the acceleration of cell cycle progression under high glucose or normal glucose/H(2)O(2) conditions. CONCLUSIONS: These results demonstrate that the downstream effectors of Irf-1 are cyclin E/CDK2 during the high glucose-induced proliferation of VSMCs, whereas they are cyclin D1/CDK4 in normal glucose conditions. The Irf-1 overexpression-induced proliferation of VSMCs, the up-regulation of cyclin E/CDK2 and the acceleration of cell cycle progression are associated with ROS/Erk1/2 signaling pathway under high glucose conditions

Development of a prognostic model to identify the metastatic nasopharyngeal carcinoma patients who may benefit from chemotherapy combination PD-1 inhibitor

BackgroundWe aimed to establish a prognostic model to identify suitable candidates for chemotherapy combination PD-1 inhibitor in metastatic nasopharyngeal carcinoma (NPC) patients.Patients and methodsIn this retrospective study, we included 524 patients (192 patients treated with chemotherapy combination PD-1 inhibitor and 332 received chemotherapy alone as first-line regimen) with metastatic NPC between January 2015 and March 2021. We developed a prognostic model to predict progression-free survival (PFS). A model-based trees approach was applied to estimate stratified treatment effects using prognostic scores and two well-matched risk groups (low-risk and high-risk) were created using propensity score matching.ResultsA prognostic nomogram was established with good accuracy for predicting PFS (c-index values of 0.71; 95% confidence interval, 0.66-0.73). The survival curves were significantly different between low-risk and high-risk groups (median PFS: 9.8 vs. 22.8 months, P < 0.001, respectively). After propensity matching analysis, chemotherapy combination PD-1 inhibitor was significantly associated with superior PFS as compared with chemotherapy alone (median PFS, 10.6 versus 9.3 months, P = 0.016) in the high-risk group. However, no significant difference between chemotherapy combination PD-1 inhibitor and chemotherapy was observed (P = 0.840) in the low-risk groups.ConclusionsOur novel prognostic model was able to stratify patients with metastatic NPC into low-risk or high-risk groups and identify candidates for PD-1 inhibitor therapy. These results are expected to be confirmed by a prospective clinical trial

A systematic review and meta-analysis of the diagnostic accuracy of metagenomic next-generation sequencing for diagnosing tuberculous meningitis

ObjectiveThe utility of metagenomic next-generation sequencing (mNGS) in the diagnosis of tuberculous meningitis (TBM) remains uncertain. We performed a meta-analysis to comprehensively evaluate its diagnostic accuracy for the early diagnosis of TBM.MethodsEnglish (PubMed, Medline, Web of Science, Cochrane Library, and Embase) and Chinese (CNKI, Wanfang, and CBM) databases were searched for relevant studies assessing the diagnostic accuracy of mNGS for TBM. Review Manager was used to evaluate the quality of the included studies, and Stata was used to perform the statistical analysis.ResultsOf 495 relevant articles retrieved, eight studies involving 693 participants (348 with and 345 without TBM) met the inclusion criteria and were included in the meta-analysis. The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, and area under the summary receiver-operating characteristic curve of mNGS for diagnosing TBM were 62% (95% confidence interval [CI]: 0.46–0.76), 99% (95% CI: 0.94–1.00), 139.08 (95% CI: 8.54–2266), 0.38 (95% CI: 0.25–0.58), 364.89 (95% CI: 18.39–7239), and 0.97 (95% CI: 0.95–0.98), respectively.ConclusionsmNGS showed good specificity but moderate sensitivity; therefore, a more sensitive test should be developed to assist in the diagnosis of TBM

PCBP-1 regulates alternative splicing of the CD44 gene and inhibits invasion in human hepatoma cell line HepG2 cells

<p>Abstract</p> <p>Background</p> <p>PCBP1 (or alpha CP1 or hnRNP E1), a member of the PCBP family, is widely expressed in many human tissues and involved in regulation of transcription, transportation process, and function of RNA molecules. However, the role of PCBP1 in CD44 variants splicing still remains elusive.</p> <p>Results</p> <p>We found that enforced PCBP1 expression inhibited CD44 variants expression including v3, v5, v6, v8, and v10 in HepG2 cells, and knockdown of endogenous PCBP1 induced these variants splicing. Invasion assay suggested that PCBP1 played a negative role in tumor invasion and re-expression of v6 partly reversed the inhibition effect by PCBP1. A correlation of PCBP1 down-regulation and v6 up-regulation was detected in primary HCC tissues.</p> <p>Conclusions</p> <p>We first characterized PCBP1 as a negative regulator of CD44 variants splicing in HepG2 cells, and loss of PCBP1 in human hepatic tumor contributes to the formation of a metastatic phenotype.</p