High expression of NOTCH2 in gastric adenocarcinoma: A novel early diagnostic target.

BACKGROUND AND AIM: NOTCH2 is overexpressed in gastric cancer (GC), and its enhanced activity is significantly correlated with worse tumor characteristics. We aim to analyze the clinicopathologic correlation between NOTCH2 and the molecular typing of GC by immunohistochemistry and by transcriptional sequencing. METHODS: In this immunohistochemical study, we detected NOTCH2, EBER, P53, HER2, MLH1, MSH2, PMS2, and MSH6 and evaluated the association of NOTCH2 with clinical and histopathological features in a large single-institutional series of gastric adenocarcinomas (n = 488). The correlation was also investigated between immunohistochemical results and survival outcomes. RESULTS: High NOTCH2 expression (2+/3+) was found in 139/488 (27.5%) samples analyzed. NOTCH2 expression was correlated with early stage T1 (P < 0.0001), GC in the fundus (P = 0.0364), and positive P53 status (P = 0.0019). We did not find an association between NOTCH2 and HER2, microsatellite instability, EBER, and overall survival. Through RNA sequencing, it was revealed that NOTCH2 plays an important biological function in the pathogenesis and development of GC. CONCLUSIONS: Our findings suggested that NOTCH2 may be a potential diagnostic target for GC due to the fact that its high expression is closely associated with the early stages of cancer.

Integrated transcriptomics and metabolomics reveal the mechanism of intestinal damage upon acute patulin exposure in mice.

Mycotoxin contamination has become a major food safety issue and greatly threatens human and animal health. Patulin (PAT), a common mycotoxin in the environment, is exposed through the food chain and damages the gastrointestinal tract. However, its mechanism of enterotoxicity at the genetic and metabolic levels remains to be elucidated. Herein, the intestinal histopathological and biochemical indices, transcriptome, and metabolome of C57BL/6 J mice exposed to different doses of PAT were successively assessed, as well as the toxicokinetics of PAT in vivo. The results showed that acute PAT exposure induced damaged villi and crypts, reduced mucus secretion, decreased SOD and GSH-Px activities, and enhanced MPO activity in the small intestine and mild damage in the colon. At the transcriptional level, the genes affected by PAT were dose-dependently altered in the small intestine and fluctuated in the colon. PAT primarily affected inflammation-related signaling pathways and oxidative phosphorylation in the small intestine and immune responses in the colon. At the metabolic level, amino acids decreased, and extensive lipids accumulated in the small intestine and colon. Seven metabolic pathways were jointly affected by PAT in two intestinal sites. Moreover, changes in PAT products and GST activity were detected in the small intestinal tissue but not in the colonic tissue, explaining the different damage degrees of the two sites. Finally, the integrated results collectively explained the toxicological mechanism of PAT, which damaged the small intestine directly and the colon indirectly. These results paint a clear panorama of intestinal changes after PAT exposure and provide valuable information on the exposure risk and toxic mechanism of PAT.

Mechanisms of Flavonoids and Their Derivatives in Endothelial Dysfunction Induced by Oxidative Stress in Diabetes.

Diabetic complications pose a significant threat to life and have a negative impact on quality of life in individuals with diabetes. Among the various factors contributing to the development of these complications, endothelial dysfunction plays a key role. The main mechanism underlying endothelial dysfunction in diabetes is oxidative stress, which adversely affects the production and availability of nitric oxide (NO). Flavonoids, a group of phenolic compounds found in vegetables, fruits, and fungi, exhibit strong antioxidant and anti-inflammatory properties. Several studies have provided evidence to suggest that flavonoids have a protective effect on diabetic complications. This review focuses on the imbalance between reactive oxygen species and the antioxidant system, as well as the changes in endothelial factors in diabetes. Furthermore, we summarize the protective mechanisms of flavonoids and their derivatives on endothelial dysfunction in diabetes by alleviating oxidative stress and modulating other signaling pathways. Although several studies underline the positive influence of flavonoids and their derivatives on endothelial dysfunction induced by oxidative stress in diabetes, numerous aspects still require clarification, such as optimal consumption levels, bioavailability, and side effects. Consequently, further investigations are necessary to enhance our understanding of the therapeutic potential of flavonoids and their derivatives in the treatment of diabetic complications.

Gas chromatography-ion mobility spectrometry (GC-IMS) technique and its recent applications in grain research.

Grains are the primary source of food for most people worldwide and constitute a major source of carbohydrates. Many novel technologies are being employed to ensure the safety and reliability of grain supply and production. Gas chromatography-ion mobility spectrometry (GC-IMS) can effectively separate and sensitively detect volatile organic compounds. It possesses advantages such as speed, convenience, high sensitivity, no pretreatment, and wide applicability. In recent years, many studies have shown that the application of GC-IMS technology for grain flavor analysis can play a crucial role in grains. This article elucidates the working principle of GC-IMS technology, reviews the application of GC-IMS in grains in the past 5 years. GC-IMS technology is mainly applied in four aspects in grains. In grain classification, it distinguishes varieties, quality, origin, production year, and processing methods based on the trace differences in volatile organic compounds, thereby fulfilling various grain classification requirements such as origin tracing, geographical indication product recognition, variety identification, production year identification, and detection of counterfeit and inferior grain samples. In optimizing the processing technology of grains and their products, it can improve food flavor, reduce undesirable flavors, and identify better processing parameters. In grain storage, it can determine the storage time, detect spoilage phenomena such as mold and discoloration during storage, eliminate pests affecting storage, and predict the vitality of seeds after storage. In aroma evaluation of grains and their processed products, it can assess the impact of new raw materials, new technologies, fermentation processes, and even oral processing on the quality of grain products. This article also summarizes the characteristics of GC-IMS technology, compiles typical grain flavor compounds, and provides prospects for the future application of GC-IMS. © 2024 Society of Chemical Industry.

A self-supervised fusion network for carotid plaque ultrasound image classification.

Carotid plaque classification from ultrasound images is crucial for predicting ischemic stroke risk. While deep learning has shown effectiveness, it heavily relies on substantial labeled datasets. Achieving high performance with limited labeled images is essential for clinical use. Self-supervised learning (SSL) offers a potential solution; however, the existing works mainly focus on constructing the SSL tasks, neglecting the use of multiple tasks for pretraining. To overcome these limitations, this study proposed a self-supervised fusion network (Fusion-SSL) for carotid plaque ultrasound image classification with limited labeled data. Fusion-SSL consists of two SSL tasks: classifying image block order (Ordering) and predicting image rotation angle (Rotating). A dual-branch residual neural network was developed to fuse feature presentations learned by the two tasks, which can extract richer visual boundary shape and contour information than a single task. In this experiment, 1270 carotid plaque ultrasound images were collected from 844 patients at Zhongnan Hospital (Wuhan, China). The results showed that Fusion-SSL outperforms single SSL methods across different percentages of labeled training data, ranging from 10 to 100%. Moreover, with only 40% labeled training data, Fusion-SSL achieved comparable results to a single SSL method (predicting image rotation angle) with 100% labeled data. These results indicate that Fusion-SSL could be beneficial for the classification of carotid plaques and the early warning of a stroke in clinical practice.

The ETV6-MECOM fusion protein promotes EMT-related properties by repressing the transactivation activity of E-cadherin promoter in K562 leukemia cells.

The ETV6-MECOM fusion gene, produced by the rare and recurrent chromosomal translocation t(3; 12) (q26; p13), is associated with high mortality and short survival in myeloid leukemia. However, its function and underlying mechanisms in leukemia progression remain unknown. In this study, leukemia-stable K562 cells expressing the ETV6-MECOM fusion protein were used to investigate the effects of the ETV6-MECOM oncoprotein. K562-ETV6-MECOM cells were undifferentiated and had reduced colony formation, increased cell migration and invasion, and increased sphere number and diameter in a spheroid formation assay, presenting epithelial-to-mesenchymal transition (EMT) traits. The expression of E-cadherin, a hallmark of EMT, was significantly downregulated at the transcriptional and translational level in K562-ETV6-MECOM cells to explore the mechanistic basis of EMT. Stepwise truncation, DNA sequence deletion, mutation analysis for E-cadherin promoter transactivation, and a dual luciferase assay indicated that the regulatory region of ETV6-MECOM is located in the DNA motif -1116 TTAAAA-1111 of E-cadherin promoter. Moreover, a chromatin immunoprecipitation assay showed that this oncoprotein binds to the DNA motif -1116 TTAAAA-1111 with the anti-EVI1 antibody. Although ETV6-MECOM upregulated the expressions of EMT master regulators, including SNAIL, SLUG, ZEB2, and TWIST2, their knockdown had no effect on EMT-related properties. However, overexpression of E-cadherin eliminated EMT traits in the presence of the ETV6-MECOM oncoprotein. These data confirmed that the ETV6-MECOM oncoprotein, not SNAIL, SLUG, ZEB2, or TWIST2, plays a critical role in inducing EMT traits in leukemia K562 cells. ETV6-MECOM induces EMT-related properties by downregulating the transcriptional expression of E-cadherin and repressing its transactivation activity by binding to its core motif -1116TTAAAA-1111 in leukemia K562 cells. These findings could contribute to the development of a therapeutic target for patients with myeloid leukemia characterized by ETV6-MECOM.

Influence of Pd-Layer Thickness on Bonding Reliability of Pd-Coated Cu Wire.

In this paper, three Pd-coated Cu (PCC) wires with different Pd-layer thicknesses were used to make bonding samples, and the influence of Pd-layer thickness on the reliability of bonded points before and after a high-temperature storage test was studied. The results show that smaller bonding pressure and ultrasonic power lead to insufficient plastic deformation of the ball-bonded point, which also leads to small contact area with the pad and low bonding strength. Excessive bonding pressure and ultrasonic power will lead to 'scratch' on the surface of the pad and large-scale Ag spatter. The wedge-bonded point has a narrowed width when the bonding pressure and ultrasonic power are too small, and the tail edge will be cocked, resulting in false bonding and low strength. When the bonding pressure or ultrasonic power is too large, it will cause stress concentration, and the pad will appear as an 'internal injury', which will improve the failure probability; a high-temperature environment can make Cu-Ag intermetallic compounds (IMCs) grow and improve the bonding strength. With the extension of high-temperature storage time, the shear force of Pd100 gradually reaches the peak and then decreases, due to Kirkendall pores caused by excessive growth of IMCs, while the shear force of Pd120 continued to increase due to the slow growth rate of IMCs. In the high-temperature storage test, the thicker the Pd layer of the bonding wire, the higher the bonding strength; in the cold/hot cycle test, the sample with the largest Pd-layer thickness has the lowest failure rate. The thicker the Pd layer, the stronger its ability to resist changes in the external environment, and the higher its stability and reliability.

Predicting ICU readmission risks in intracerebral hemorrhage patients: Insights from machine learning models using MIMIC databases.

BACKGROUND: Intracerebral hemorrhage (ICH) is a stroke subtype characterized by high mortality and complex post-event complications. Research has extensively covered the acute phase of ICH; however, ICU readmission determinants remain less explored. Utilizing the MIMIC-III and MIMIC-IV databases, this investigation develops machine learning (ML) models to anticipate ICU readmissions in ICH patients. METHODS: Retrospective data from 2242 ICH patients were evaluated using ICD-9 codes. Recursive feature elimination with cross-validation (RFECV) discerned significant predictors of ICU readmissions. Four ML models-AdaBoost, RandomForest, LightGBM, and XGBoost-underwent development and rigorous validation. SHapley Additive exPlanations (SHAP) elucidated the effect of distinct features on model outcomes. RESULTS: ICU readmission rates were 9.6% for MIMIC-III and 10.6% for MIMIC-IV. The LightGBM model, with an AUC of 0.736 (95% CI: 0.668-0.801), surpassed other models in validation datasets. SHAP analysis revealed hydrocephalus, sex, neutrophils, Glasgow Coma Scale (GCS), specific oxygen saturation (SpO2) levels, and creatinine as significant predictors of readmission. CONCLUSION: The LightGBM model demonstrates considerable potential in predicting ICU readmissions for ICH patients, highlighting the importance of certain clinical predictors. This research contributes to optimizing patient care and ICU resource management. Further prospective studies are warranted to corroborate and enhance these predictive insights for clinical utilization.

Accumulation and metabolism of selenium in the rare yeast Kazachstania unispora during the selenium enrichment process.

Selenium (Se)-enriched yeast is a good nutritional source for human being. Kazachstania unispora (K. unispora) has shown the positive physiological functionality for human health, whose potential for Se enrichment, however, remains elusive. This study demonstrated the ability of K. unispora to convert inorganic Se to organic Se, and then comprehensively investigated the accumulation and metabolism of Se in K. unispora. The results indicated that K. unispora can effectively accumulate organic Se, of which 95% of absorbed Se was converted to organic forms. Among these organic Se, 46.17% of them was bound to protein and 16.78% was combined with polysaccharides. In addition, some of the organic Se was metabolized to selenomethionine (30.26%) and selenocystine (3.02%), during which four low-molecular weight selenometabolites were identified in K. unispora. These findings expand the scope of Se-enriched yeast species, and provide useful knowledge for further investigation of Se enrichment mechanism in K. unispora.

Exploring non-coding RNA mechanisms in hepatocellular carcinoma: implications for therapy and prognosis.

Hepatocellular carcinoma (HCC) is a significant contributor to cancer-related deaths in the world. The development and progression of HCC are closely correlated with the abnormal regulation of non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs). Important biological pathways in cancer biology, such as cell proliferation, death, and metastasis, are impacted by these ncRNAs, which modulate gene expression. The abnormal expression of non-coding RNAs in HCC raises the possibility that they could be applied as new biomarkers for diagnosis, prognosis, and treatment targets. Furthermore, by controlling the expression of cancer-related genes, miRNAs can function as either tumor suppressors or oncogenes. On the other hand, lncRNAs play a role in the advancement of cancer by interacting with other molecules within the cell, which, in turn, affects processes such as chromatin remodeling, transcription, and post-transcriptional processes. The importance of ncRNA-driven regulatory systems in HCC is being highlighted by current research, which sheds light on tumor behavior and therapy response. This research highlights the great potential of ncRNAs to improve patient outcomes in this difficult disease landscape by augmenting the present methods of HCC care through the use of precision medicine approaches.

Proteomic characterization of the medial prefrontal cortex in chronic restraint stress mice.

Depression is a prominent contributor to global disability. A growing body of data suggests that depression is associated with the pathophysiology of the medial prefrontal cortex (mPFC), but the underlying mechanisms remain poorly understood. Mice were subjected to chronic restraint stress (CRS) for 3 weeks to create depression models during this investigation. Protein tandem mass tag (TMT) quantification and LC-MS/MS analysis were conducted to examine proteome patterns. Afterwards, to further explore the enrichment of differential proteins and the signaling pathways involved, we annotated these differentially expressed proteins. We confirmed that CRS mice developed depression-like and anxiety-like behaviors. Among the 8081 measured proteins, a total of 15 proteins were found to be differentially expressed. These proteins exhibited functional enrichment in a variety of biological functions, and among these pathways, alterations in synaptic function and autophagy are noteworthy. In addition, we identified a differentially expressed protein called Wnt2b and found that CRS may disrupt synaptic plasticity by affecting the activation of the Wnt2b/ß-catenin pathway. Our findings showed depression-like behaviors in the CRS mouse model and molecular alterations in the mPFC, which may help explain the pathogenesis of depression and identify novel antidepressant medication targets. SIGNIFICANCE: Depression is a prevalent and frequent chronic mental illness and is now a significant contributor to global disability. In this study, we used chronic restraint stress to establish a mouse model of depression, and differentially expressed proteins in the medial prefrontal cortex of depressed model mice were detected by TMT proteomics. Our study verified the presence of altered synaptic function and excessive autophagy in the mPFC of CRS-induced mice from a proteomic perspective. Furthermore, we demonstrated that CRS may disrupt synaptic plasticity by affecting the activation of the Wnt2b/ß-catenin pathway, which may be a key link in the pathogenesis of depression and may provide new insights for identifying new antidepressant drug targets.

Biodegradation of humic acids by Streptomyces rochei to promote the growth and yield of corn.

Humic acids (HAs) are organic macromolecules that play an important role in improving soil properties, plant growth and agronomic parameters. However, the feature of relatively complex aromatic structure makes it difficult to be degraded, which restricts the promotion to the crop growth. Thus, exploring microorganisms capable of degrading HAs may be a potential solution. Here, a HAs-degrading strain, Streptomyces rochei L1, and its potential for biodegradation was studied by genomics, transcriptomics, and targeted metabolomics analytical approaches. The results showed that the high molecular weight HAs were cleaved to low molecular aliphatic and aromatic compounds and their derivatives. This cleavage may be associated with the laccase (KatE). In addition, the polysaccharide deacetylase (PdgA) catalyzes the removal of acetyl groups from specific sites on the HAs molecule, resulting in structural changes. The field experiment showed that the degraded HAs significantly promote the growth of corn seedlings and increase the corn yield by 3.6 %. The HAs-degrading products, including aromatic and low molecular weight aliphatic substances as well as secondary metabolites from S. rochei L1, might be the key components responsible for the corn promotion. Our findings will advance the application of HAs as soil nutrients for the green and sustainable agriculture.

The development of the neurocritical care specialty in China based on the analysis of neurocritical care unit volume and quality.

PURPOSE: Through three neurocritical care unit (NCCU) surveys in China, we tried to understand the development status of neurocritical care and clarify its future development. METHODS: Using a cross-sectional survey method and self-report questionnaires, the number and quality of NCCUs were investigated through three steps: administering the questionnaire, sorting the survey data, and analyzing the survey data. RESULTS: At the second and third surveys, the number of NCCUs (76/112/206) increased by 47% and 84%, respectively. The NCCUs were located in tertiary grade A hospitals or teaching hospitals (65/100/181) in most provinces (24/28/29). The numbers of full-time doctors (359/668/1337) and full-time nurses (904/1623/207) in the NCCUs increased, but the doctor-bed ratio and nurse-bed ratio were still insufficient (0.4:1 and 1.3:1). CONCLUSION: In the past 20 years, the growth rate of NCCUs in China has accelerated, while the allocation of medical staff has been insufficient. Although most NCCU hospital bed facilities and instruments and equipment tend to be adequate, there are obvious defects in some aspects of NCCUs.

Leritrelvir for the treatment of mild or moderate COVID-19 without co-administered ritonavir: a multicentre randomised, double-blind, placebo-controlled phase 3 trial.

Background: Leritrelvir is a novel α-ketoamide based peptidomimetic inhibitor of SARS-CoV-2 main protease. A preclinical study has demonstrated leritrelvir poses similar antiviral activities towards different SARS-CoV-2 variants compared with nirmatrelvir. A phase 2 clinical trial has shown a comparable antiviral efficacy and safety between leritrelvir with and without ritonavir co-administration. This trial aims to test efficacy and safety of leritrelvir monotherapy in adults with mild-to-moderate COVID-19. Methods: This was a randomised, double-blind, placebo-controlled, multicentre phase 3 trial at 29 clinical sites in China. Enrolled patients were from 18 to 75 years old, diagnosed with mild or moderate COVID-19 and not requiring hospitalization. Patients had a positive SARS-CoV-2 nucleic acid test (NAT) and at least one of the COVID-19 symptoms within 48 h before randomization, and the interval between the first positive SARS-CoV-2 NAT and randomization was ≤120 h (5 days). Patients were randomly assigned in a 1:1 ratio to receive a 5-day course of either oral leritrelvir 400 mg TID or placebo. The primary efficacy endpoint was the time from the first dose to sustained clinical recovery of all 11 symptoms (stuffy or runny nose, sore throat, shortness of breath or dyspnea, cough, muscle or body aches, headache, chills, fever ≥37 °C, nausea, vomiting, and diarrhea). The safety endpoint was the incidence of adverse events (AE). Primary and safety analyses were performed in the intention-to-treat (ITT) population. This study is registered with ClinicalTrials.gov, NCT05620160. Findings: Between Nov 12 and Dec 30, 2022 when the zero COVID policy was abolished nationwide, a total of 1359 patients underwent randomization, 680 were assigned to leritrelvir group and 679 to placebo group. The median time to sustained clinical recovery in leritrelvir group was significantly shorter (251.02 h [IQR 188.95-428.68 h]) than that of Placebo (271.33 h [IQR 219.00-529.63 h], P = 0.0022, hazard ratio [HR] 1.20, 95% confidence interval [CI], 1.07-1.35). Further analysis of subgroups for the median time to sustained clinical recovery revealed that (1) subgroup with positive viral nucleic acid tested ≤72 h had a 33.9 h difference in leritrelvir group than that of placebo; (2) the subgroup with baseline viral load >8 log 10 Copies/mL in leritrelvir group had 51.3 h difference than that of placebo. Leritrelvir reduced viral load by 0.82 log10 on day 4 compared to placebo. No participants in either group progressed to severe COVID-19 by day 29. Adverse events were reported in two groups: leritrelvir 315 (46.46%) compared with placebo 292 (43.52%). Treatment-relevant AEs were similar 218 (32.15%) in the leritrelvir group and 186 (27.72%) in placebo. Two cases of COVID-19 pneumonia were reported in placebo group, and one case in leritrelvir group, none of them were considered by the investigators to be leritrelvir related. The most frequently reported AEs (occurring in ≥5% of participants in at least one group) were laboratory finding: hypertriglyceridemia (leritrelvir 79 [11.7%] vs. placebo 70 [10.4%]) and hyperlipidemia (60 [8.8%] vs. 52 [7.7%]); all of them were nonserious. Interpretation: Leritrelvir monotherapy has good efficacy for mild-to-moderate COVID-19 and without serious safety concerns. Funding: This study was funded by the National Multidisciplinary Innovation Team Project of Traditional Chinese Medicine, Guangdong Science and Technology Foundation, Guangzhou Science and Technology Planning Project and R&D Program of Guangzhou Laboratory.