Efficacy and safety of teriparatide vs. bisphosphonates and denosumab vs. bisphosphonates in osteoporosis not previously treated with bisphosphonates: a systematic review and meta-analysis of randomized controlled trials.

The study found that in osteoporosis patients who had not previously received bisphosphonate treatment and were in a treatment cycle of over 12 months, both teriparatide and denosumab significantly increased bone mineral density compared to bisphosphonates. Additionally, teriparatide was also shown to significantly decrease the risk of fractures. OBJECTIVE: The systematic review and meta-analysis aimed to assess and compare the safety and efficacy of teriparatide vs. bisphosphonates and denosumab vs. bisphosphonates in patients with osteoporosis who had not previously received bisphosphonates. METHODS: We conducted a search of published literature from inception to May 31, 2023, including databases such as PubMed, Embase, Cochrane Library, CNKI, SinoMed, VIP, and WanFang. The study only included head-to-head randomized controlled trials (RCTs) that compared teriparatide and denosumab with bisphosphonates to treat patients with osteoporosis. Fixed-effect model and random-effect model were used due to clinical heterogeneity. Meta-analysis was performed via Stata 17.0. RESULTS: A total of 6680 patients were enrolled across 23 eligible trials. The results of the meta-analysis showed that teriparatide was superior to bisphosphonates in decreasing the risk of fracture (risk ratio (RR) = 0.61, 95% confidence interval (CI) (0.51, 0.74), P < 0.001). Denosumab showed no benefit compared to bisphosphonates in reducing the risk of fracture in treating osteoporosis (RR 0.99, 95% CI (0.62, 1.57), P = 0.96). Compared with bisphosphonates, teriparatide and denosumab could significantly improve femoral neck, total hip, and lumbar spine bone mineral density (BMD) (P < 0.05). Furthermore, teriparatide and denosumab did not increase the incidence of adverse events (teriparatide vs. bisphosphonates, RR 0.92, 95% CI (0.79, 1.08), P = 0.32; denosumab vs. bisphosphonates, RR 0.98, 95% CI (0.95, 1.02), P = 0.37). CONCLUSIONS: Teriparatide is superior to bisphosphonates in decreasing the risk of fracture in patients with osteoporosis. In addition, teriparatide and denosumab were more efficacious than bisphosphonates in increasing the percentage change in BMD at the femoral neck, total hip, and lumbar spine.

Positional Isomerism of Aromatic Heterocyclic Spacer Cations in Two-Dimensional Dion-Jacobson Hybrid Perovskites.

Ligand engineering of aromatic heterocyclic cations in two-dimensional (2D) Dion-Jacobson (DJ) perovskites has been widely explored in recent years. In this study, how the positional isomers of aromatic heterocyclic cations tune the lattice of 2D perovskites, thereby influencing the transport and recombination dynamics of charge carriers, has been investigated through nonadiabatic molecular dynamics simulations. We demonstrate that the meta-substituted 3-(aminomethyl)pyridinium (3AMPY) cations greatly reduce the strength of electron-vibration coupling since the strong hydrogen-bonding network introduced by the changes in the arrangement of spacer cations significantly suppresses the structural thermal fluctuations. Compared to the para-substituted 4-(aminomethyl)pyridinium (4AMPY) cation, using the asymmetric 3AMPY as a spacer cation can achieve improved in-plane transport performance, enhanced thermal stability, and suppressed charge carrier recombination through weakening electron-vibration interactions. Our results explain the observed lifetime difference between the two types of DJ-phase perovskites in experiments and provide new guidance for optimizing the performance of perovskite devices.

CRISPR screening identifies PRMT1 as a key pro-ferroptotic gene via a two-layer regulatory mechanism.

Ferroptosis is a form of nonapoptotic cell death characterized by iron-dependent peroxidation of polyunsaturated phospholipids. However, much remains unknown about the regulators of ferroptosis. Here, using CRISPR-Cas9-mediated genetic screening, we identify protein arginine methyltransferase 1 (PRMT1) as a crucial promoter of ferroptosis. We find that PRMT1 decreases the expression of solute carrier family 7 member 11 (SLC7A11) to limit the abundance of intracellular glutathione (GSH). Moreover, we show that PRMT1 interacts with ferroptosis suppressor protein 1 (FSP1), a GSH-independent ferroptosis suppressor, to inhibit the membrane localization and enzymatic activity of FSP1 through arginine dimethylation at R316, thus reducing CoQ10H2 content and inducing ferroptosis sensitivity. Importantly, genetic depletion or pharmacological inhibition of PRMT1 in mice prevents ferroptotic events in the liver and improves the overall survival under concanavalin A (ConA) exposure. Hence, our findings suggest that PRMT1 is a key regulator of ferroptosis and a potential target for antiferroptosis therapeutics.

Unveiling the Hub Genes Involved in Cadmium-Induced Hepatotoxicity.

Cadmium (Cd) is a highly toxic heavy metal that can cause severe liver damage in both humans and animals. However, the specific genes responsible for Cd-induced hepatotoxicity are still not fully understood. Therefore, the aim of this study was to identify the key genes associated with Cd-induced liver damage. To achieve this, we utilized the GSE19662 dataset from the Gene Expression Omnibus (GEO), which consisted of rat hepatocyte samples treated with cadmium chloride (CdCl2) as well as control groups. By focusing on rat hepatocytes treated with 0.10 ppm of CdCl2, the study identified 851 differentially expressed genes (DEGs), with 438 genes being upregulated and 413 genes being downregulated. Gene Ontology (GO) analysis revealed that these DEGs were primarily involved in inflammatory responses, xenobiotic metabolic processes, and the response to drugs and xenobiotic stimuli. Finally, the study identified several hub genes, including CYP2E1, CYP3A62, CYP2C11, CYP2C13, CYP2B3, HSP90B1, HSP90AA1, GSTA2, and MAPK8, which were associated with CdCl2-induced liver damage. Furthermore, pathway analysis demonstrated that these hub genes were mainly linked to pathways involved in chemical carcinogenesis, metabolic processes, steroid hormone biosynthesis, retinol metabolism, linoleic acid metabolism, arachidonic acid metabolism, inflammatory mediator regulation, Ras, and protein processing in the endoplasmic reticulum. In conclusion, this study provides important insights into the molecular mechanisms underlying Cd-induced liver damage.

Impact of atropisomerism on a non-steroidal glucocorticoid receptor agonist.

To investigate atropisomers of non-steroidal glucocorticoid receptor modulator GSK866, a virtual library of substituted benzoic acid analogues was enumerated. Compounds from this library were subjected to a torsion angle scan using Spartan'20 to calculate the torsion rotation energy barrier which identified compounds predicted to be stable as atropisomers. After synthesis of the library, analysis showed that compounds 13 and 14 existed as stable atropisomers 13a, 13b, 14a and 14b, in agreement with the earlier calculations. Screening in a glucocorticoid receptor cellular assay showed that one compound from each atropisomer pair was significantly more potent than the other. Docking in a public structure of the glucocorticoid receptor (PBD code 3E7C) enabled the stereochemistry of the two most potent compounds 13a and 14b to be assigned as (R a) and (S a), respectively.

Identification of novel PD-1/PD-L1 small molecule inhibitors: virtual screening, synthesis and in vitro characterisation.

The PD-1/PD-L1 pathway is considered as one of the most promising immune checkpoints in tumour immunotherapy. However, researchers are faced with the inherent limitations of antibodies, driving them to pursue PD-L1 small molecule inhibitors. Virtual screening followed by experimental validation is a proven approach to discover active compounds. In this study, we employed multistage virtual screening methods to screen multiple compound databases to predict new PD-1/PD-L1 ligands. 35 compounds were proposed by combined analysis of fitness scores, interaction pattern and MM-GBSA binding affinities. Enzymatic assay confirmed that 10 out of 35 ligands were potential PD-L1 inhibitors, with inhibitory rate higher than 50% at the concentration of 30 µM. Among them, ZDS20 was identified as the most effective inhibitor with low micromolar activity (IC50 = 3.27 µM). Altogether, ZDS20 carrying novel scaffold was identified and could serve as a lead for the development of new classes of PD-L1 inhibitors.

Causal effect between gut microbiota and metabolic syndrome in European population: a bidirectional mendelian randomization study.

BACKGROUND: Observational studies have reported that gut microbiota composition is associated with metabolic syndrome. However, the causal effect of gut microbiota on metabolic syndrome has yet to be confirmed. METHODS: We performed a bidirectional Mendelian randomization study to investigate the causal effect between gut microbiota and metabolic syndrome in European population. Summary statistics of gut microbiota were from the largest available genome-wide association study meta-analysis (n = 13,266) conducted by the MiBioGen consortium. The summary statistics of outcome were obtained from the most comprehensive genome-wide association studies of metabolic syndrome (n = 291,107). The inverse-variance weighted method was applied as the primary method, and the robustness of the results was assessed by a series of sensitivity analyses. RESULTS: In the primary causal estimates, Actinobacteria (OR = 0.935, 95% CI = 0.878-0.996, P = 0.037), Bifidobacteriales (OR = 0.928, 95% CI = 0.868-0.992, P = 0.028), Bifidobacteriaceae (OR = 0.928, 95% CI = 0.868-0.992, P = 0.028), Desulfovibrio (OR = 0.920, 95% CI = 0.869-0.975, P = 0.005), and RuminococcaceaeUCG010 (OR = 0.882, 95% CI = 0.803-0.969, P = 0.009) may be associated with a lower risk of metabolic syndrome, while Lachnospiraceae (OR = 1.130, 95% CI = 1.016-1.257, P = 0.025), Veillonellaceae (OR = 1.055, 95% CI = 1.004-1.108, P = 0.034) and Olsenella (OR = 1.046, 95% CI = 1.009-1.085, P = 0.015) may be linked to a higher risk for metabolic syndrome. Reverse MR analysis demonstrated that abundance of RuminococcaceaeUCG010 (OR = 0.938, 95% CI = 0.886-0.994, P = 0.030) may be downregulated by metabolic syndrome. Sensitivity analyses indicated no heterogeneity or horizontal pleiotropy. CONCLUSIONS: Our Mendelian randomization study provided causal relationship between specific gut microbiota and metabolic syndrome, which might provide new insights into the potential pathogenic mechanisms of gut microbiota in metabolic syndrome and the assignment of effective therapeutic strategies.

Hippo-signaling-controlled MHC class I antigen processing and presentation pathway potentiates antitumor immunity.

The major histocompatibility complex class I (MHC class I)-mediated tumor antigen processing and presentation (APP) pathway is essential for the recruitment and activation of cytotoxic CD8+ T lymphocytes (CD8+ CTLs). However, this pathway is frequently dysregulated in many cancers, thus leading to a failure of immunotherapy. Here, we report that activation of the tumor-intrinsic Hippo pathway positively correlates with the expression of MHC class I APP genes and the abundance of CD8+ CTLs in mouse tumors and patients. Blocking the Hippo pathway effector Yes-associated protein/transcriptional enhanced associate domain (YAP/TEAD) potently improves antitumor immunity. Mechanistically, the YAP/TEAD complex cooperates with the nucleosome remodeling and deacetylase complex to repress NLRC5 transcription. The upregulation of NLRC5 by YAP/TEAD depletion or pharmacological inhibition increases the expression of MHC class I APP genes and enhances CD8+ CTL-mediated killing of cancer cells. Collectively, our results suggest a crucial tumor-promoting function of YAP depending on NLRC5 to impair the MHC class I APP pathway and provide a rationale for inhibiting YAP activity in immunotherapy for cancer.

Linker substitution influences succinimide ring hydrolysis equilibrium impacting the stability of attachment to antibody-drug conjugates.

Maleimide chemistry is widely used in antibody-drug conjugate (ADC) generation to connect drugs to antibodies through a succinimide linker. The resulting ADC is prone to payload loss via a reverse Michael reaction, leading to premature drug release in vivo. Complete succinimide hydrolysis is an effective strategy to overcome the instability of ADC. However, we discovered through previous work that hydrolysed succinimide rings can close again in a liquid formulation during storage and under thermal stress conditions. In this work, a set of maleimide linkers with hydrolysis-prone groups were designed. The corresponding ADCs were prepared and subjected to thermal stress conditions. The extent of succinimide hydrolysis and drug release was measured, and ADC properties such as SEC, DAR, pI and clog P of linkers were calculated. Our results demonstrated that even though all these groups increased the hydrolysis rate, they have different impacts on maintaining the hydrolysed succinimide ring in an open conformation and ADC stability in a liquid formulation.

Impact of dipeptide on ADC physicochemical properties and efficacy identifies Ala-Ala as the optimal dipeptide.

Side chains of natural occurring amino acids vary greatly in terms of charge state, polarity, size and hydrophobicity. Using a linear synthetic route, two amino acids were sequentially coupled to a potent glucocorticoid receptor modulator (GRM) to afford a library of dipeptide-GRM linker payloads with a range of in silico properties. The linker payloads were conjugated to a mouse anti-TNF antibody through interchain disulfide Cys. Impact of various dipeptide linkers on ADC physical properties, including solubility, hydrophobicity, and aggregation were evaluated and the in silico properties pI, Log P and tPSA of the linker drugs used to correlate with these properties. ADCs were screened in a GRE luciferase reporter assay to compare their in vitro efficacy. Data identified Ala-Ala as a superior dipeptide linker that allowed a maximum drug load of 10 while affording ADCs with low aggregation.

Identification of the hub genes linked to zearalenone-induced hepatotoxicity in broiler chickens.

Zearalenone (ZEN) is a mycotoxin found in food and feed that impairs the function of multiple organs, especially the liver. However, the specific mechanisms through which ZEN induces liver damage in broiler chickens are not well understood. Therefore, this study aimed to identify the key genes linked to the hepatotoxicity induced by ZEN exposure in broiler chickens. Gene expression data from ZEN-treated and control chicken embryo primary hepatocytes (CEPHs) were used to implement differential expression analysis. Totally, 436 differentially expressed genes (DEGs) were detected, in which 223 and 213 genes were up- and down-regulated in ZEN-treated CEPHs, respectively. Gene ontology analysis suggested that these DEGs were involved in various biological processes, including chromosome segregation, mitotic cytokinesis, mitotic cell cycle, cell division, and mitotic spindle organization. Pathway analysis showed that the DEGs were associated with p53, FoxO, ubiquitin-mediated proteolysis, cell cycle, and mismatch repair signaling pathways. Furthermore, the hub genes, including BRCA1, CDC45, CDCA3, CDKN3, CENPE, CENPF, CENPI, CENPM, CENPU, and CEP55, potentially contributed to ZEN-induced hepatotoxicity. In conclusion, our study provides the valuable insight into the mechanism underlying ZEN-induced hepatotoxicity in broiler chickens.

Ant may well destroy a whole dam: glycans of colonic mucus barrier disintegrated by gut bacteria.

The colonic mucus layer plays a critical role in maintaining the integrity of the colonic mucosal barrier, serving as the primary defense against colonic microorganisms. Predominantly composed of mucin 2 (MUC2), a glycosylation-rich protein, the mucus layer forms a gel-like coating that covers the colonic epithelium surface. This layer provides a habitat for intestinal microorganisms, which can utilize mucin glycans present in the mucus layer as a sustainable source of nutrients. Additionally, metabolites produced by the microbiota during the metabolism of mucus glycans have a profound impact on host health. Under normal conditions, the production and consumption of mucus maintain a dynamic balance. However, several studies have demonstrated that certain factors, such as dietary fiber deficiency, can enhance the metabolism of mucus glycans by gut bacteria, thereby disturbing this balance and weakening the mucus barrier function of the mucus layer. To better understand the occurrence and development of colon-related diseases, it is crucial to investigate the complex metabolic patterns of mucus glycosylation by intestinal microorganisms. Our objective was to comprehensively review these patterns in order to clarify the effects of mucus layer glycan metabolism by intestinal microorganisms on the host.

Discovery of LAH-1 as potent c-Met inhibitor for the treatment of non-small cell lung cancer.

ABSTRCTDysregulated HGF/c-Met pathway has been implicated in multiple human cancers and has become an attractive target for cancer intervention. Herein, we report the discovery of N-(3-fluoro-4-((2-(3-hydroxyazetidine-1-carboxamido)pyridin-4-yl)oxy)phenyl)-1-(4-fluorophenyl)-4-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide (LAH-1), which demonstrated nanomolar MET kinase activity as well as desirable antiproliferative activity, especially against EBC-1 cells. Mechanism studies confirmed the effects of LAH-1 on modulation of HGF/c-Met pathway, induction of cell apoptosis, inhibition on colony formation as well as cell migration and invasion. In addition, LAH-1 also showed desirable in vitro ADME properties as well as acceptable in vivo PK parameters. The design, synthesis, and characterisation of LAH-1 are described herein.

Identification of the Hub Genes Linked to Lead (IV)-Induced Spleen Toxicity Using the Rat Model.

Exposure to lead (Pb) has harmful effects on the organs of both humans and animals, particularly the spleen. However, the precise mechanisms through which Pb (IV) exposure leads to spleen toxicity remain unclear. Hence, this study aimed to identify the key genes and signaling pathways involved in spleen toxicity caused by Pb (IV) incubation. We obtained the dataset GSE59925 from the Gene Expression Omnibus, which included spleen samples treated with lead tetraacetate (PbAc4) as well as control samples on the 1st and 5th day. Through differential expression analysis, we identified 607 and 704 differentially expressed genes (DEGs) in the spleens on the 1st and 5th day following PbAc4 treatment, respectively, with 245 overlapping DEGs between the two time points. Gene ontology analysis revealed that the commonly shared DEGs were primarily involved in signal transduction, drug response, cell proliferation, adhesion, and migration. Pathway analysis indicated that the common DEGs were primarily associated with MAPK, TNF, cAMP, Hippo, and TGF-ß signaling pathways. Furthermore, we identified the hub genes such as CXCL10, PARP1, APOE, and VDR contributing to PbAc4-induced spleen toxicity. This study enhances our understanding of the molecular mechanisms underlying Pb (IV) toxicity in the spleen.

Dynamic mechanical response of hot central plant recycling asphalt pavement considering the rutting deformation of existing structure: pollution reduction and durability promotion.

In the pavement industry, there is a pressing need for the reuse of recycled asphalt pavement (RAP) materials. However, the rutting deformation in existing pavement structures is often overlooked in the design of recycled asphalt pavement, which hinders long-term performance prediction and durability assessment. This study examined the viscoelastic properties and fatigue performance of recycled asphalt mixtures. Different combinations of surface layers with varying RAP contents and binder layers with different rutting damage levels were designed. A 3D-Move Analysis model was used to analyze the dynamic mechanical response of these structures under moving loads. Results showed that the stiffness of recycled asphalt mixture increased with the RAP content, but the fatigue performance decreased by 39.4% when the RAP content reached 50%. Incorporating 50% RAP in the surface layer can reduce the compressive stress caused by vehicle loading, thus reducing the vertical compression strain and permanent deformation of the asphalt layers and the subgrade. However, the surface layer with higher RAP content is exposed to intense alternating tensile and compressive strains, leading to poor fatigue durability. The dynamic mechanical behavior of recycled asphalt pavement structures was found to be significantly impacted by the characteristics of the binder layer. The lower dynamic modulus of the binder layer (e.g., 18 mm rutting depth) can lead to more deformation and an increased risk of fatigue cracking. Moreover, the dynamic performance of mixtures with 0% and 50% RAP in the surface layer is even more affected by changes in the binder layer properties. It is recommended to consider the design of dynamic modulus combinations of existing binder layer materials and surface materials with higher RAP, in order to increase the utilization of RAP for high-grade highways and improve the stress distribution to enhance their durability.

Multi-Omics Analysis Reveals Intricate Gene Networks Involved in Female Development in Melon.

Sexual differentiation is an important developmental phenomenon in cucurbits that directly affects fruit yield. The natural existence of multiple flower types in melon offers an inclusive structure for studying the molecular basis of sexual differentiation. The current study aimed to identify and characterize the molecular network involved in sex determination and female development in melon. Male and female pools separated by the F2 segregated generation were used for sequencing. The comparative multi-omics data revealed 551 DAPs and 594 DEGs involved in multiple pathways of melon growth and development, and based on functional annotation and enrichment analysis, we summarized four biological process modules, including ethylene biosynthesis, flower organ development, plant hormone signaling, and ubiquitinated protein metabolism, that are related to female development. Furthermore, the detailed analysis of the female developmental regulatory pathway model of ethylene biosynthesis, signal transduction, and target gene regulation identified some important candidates that might have a crucial role in female development. Two CMTs ((cytosine-5)-methyltransferase), one AdoHS (adenosylhomocysteinase), four ACSs (1-aminocyclopropane-1-carboxylic acid synthase), three ACOs (ACC oxidase), two ARFs (auxin response factor), four ARPs (auxin-responsive protein), and six ERFs (Ethylene responsive factor) were identified based on various female developmental regulatory models. Our data offer new and valuable insights into female development and hold the potential to offer a deeper comprehension of sex differentiation mechanisms in melon.

A specific phenotype of pouchitis was associated with worst prognosis in patients with ulcerative colitis according to Chicago classification.

BACKGROUND: The impact of different pouch phenotypes on long-term functional outcomes and quality of life (QoL) remains unclear. Our aim is to investigate the association between endoscopic pouchitis phenotypes and patients' long-term prognosis by assessing pouch function and QoL. METHODS: Pouchitis was classified into distinct phenotypes according to the Chicago Classification. Pouch function was assessed using the Pouch Functional Score (PFS), and QoL was evaluated using the Cleveland Global Quality of Life (CGQL) score. RESULTS: A total of 252 patients were enrolled in the study, with 78 patients diagnosed with pouchitis. According to the Chicago classification, 42 of these pouchitis patients exhibited an endoscopic phenotype characterized by a combination of diffuse inflammation of the pouch body, inlet involvement, and cuffitis, referred to as the Diffuse-Inlet-Cuffitis phenotype. Patients with pouchitis of the Diffuse-Inlet-Cuffitis phenotype showed significantly higher PFS (11.5 vs 5.5, p = 0.013) and lower CGQL scores (0.67 vs 0.7, p = 0.029) compared to those with other pouch phenotypes. Independent risk factors for this severe phenotype were identified as preoperative disease duration (OR = 1.062, 95% CI: 1.006-1.122, p = 0.030) and disease extent E3 (OR = 2.836, 95% CI: 1.052-7.644, p = 0.036). CONCLUSIONS: Our study suggested that pouchitis with the Diffuse-Inlet-Cuffitis endoscopic phenotype is common and seriously impairs the long-term prognosis in patients with UC after IPAA. The finding will be beneficial to the stratified management of patients with pouchitis.

Development and validation of two nomograms for predicting overall survival and Cancer-specific survival in prostate cancer patients with bone metastases: a population-based study.

BACKGROUND: Prostate cancer with bone metastasis has significant invasiveness and markedly poorer prognosis. The purpose of this study is to establish two nomograms for predicting the overall survival (OS) and cancer-specific survival (CSS) of prostate cancer patients with bone metastasis. METHODS: From January 2000 to December 2018, a total of 2683 prostate adenocarcinoma with bone metastasis patients were identified from the Surveillance, Epidemiology, and End Results Program (SEER) database. These patients were then divided into a training cohort and a validation cohort, with OS and CSS as the study endpoints. Correlation analyses were employed to assess the relationship between variables. Univariate and multivariate Cox analyses were utilized to ascertain the independent prognostic factors. Calibration curves and the area under the time-dependent receiver operating characteristic curve (time-dependent AUC) were employed to evaluate discrimination and calibration of the nomogram. DCA was applied to examine accuracy and clinical benefits. The clinical utility of the nomogram and the AJCC Stage System was compared using net reclassification improvement (NRI) and integrated discrimination improvement (IDI). Lastly, the risk stratifications of the nomogram and the AJCC Stage System were compared. RESULTS: There was no collinearity among the variables that were screened. The results of multivariate Cox regression analysis showed that seven variables (age, surgery, brain metastasis, liver metastasis, lung metastasis, Gleason score, marital status) and six variables (age, surgery, lung metastasis, liver metastasis, Gleason score, marital status) were identified to establish the nomogram for OS and CSS, respectively. The calibration curves, time-dependent AUC curves, and DCA revealed that both nomograms had pleasant predictive power. Furthermore, NRI and IDI confirmed that the nomogram outperformed the AJCC Stage System. CONCLUSION: Both nomograms had satisfactory accuracy and were validated to assist clinicians in evaluating the prognosis of PABM patients.

A Two-Stage Automatic System for Detection of Interictal Epileptiform Discharges from Scalp Electroencephalograms.

The objective of this work was to develop a deep learning-based automatic system with reliable performance in detecting interictal epileptiform discharges (IEDs) from scalp electroencephalograms (EEGs). For the present study, 484 raw scalp EEG recordings were included, standardized, and split into 406 for training and 78 for testing. Two neurophysiologists individually annotated the recordings for training in channel-wise manner. Annotations were divided into segments, on which nine deep neural networks (DNNs) were trained for the multiclassification of IED, artifact, and background. The fitted IED detectors were then evaluated on 78 EEG recordings with IED events fully annotated by three experts independently (majority agreement). A two montage-based decision mechanism (TMDM) was designed to determine whether an IED event occurred at a single time instant. Area under the precision-recall curve (AUPRC), as well as false-positive rates, F1 scores, and kappa agreement scores for sensitivity = 0.8 were estimated. In multitype classification, five DNNs provided one-versus-rest AUPRC mean value >0.993 using fivefold cross-validation. In IED detection, the system that had integrated the temporal convolutional network (TCN)-based IED detector and the TMDM rule achieved an AUPRC of 0.811. The false positive was 0.194/min (11.64/h), and the F1 score was 0.745. The agreement score between the system and the experts was 0.905. The proposed framework provides a TCN-based IED detector and a novel two montage-based determining mechanism that combined to make an automatic IED detection system. The system would be useful in aiding clinic EEG interpretation.

Investigations of Single-Subunit tRNA Methyltransferases from Yeast.

tRNA methylations, including base modification and 2'-O-methylation of ribose moiety, play critical roles in the structural stabilization of tRNAs and the fidelity and efficiency of protein translation. These modifications are catalyzed by tRNA methyltransferases (TRMs). Some of the TRMs from yeast can fully function only by a single subunit. In this study, after performing the primary bioinformatic analyses, the progress of the studies of yeast single-subunit TRMs, as well as the studies of their homologues from yeast and other types of eukaryotes and the corresponding TRMs from other types of organisms was systematically reviewed, which will facilitate the understanding of the evolutionary origin of functional diversity of eukaryotic single-subunit TRM.