Deep learning based method for predicting DNA N6-methyladenosine sites.

DNA N6 methyladenine (6mA) plays an important role in many biological processes, and accurately identifying its sites helps one to understand its biological effects more comprehensively. Previous traditional experimental methods are very labor-intensive and traditional machine learning methods also seem to be somewhat insufficient as the database of 6mA methylation groups becomes progressively larger, so we propose a deep learning-based method called multi-scale convolutional model based on global response normalization (CG6mA) to solve the prediction problem of 6mA site. This method is tested with other methods on three different kinds of benchmark datasets, and the results show that our model can get more excellent prediction results.

Zero Voltage-Degradation of Li2MnO3 with Ultrathin Amorphous Li─Mn─O Coating.

Manganese-based lithium-rich layered oxides (Mn-LLOs) are promising candidate cathode materials for lithium-ion batteries, however, the severe voltage decay during cycling is the most concern for their practical applications. Herein, an Mn-based composite nanostructure constructed Li2MnO3 (LMO@Li2MnO3) is developed via an ultrathin amorphous functional oxide LixMnOy coating at the grain surface. Due to the thin and universal LMO amorphous surface layer etched from the lithiation process by the high-concentration alkaline solution, the structural and interfacial stability of Li2MnO3 are enhanced apparently, showing the significantly improved voltage maintenance, cycle stability, and energy density. In particular, the LMO@Li2MnO3 cathode exhibits zero voltage decay over 200 cycles. Combining with ex situ spectroscopic and microscopic techniques, the Mn2+/4+ coexisted behavior of the amorphous LMO is revealed, which enables the stable electrochemistry of Li2MnO3. This work provides new possible routes for suppressing the voltage decay of Mn-LLOs by modifying with the composite functional unit construction.

Association between the ROX index and mortality in patients with acute hypoxemic respiratory failure: a retrospective cohort study.

BACKGROUND: Although ROX index is frequently used to assess the efficacy of high-flow nasal cannula treatment in acute hypoxemic respiratory failure (AHRF) patients, the relationship between the ROX index and the mortality remains unclear. Therefore, a retrospective cohort study was conducted to evaluate the ability of the ROX index to predict mortality risk in patients with AHRF. METHOD: Patients diagnosed with AHRF were extracted from the MIMIC-IV database and divided into four groups based on the ROX index quartiles. The primary outcome was 28-day mortality, while in-hospital mortality and follow-up mortality were secondary outcomes. To investigate the association between ROX index and mortality in AHRF patients, restricted cubic spline curve and COX proportional risk regression were utilized. RESULT: A non-linear association (L-shaped) has been observed between the ROX index and mortality rate. When the ROX index is below 8.28, there is a notable decline in the 28-day mortality risk of patients as the ROX index increases (HR per SD, 0.858 [95%CI 0.794-0.928] P < 0.001). When the ROX index is above 8.28, no significant association was found between the ROX index and 28-day mortality. In contrast to the Q1 group, the mortality rates in the Q2, Q3, and Q4 groups had a substantial reduction (Q1 vs. Q2: HR, 0.749 [0.590-0.950] P = 0.017; Q3: HR, 0.711 [0.558-0.906] P = 0.006; Q4: HR, 0.641 [0.495-0.830] P < 0.001). CONCLUSION: The ROX index serves as a valuable predictor of mortality risk in adult patients with AHRF, and that a lower ROX index is substantially associated with an increase in mortality.

Convolutional neural network applied to preoperative venous-phase CT images predicts risk category in patients with gastric gastrointestinal stromal tumors.

OBJECTIVE: The risk category of gastric gastrointestinal stromal tumors (GISTs) are closely related to the surgical method, the scope of resection, and the need for preoperative chemotherapy. We aimed to develop and validate convolutional neural network (CNN) models based on preoperative venous-phase CT images to predict the risk category of gastric GISTs. METHOD: A total of 425 patients pathologically diagnosed with gastric GISTs at the authors' medical centers between January 2012 and July 2021 were split into a training set (154, 84, and 59 with very low/low, intermediate, and high-risk, respectively) and a validation set (67, 35, and 26, respectively). Three CNN models were constructed by obtaining the upper and lower 1, 4, and 7 layers of the maximum tumour mask slice based on venous-phase CT Images and models of CNN_layer3, CNN_layer9, and CNN_layer15 established, respectively. The area under the receiver operating characteristics curve (AUROC) and the Obuchowski index were calculated to compare the diagnostic performance of the CNN models. RESULTS: In the validation set, CNN_layer3, CNN_layer9, and CNN_layer15 had AUROCs of 0.89, 0.90, and 0.90, respectively, for low-risk gastric GISTs; 0.82, 0.83, and 0.83 for intermediate-risk gastric GISTs; and 0.86, 0.86, and 0.85 for high-risk gastric GISTs. In the validation dataset, CNN_layer3 (Obuchowski index, 0.871) provided similar performance than CNN_layer9 and CNN_layer15 (Obuchowski index, 0.875 and 0.873, respectively) in prediction of the gastric GIST risk category (All P >.05). CONCLUSIONS: The CNN based on preoperative venous-phase CT images showed good performance for predicting the risk category of gastric GISTs.

Unlock the C-N Bond Amidation of Enaminones: Metal-Free Synthesis of Enamides by Water-Assisted Transamidation.

The C-N bond transamidation of primary amides with N,N-dimethyl enaminones has been efficiently realized by heating in the presence of trifluoromethanesulfonic acid (TfOH). The method enables the practical synthesis of valuable enamides without the use of any metal reagent. In addition, this transamidation protocol can also be expanded to the reactions of sulfonamides, and the late-stage functionalization on sulfonamide drugs such as Celecoxib and Valdecoxib has been verified. Moreover, the participation of water in assisting the transamidation process has been identified by the isotope labeling experiments using D2O, disclosing a new possibility in designing catalytic tactic to other transamidation reactions.

Photocatalytic Pyridine Synthesis with Enaminones and TMEDA under Metal-Free Conditions.

Reported herein is a new photocatalytic annulation for the synthesis of 2,3,4,6-tetrasubstituted pyridines with enaminones and N,N,N',N'-tetramethyl ethylenediamine (TMEDA). The photocatalytic reactions take place without requiring a transition metal reagent and provide products with broad scope. The methyl in TMEDA acts as the carbon source in pyridine ring construction, and BrCF2CO2Et plays the role of the terminal oxidant for free radical quenching.

Transition-Metal-Free C-H Trifluoromethylthiolation of N,N-Disubstituted Enaminones To Access CF3S-Functionalized Enaminones and Their Application in the Synthesis of CF3S-Heteroaryls.

The α-C-H trifluoromethylthiolation of N,N-disubstituted enaminones has been achieved with simple and cheap CF3SO2Na as the CF3S source. The reactions were run at mild temperature (0 °C to rt) using POCl3 as the only reducing reagent. The work represents the first example on the synthesis of α-trifluoromethylthio enaminones via direct C-H functionalization. In addition, the resulting CF3S-functionalized enaminones have been proven as useful building blocks in the synthesis of various CF3S-functionalized heteroaromatic compounds by simple annulation reactions.

Association between driving pressure-guided ventilation and postoperative pulmonary complications in surgical patients: a meta-analysis with trial sequential analysis.

BACKGROUND: Prior studies have reported inconsistent results regarding the association between driving pressure-guided ventilation and postoperative pulmonary complications (PPCs). We aimed to investigate whether driving pressure-guided ventilation is associated with a lower risk of PPCs. METHODS: We systematically searched electronic databases for RCTs comparing driving pressure-guided ventilation with conventional protective ventilation in adult surgical patients. The primary outcome was a composite of PPCs. Secondary outcomes were pneumonia, atelectasis, and acute respiratory distress syndrome (ARDS). Meta-analysis and subgroup analysis were conducted to calculate risk ratios (RRs) with 95% confidence intervals (CI). Trial sequential analysis (TSA) was used to assess the conclusiveness of evidence. RESULTS: Thirteen RCTs with 3401 subjects were included. Driving pressure-guided ventilation was associated with a lower risk of PPCs (RR 0.70, 95% CI 0.56-0.87, P=0.001), as indicated by TSA. Subgroup analysis (P for interaction=0.04) found that the association was observed in non-cardiothoracic surgery (nine RCTs, 1038 subjects, RR 0.61, 95% CI 0.48-0.77, P< 0.0001), with TSA suggesting sufficient evidence and conclusive result; however, it did not reach significance in cardiothoracic surgery (four RCTs, 2363 subjects, RR 0.86, 95% CI 0.67-1.10, P=0.23), with TSA indicating insufficient evidence and inconclusive result. Similarly, a lower risk of pneumonia was found in non-cardiothoracic surgery but not in cardiothoracic surgery (P for interaction=0.046). No significant differences were found in atelectasis and ARDS between the two ventilation strategies. CONCLUSIONS: Driving pressure-guided ventilation was associated with a lower risk of postoperative pulmonary complications in non-cardiothoracic surgery but not in cardiothoracic surgery. SYSTEMATIC REVIEW PROTOCOL: INPLASY 202410068.

Zonisamide attenuates pressure overload-induced myocardial hypertrophy in mice through proteasome inhibition.

Myocardial hypertrophy is a pathological thickening of the myocardium which ultimately results in heart failure. We previously reported that zonisamide, an antiepileptic drug, attenuated pressure overload-caused myocardial hypertrophy and diabetic cardiomyopathy in murine models. In addition, we have found that the inhibition of proteasome activates glycogen synthesis kinase 3 (GSK-3) thus alleviates myocardial hypertrophy, which is an important anti-hypertrophic strategy. In this study, we investigated whether zonisamide prevented pressure overload-caused myocardial hypertrophy through suppressing proteasome. Pressure overload-caused myocardial hypertrophy was induced in mice by trans-aortic constriction (TAC) surgery. Two days after the surgery, the mice were administered zonisamide (10, 20, 40 mg·kg-1·d-1, i.g.) for four weeks. We showed that zonisamide administration significantly mitigated impaired cardiac function. Furthermore, zonisamide administration significantly inhibited proteasome activity as well as the expression levels of proteasome subunit beta types (PSMB) of the 20 S proteasome (PSMB1, PSMB2 and PSMB5) and proteasome-regulated particles (RPT) of the 19 S proteasome (RPT1, RPT4) in heart tissues of TAC mice. In primary neonatal rat cardiomyocytes (NRCMs), zonisamide (0.3 µM) prevented myocardial hypertrophy triggered by angiotensin II (Ang II), and significantly inhibited proteasome activity, proteasome subunits and proteasome-regulated particles. In Ang II-treated NRCMs, we found that 18α-glycyrrhetinic acid (18α-GA, 2 mg/ml), a proteasome inducer, eliminated the protective effects of zonisamide against myocardial hypertrophy and proteasome. Moreover, zonisamide treatment activated GSK-3 through inhibiting the phosphorylated AKT (protein kinase B, PKB) and phosphorylated liver kinase B1/AMP-activated protein kinase (LKB1/AMPKα), the upstream of GSK-3. Zonisamide treatment also inhibited GSK-3's downstream signaling proteins, including extracellular signal-regulated kinase (ERK) and GATA binding protein 4 (GATA4), both being the hypertrophic factors. Collectively, this study highlights the potential of zonisamide as a new therapeutic agent for myocardial hypertrophy, as it shows potent anti-hypertrophic potential through the suppression of proteasome.

Impaired synaptic plasticity and decreased glutamatergic neuron excitability induced by SIRT1/BDNF downregulation in the hippocampal CA1 region are involved in postoperative cognitive dysfunction.

BACKGROUND: Postoperative cognitive dysfunction (POCD) is a common complication after anesthesia/surgery, especially among elderly patients, and poses a significant threat to their postoperative quality of life and overall well-being. While it is widely accepted that elderly patients may experience POCD following anesthesia/surgery, the exact mechanism behind this phenomenon remains unclear. Several studies have indicated that the interaction between silent mating type information regulation 2 homologue 1 (SIRT1) and brain-derived neurotrophic factor (BDNF) is crucial in controlling cognitive function and is strongly linked to neurodegenerative disorders. Hence, this research aims to explore how SIRT1/BDNF impacts cognitive decline caused by anesthesia/surgery in aged mice. METHODS: Open field test (OFT) was used to determine whether anesthesia/surgery affected the motor ability of mice, while the postoperative cognitive function of 18 months old mice was evaluated with Novel object recognition test (NORT), Object location test (OLT) and Fear condition test (FC). The expressions of SIRT1 and other molecules were analyzed by western blot and immunofluorescence staining. The hippocampal synaptic plasticity was detected by Golgi staining and Long-term potentiation (LTP). The effects of SIRT1 and BDNF overexpression as well as chemogenetic activation of glutamatergic neurons in hippocampal CA1 region of 18 months old vesicular glutamate transporter 1 (VGLUT1) mice on POCD were further investigated. RESULTS: The research results revealed that older mice exhibited cognitive impairment following intramedullary fixation of tibial fracture. Additionally, a notable decrease in the expression of SIRT1/BDNF and neuronal excitability in hippocampal CA1 glutamatergic neurons was observed. By increasing levels of SIRT1/BDNF or enhancing glutamatergic neuron excitability in the CA1 region, it was possible to effectively mitigate synaptic plasticity impairment and ameliorate postoperative cognitive dysfunction. CONCLUSIONS: The decline in SIRT1/BDNF levels leading to changes in synaptic plasticity and neuronal excitability in older mice could be a significant factor contributing to cognitive impairment after anesthesia/surgery.

Identification of histopathological classification and establishment of prognostic indicators of gastric adenocarcinoma based on deep learning algorithm.

The aim of this study is to establish a deep learning (DL) model to predict the pathological type of gastric adenocarcinoma cancer based on whole-slide images(WSIs). We downloaded 356 histopathological images of gastric adenocarcinoma (STAD) patients from The Cancer Genome Atlas database and randomly divided them into the training set, validation set and test set (8:1:1). Additionally, 80 H&E-stained WSIs of STAD were collected for external validation. The CLAM tool was used to cut the WSIs and further construct the model by DL algorithm, achieving an accuracy of over 90% in identifying and predicting histopathological subtypes. External validation results demonstrated the model had a certain generalization ability. Moreover, DL features were extracted from the model to further investigate the differences in immune infiltration and patient prognosis between the two subtypes. The DL model can accurately predict the pathological classification of STAD patients, and provide certain reference value for clinical diagnosis. The nomogram combining DL-signature, gene-signature and clinical features can be used as a prognostic classifier for clinical decision-making and treatment.

Electrochemical Enaminone-Thioamide Annulation and Thioamide Dimeric Annulation for the Tunable Synthesis of Thiazoles and 1,2,4-Thiadiazole.

A green and sustainable electrochemical oxidative cyclization of enaminones with thioamides under metal- and oxidant-free conditions has been developed, providing an efficient approach for thiazole synthesis. Furthermore, 1,2,4-thiadiazoles can be selectively accessed via the electrochemical dimerization of thioamides in the absence of enaminones.

Review of the research status on the transmission and diffusion characteristics of indoor viral aerosol particles.

This study reviews the generation and diffusion characteristics of indoor viral aerosol particles, numerical simulation methods for the diffusion process of viral aerosols, and related research on the impact mechanism of different ventilation methods on the diffusion process of viral aerosols. Research has shown that the selection of initial conditions such as exhalation mode, initial airflow velocity, particle size, turbulence model, and calculation method for the generation of aerosol particles by the human body is of great significance for the numerical simulation of the diffusion process of viral aerosol particles. At the same time, on the basis of selecting appropriate ventilation methods, the reasonable setting of ventilation parameters (temperature, speed, height, etc.) can effectively suppress the spread of viral aerosols. This study can provide a theoretical basis for the study of related respiratory diseases, as well as technical and theoretical support for the selection of indoor ventilation methods to reduce the risk of human exposure caused by viral aerosols in the construction field. It also provides guidance and reference for aerosol transport and environmental protection in indoor atmospheric environments.

Annulative Nonaromatic Newman-Kwart-Type Rearrangement for the Synthesis of Sulfur Heteroaryls.

By employing enaminones and thiuram disulfides as starting materials, the frontiers of Newman-Kwart rearrangement have been expanded to the alkenyl system for the first time. In addition, instead of leading to the formation of simple carbamothioates, the rearrangement has led to the unprecedented construction of S-heteroaryls. Depending on the differences in the enaminone structure, the efficient synthesis of functionalized isothiazoles and thiophenes has been achieved.

Visible-light-induced Ritter-type amidation of α-hydroxy ketones in the selective synthesis of α,α-diamido and monoamido ketones.

Visible light-induced, transition metal-free oxidative dehydroxylation and C-H amidation of α-hydroxy ketones involving Ritter-type amidation has been developed, leading to the selective synthesis of α,α-diamido- and α-monoamido ketones with tunable selectivity as well as broad substrate tolerance.

Co-stimulators CD40-CD40L, a potential immune-therapy target for atherosclerosis: A review.

The interaction between CD40 and CD40 ligand (CD40L) a crucial co-stimulatory signal for activating adaptive immune cells, has a noteworthy role in atherosclerosis. It is well-known that atherosclerosis is linked to immune inflammation in blood vessels. In atherosclerotic lesions, there is a multitude of proinflammatory cytokines, adhesion molecules, and collagen, as well as smooth muscle cells, macrophages, and T lymphocytes, particularly the binding of CD40 and CD40L. Therefore, research on inhibiting the CD40-CD40L system to prevent atherosclerosis has been ongoing for more than 30 years. However, it's essential to note that long-term direct suppression of CD40 or CD40L could potentially result in immunosuppression, emphasizing the critical role of the CD40-CD40L system in atherosclerosis. Thus, specifically targeting the CD40-CD40L interaction on particular cell types or their downstream signaling pathways may be a robust strategy for mitigating atherosclerosis, reducing potential side effects. This review aims to summarize the potential utility of the CD40-CD40L system as a viable therapeutic target for atherosclerosis.

Compartment syndrome associations with drugs: a pharmacovigilance study of the FDA adverse event reporting system (FAERS).

BACKGROUND: Compartment syndrome is an uncommon but life-threatening condition. No study has comprehensively compared compartment syndrome (CS) association with available drugs. The objective of this study was to estimate the association between CS and drugs using the FDA Adverse Event Report System (FAERS). RESEARCH DESIGN AND METHODS: FAERS reports from the first quarter of 2004 to the third quarter of 2023 were analyzed. The Medical Dictionary for Regulatory Activities (MedDRA) was used to identify CS cases. Reporting odds ratio (ROR), corresponding to 95% confidence intervals (95% CI) were calculated to detect a positive signal. RESULTS: A total of 2197 reports were considered in the study after the inclusion criteria were applied. Totally 100 drugs were found to be associated with CS. The median time for drug-associated CS was 45 days. CONCLUSIONS: By analyzing the FAERS database, the study revealed that certain drugs are significantly associated with compartment syndrome. Further studies are needed to verify whether these drugs are associated with such a risk.

Exploration of the Amino Acid Metabolic Profiling and Pathway in Clonorchis sinensis-Infected Rats Revealed by the Targeted Metabolomic Analysis.

Background: Clonorchiasis remains a serious public health problem. However, the molecular mechanism underlying clonorchiasis remains largely unknown. Amino acid (AA) metabolism plays key roles in protein synthesis and energy sources, and improves immunity in pathological conditions. Therefore, this study aimed to explore the AA profiles of spleen in clonorchiasis and speculate the interaction between the host and parasite. Methods: Here targeted ultrahigh performance liquid chromatography multiple reaction monitoring mass spectrometry was applied to discover the AA profiles in spleen of rats infected with Clonorchis sinensis. Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis (KEGG) was performed to characterize the dysregulated metabolic pathways. Results: Pathway analysis revealed that phenylalanine, tyrosine, and tryptophan biosynthesis and ß-alanine metabolism were significantly altered in clonorchiasis. There were no significant correlations between 14 significant differential AAs and interleukin (IL)-1ß. Although arginine, asparagine, histidine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine were positively correlated with IL-6, IL-10, tumor necrosis factor (TNF)-α as well as aspartate aminotransferase and alanine aminotransferase; ß-alanine and 4-hydroxyproline were negatively correlated with IL-6, IL-10, and TNF-α. Conclusion: This study reveals the dysregulation of AA metabolism in clonorchiasis and provides a useful insight of metabolic mechanisms at the molecular level.

Quercetin alleviates liver fibrosis via regulating glycolysis of liver sinusoidal endothelial cells and neutrophil infiltration.

Liver fibrosis, a common characteristic in various chronic liver diseases, is largely influenced by glycolysis. Quercetin (QE), a natural flavonoid known to regulate glycolysis, was studied for its effects on liver fibrosis and its underlying mechanism. In a model of liver fibrosis induced by carbon tetrachloride (CCl4), we aimed to assess pathological features, serum marker levels, and analyze the expression of glycolysis-related enzymes at both mRNA and protein levels, with a focus on changes in liver sinusoidal endothelial cells (LSECs). Our results showed that QE effectively improved liver injury and fibrosis evident by improved pathological features and lowered levels of serum markers, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), γ-glutamyl transferase (GGT), total bile acid (TBA), total bilirubin (TBIL), direct bilirubin (DBIL), hyaluronic acid (HA), laminin (LN), and procollagen type III (PCIII). QE also decreased lactate production and downregulated the expression of glycolysis-related enzymes­pyruvate kinase M2 (PKM2), phosphofructokinase platelet (PFKP), and hexokinase II (HK2)­at both the mRNA and protein levels. QE reduced the expression and activity of these enzymes, resulting in reduced glucose consumption, adenosine triphosphate (ATP) production, and lactate generation. Further analysis revealed that QE inhibited the production of chemokine (C-X-C motif) ligand 1 (CXCL1) and suppressed neutrophil recruitment. Overall, QE showed promising therapeutic potential for liver fibrosis by targeting LSEC glycolysis and reducing neutrophil infiltration.