EH domain-containing protein 2 (EHD2): Overview, biological function, and therapeutic potential.

EH domain-containing protein 2 (EHD2) is a member of the EHD protein family and is mainly located in the plasma membrane, but can also be found in the cytoplasm and endosomes. EHD2 is also a nuclear-cytoplasmic shuttle protein. After entering the cell nuclear, EHD2 acts as a corepressor of transcription to inhibit gene transcription. EHD2 regulates a series of biological processes. As a key regulator of endocytic transport, EHD2 is involved in the formation and maintenance of endosomal tubules and vesicles, which are critical for the intracellular transport of proteins and other substances. The N-terminal of EHD2 is attached to the cell membrane, while its C-terminal binds to the actin-binding protein. After binding, EHD2 connects with the actin cytoskeleton, forming the curvature of the membrane and promoting cell endocytosis. EHD2 is also associated with membrane protein trafficking and receptor signaling, as well as in glucose metabolism and lipid metabolism. In this review, we highlight the recent advances in the function of EHD2 in various cellular processes and its potential implications in human diseases such as cancer and metabolic disease. We also discussed the prospects for the future of EHD2. EHD2 has a broad prospect as a therapeutic target for a variety of diseases. Further research is needed to explore its mechanism, which could pave the way for the development of targeted treatments.

Association of preoperative coronavirus disease 2019 with mortality, respiratory morbidity and extrapulmonary complications after elective, noncardiac surgery: An observational cohort study.

STUDY OBJECTIVE: To assess the impact of preoperative infection with the contemporary strain of severe acute respiratory coronavirus 2 (SARS-CoV-2) on postoperative mortality, respiratory morbidity and extrapulmonary complications after elective, noncardiac surgery. DESIGN: An ambidirectional observational cohort study. SETTING: A tertiary and teaching hospital in Shanghai, China. PATIENTS: All adult patients (≥ 18 years of age) who underwent elective, noncardiac surgery under general anesthesia at Huashan Hospital of Fudan University from January until March 2023 were screened for eligibility. A total of 2907 patients were included. EXPOSURE: Preoperative coronavirus disease 2019 (COVID-19) positivity. MEASUREMENTS: The primary outcome was 30-day postoperative mortality. The secondary outcomes included postoperative pulmonary complications (PPCs), myocardial injury after noncardiac surgery (MINS), acute kidney injury (AKI), postoperative delirium (POD) and postoperative sleep quality. Multivariable logistic regression was used to assess the risk of postoperative mortality and morbidity imposed by preoperative COVID-19. MAIN RESULTS: The risk of 30-day postoperative mortality was not associated with preoperative COVID-19 [adjusted odds ratio (aOR), 95% confidence interval (CI): 0.40, 0.13-1.28, P = 0.123] or operation timing relative to diagnosis. Preoperative COVID-19 did not increase the risk of PPCs (aOR, 95% CI: 0.99, 0.71-1.38, P = 0.944), MINS (aOR, 95% CI: 0.54, 0.22-1.30; P = 0.168), or AKI (aOR, 95% CI: 0.34, 0.10-1.09; P = 0.070) or affect postoperative sleep quality. Patients who underwent surgery within 7 weeks after COVID-19 had increased odds of developing delirium (aOR, 95% CI: 2.26, 1.05-4.86, P = 0.036). CONCLUSIONS: Preoperative COVID-19 or timing of surgery relative to diagnosis did not confer any added risk of 30-day postoperative mortality, PPCs, MINS or AKI. However, recent COVID-19 increased the risk of POD. Perioperative brain health should be considered during preoperative risk assessment for COVID-19 survivors.

Erratum: [Corrigendum] miR­137 suppresses proliferation, migration and invasion of colon cancer cell lines by targeting TCF4.

[This corrects the article DOI: 10.3892/ol.2018.8364.].

Loss of CREBBP and KMT2D cooperate to accelerate lymphomagenesis and shape the lymphoma immune microenvironment.

Despite regulating overlapping gene enhancers and pathways, CREBBP and KMT2D mutations recurrently co-occur in germinal center (GC) B cell-derived lymphomas, suggesting potential oncogenic cooperation. Herein, we report that combined haploinsufficiency of Crebbp and Kmt2d induces a more severe mouse lymphoma phenotype (vs either allele alone) and unexpectedly confers an immune evasive microenvironment manifesting as CD8+ T-cell exhaustion and reduced infiltration. This is linked to profound repression of immune synapse genes that mediate crosstalk with T-cells, resulting in aberrant GC B cell fate decisions. From the epigenetic perspective, we observe interaction and mutually dependent binding and function of CREBBP and KMT2D on chromatin. Their combined deficiency preferentially impairs activation of immune synapse-responsive super-enhancers, pointing to a particular dependency for both co-activators at these specialized regulatory elements. Together, our data provide an example where chromatin modifier mutations cooperatively shape and induce an immune-evasive microenvironment to facilitate lymphomagenesis.

ARID1A orchestrates SWI/SNF-mediated sequential binding of transcription factors with ARID1A loss driving pre-memory B cell fate and lymphomagenesis.

ARID1A, a subunit of the canonical BAF nucleosome remodeling complex, is commonly mutated in lymphomas. We show that ARID1A orchestrates B cell fate during the germinal center (GC) response, facilitating cooperative and sequential binding of PU.1 and NF-kB at crucial genes for cytokine and CD40 signaling. The absence of ARID1A tilts GC cell fate toward immature IgM+CD80-PD-L2- memory B cells, known for their potential to re-enter new GCs. When combined with BCL2 oncogene, ARID1A haploinsufficiency hastens the progression of aggressive follicular lymphomas (FLs) in mice. Patients with FL with ARID1A-inactivating mutations preferentially display an immature memory B cell-like state with increased transformation risk to aggressive disease. These observations offer mechanistic understanding into the emergence of both indolent and aggressive ARID1A-mutant lymphomas through the formation of immature memory-like clonal precursors. Lastly, we demonstrate that ARID1A mutation induces synthetic lethality to SMARCA2/4 inhibition, paving the way for potential precision therapy for high-risk patients.

Predicting Rate Constants of Alkane Cracking Reactions Using Machine Learning.

Calculating the thermal rate constants of elementary combustion reactions is of great importance in theoretical chemistry. Machine learning has become a powerful, data-driven method for predicting rate constants nowadays. Recently, the molecular similarity combined with the topological indices were proposed to represent the hydrogen abstraction reactions of alkane [J. Chem. Inf. Model. 2023, 63, 5097-5106], which are, however, not applicable to alkane cracking reactions, another important class of combustion reactions, due to the cleavage of the C-C bond. In this work, a new feature selection scheme is proposed to describe both bimolecular and unimolecular cracking reactions. Molecular descriptors are elaborately selected individually for both reactants and products from those generated by the open-source software RDKit. Machine learning models combined with these molecular descriptors are proven to have the ability to accurately predict rate constants of both the hydrogen abstraction reactions of alkanes by CH3 and the alkane cracking reactions. The average deviation of the XGB-FNN model for prediction is around 60% for the hydrogen abstraction reactions of alkanes and 100% for the alkane cracking reactions. It is expected that the descriptors proposed in this work can be applied to build machine learning models for other reactions.

Can the width of lower tongue base preoperative sonography measurements predict hypoxemia during esophagogastroduodenoscopy under sedation in ASA I-II patients?

AIM: The most common complication during esophagogastroduodenoscopy (EGD) under sedation is hypoxemia. There is a scarcity of indicators to predict the risk of hypoxemia during EGD under sedation accurately. The width of the lower tongue base measured by ultrasound (US) is considered to be a significant predictor of the presence and severity of obstructive sleepapnea syndrome (OSAS), which develops hypoxemia by a similar mechanism to EGD under sedation. This study aimed to observe its ability to predict hypoxemia during EGD under sedation.Material and methodsː Adult patients undergoing EGD under sedation at our hospital after assessment in the anesthesia clinic were enrolled in the study. The width of the lower tongue base was measured as the distance between the lingual arteries (DLA) on both sides of the inferior lateral margin of the tongue by US. The primary outcome was hypoxemia defined as the SpO2 <90% for longer than 10 seconds during EGD under sedation. ResultsːA total of 304 patients were successfully included, and hypoxemia was reported in 32 patients (10.5%). The DLA prediction criterion for hypoxemia was >31 mm. The DLA was correlated with hypoxemia (Spearman correlation coefficient, 0.455; p<0.001) and owned the highest area under the receiver operating characteristic curve (0.927; 99% CI, 0.891 to 0.953, compared with that of the other predictors, p< 0.001) with hypoxemia.Conclusionsː The width of the lower tongue base, measured as the DLA by US examination can be used to effectively predict the risk of hypoxemia during EGD under sedation.

Alistipes indistinctus-derived hippuric acid promotes intestinal urate excretion to alleviate hyperuricemia.

Hyperuricemia induces inflammatory arthritis and accelerates the progression of renal and cardiovascular diseases. Gut microbiota has been linked to the development of hyperuricemia through unclear mechanisms. Here, we show that the abundance and centrality of Alistipes indistinctus are depleted in subjects with hyperuricemia. Integrative metagenomic and metabolomic analysis identified hippuric acid as the key microbial effector that mediates the uric-acid-lowering effect of A. indistinctus. Mechanistically, A. indistinctus-derived hippuric acid enhances the binding of peroxisome-proliferator-activated receptor γ (PPARγ) to the promoter of ATP-binding cassette subfamily G member 2 (ABCG2), which in turn boosts intestinal urate excretion. To facilitate this enhanced excretion, hippuric acid also promotes ABCG2 localization to the brush border membranes in a PDZ-domain-containing 1 (PDZK1)-dependent manner. These findings indicate that A. indistinctus and hippuric acid promote intestinal urate excretion and offer insights into microbiota-host crosstalk in the maintenance of uric acid homeostasis.

Electroencephalogram findings in 10 patients with post-stroke epilepsy: A retrospective study.

BACKGROUND: Post-stroke epilepsy is a common and easily overlooked complication of acute cerebrovascular disease. Long-term seizures can seriously affect the prognosis and quality of life of patients. Electroencephalogram (EEG) is the simplest way to diagnose epilepsy, and plays an important role in predicting seizures and guiding medication. AIM: To explore the EEG characteristics of patients with post-stroke epilepsy and improve the detection rate of inter-seizure epileptiform discharges. METHODS: From January 2017 to June 2020, 10 patients with post-stroke epilepsy in our hospital were included. The clinical, imaging, and EEG characteristics were collected. The stroke location, seizure type, and ictal and interictal EEG manifestations of the patients with post-stroke epilepsy were then retrospectively analyzed. RESULTS: In all 10 patients, epileptiform waves occurred in the side opposite to the stroke lesion during the interictal stage; these manifested as sharp wave, sharp-wave complex, or spike discharges in the anterior head lead of the side opposite to the lesion. CONCLUSION: In EEG, epileptiform waves can occur in the side opposite to the stroke lesion in patients with post-stroke epilepsy.

The lipid metabolism remodeling: A hurdle in breast cancer therapy.

Lipids, as one of the three primary energy sources, provide energy for all cellular life activities. Lipids are also known to be involved in the formation of cell membranes and play an important role as signaling molecules in the intracellular and microenvironment. Tumor cells actively or passively remodel lipid metabolism, using the function of lipids in various important cellular life activities to evade therapeutic attack. Breast cancer has become the leading cause of cancer-related deaths in women, which is partly due to therapeutic resistance. It is necessary to fully elucidate the formation and mechanisms of chemoresistance to improve breast cancer patient survival rates. Altered lipid metabolism has been observed in breast cancer with therapeutic resistance, indicating that targeting lipid reprogramming is a promising anticancer strategy.

The possibility of visualizing TGF-ß1 expression in ApoE-/- mice atherosclerosis using MR targeted imaging.

BACKGROUND: Endothelial TGF-ß1 signaling is a primary driver of atherosclerosis-associated vascular inflammation. Targeted imaging and inhibition of the expression of TGF-ß1 may reduce the atherosclerotic vessel wall inflammation and stop the progression of atherosclerotic plaque. PURPOSE: To investigate the possibility of the anti-TGF-ß1-ultrasmall superparamagnetic iron oxide (USPIO) specific probe as an imaging marker for the expression of TGF-ß1 in ApoE-/- mice atherosclerosis detected with 7.0-T magnetic resonance imaging (MRI). MATERIAL AND METHODS: Here, 70 ApoE-/- mice on a high-fat diet served as the experimental group and 30 C57BL/6 mice on a normal diet served as the control group. The morphology of plaques was viewed by H&E staining, and the expression and distribution of TNC and TGF-ß1 were detected by immunohistochemical staining. Another 40 mice in the experimental group were classified into a targeted group, which was administrated an anti-TGF-ß1-USPIO probe, and the pure group, which was injected with pure USPIO. RESULTS: The 7.0-T MRI showed that the relative signal intensity (rSI) changes of the targeted group decreased more than those of the pure group (-19.34 ± 0.68% vs. -5.61 ± 0.57%; P < 0.05). Histopathological analyses demonstrated expression of TGF-ß1 in atherosclerotic plaque formation progression from 10 to 28 weeks. The MR images of the expression of TGF-ß1 in atherosclerosis correlated well with the pathological progression of atherosclerotic plaque formation. CONCLUSIONS: Anti-TGF-ß1-USPIO could provide a useful molecular imaging tool for detecting and monitoring the expression of TGF-ß1 in atherosclerotic plaques by MRI.

Asymmetric Synthesis of Chiral 1,2-Bis(Boronic) Esters Featuring Acyclic, Non-Adjacent 1,3-Stereocenters.

The construction of acyclic, non-adjacent 1,3-stereogenic centers, prevalent motifs in drugs and bioactive molecules, has been a long-standing synthetic challenge due to acyclic nucleophiles being distant from the chiral environment. In this study, we successfully synthesized highly valuable 1,2-bis(boronic) esters featuring acyclic and nonadjacent 1,3-stereocenters. Notably, this reaction selectively produces migratory coupling products rather than alternative deborylative allylation or direct allylation byproducts. This approach introduces a new activation mode for selective transformations of gem-diborylmethane in asymmetric catalysis. Additionally, we found that other gem-diborylalkanes, previously challenging due to steric hindrance, also successfully participated in this reaction. The incorporation of 1,2-bis(boryl)alkenes facilitated the diversification of the alkenyl and two boron moieties in our target compounds, thereby enabling access to a broad array of versatile molecules. DFT calculations were performed to elucidate the reaction mechanism and shed light on the factors responsible for the observed excellent enantioselectivity and diastereoselectivity. These were determined to arise from ligand-substrate steric repulsions in the syn-addition transition state.

Upregulation of miR-21-5p rescues the inhibition of cardiomyocyte proliferation induced by high glucose through negative regulation of Rhob.

Increasing evidence shows that maternal hyperglycemia inhibits cardiomyocyte (CM) proliferation and promotes cell apoptosis during fetal heart development, which leads to cardiac dysplasia. Accumulating evidence suggests that the overexpression of miR-21 in CMs has a protective role in cardiac function. Therefore, we investigated whether miR-21 can rescue CM injury caused by high glucose. First, we performed biological function analysis of miR-21-5p overexpression in H9c2 cells treated with high glucose. We found that the proliferation of H9c2 cells treated with high glucose decreased significantly and was rescued after overexpression of miR-21-5p. CCK-8 and EdU incorporation assays were performed to assess cell proliferation. The cell proliferation of the miR-21-5p mimic transfection group was improved compared with that of the NC mimic group (*p < 0.05, miR-21-5p mimics vs. NC mimics) when the proliferation of H9c2 cells was reduced by high glucose (****p < 0.0001, high glucose (HG) vs. normal glucose (NG)). Then, we verified the targeted and negative regulation of miR-21-5p on Rhob using a dual-luciferase activity assay and RT-qPCR, respectively. We further demonstrated that miR-21-5p regulates Rhob to rescue the inhibition of CM proliferation induced by high glucose. The CCK-8 results showed that the cell proliferation of the siRNA-Rhob group was higher than that of the NC mimic group (***p < 0.001) and that of the cotransfection group with Up-Rhob plasmids and miR-21-5p mimics was lower than that of the miR-21-5p mimic group (*p < 0.05). Conclusion: Overexpression of miR-21-5p rescues the inhibition of high glucose-induced CM proliferation through regulation of Rhob.

Action Recognition Based on Multi-Level Topological Channel Attention of Human Skeleton.

In action recognition, obtaining skeleton data from human poses is valuable. This process can help eliminate negative effects of environmental noise, including changes in background and lighting conditions. Although GCN can learn unique action features, it fails to fully utilize the prior knowledge of human body structure and the coordination relations between limbs. To address these issues, this paper proposes a Multi-level Topological Channel Attention Network algorithm: Firstly, the Multi-level Topology and Channel Attention Module incorporates prior knowledge of human body structure using a coarse-to-fine approach, effectively extracting action features. Secondly, the Coordination Module utilizes contralateral and ipsilateral coordinated movements in human kinematics. Lastly, the Multi-scale Global Spatio-temporal Attention Module captures spatiotemporal features of different granularities and incorporates a causal convolution block and masked temporal attention to prevent non-causal relationships. This method achieved accuracy rates of 91.9% (Xsub), 96.3% (Xview), 88.5% (Xsub), and 90.3% (Xset) on NTU-RGB+D 60 and NTU-RGB+D 120, respectively.

Improved dispersion-encoded full-range spectral interferometry for large depth, large inclination and rough samples.

In this study, we provide and validate an enhanced dispersion-encoded full-range spectral interferometry that offers improved measurement accuracy for samples characterized by significant depth, inclination, and roughness. Due to the low intensity of the optical signal in these samples, the optical signal is easy to be overwhelmed by the disturbance terms, demanding a more precise phase compensation. To address this issue, the direct current is removed by subtracting the envelope of the interference spectrum, allowing the weak signal near zero optical delay can be identified. Besides, considering the unwrapped phase error caused by the spectrometer aberrations, only the data with good phase continuity are preserved, which improves the accuracy of phase compensation. Using the proposed technique, the depth measurement range of the system is extended from 6 mm to 12 mm, while achieving an axial measurement precision of 2.5µm. In addition, the full-depth images of a ceramic standard step block and a 3D-printed sample are measured. It shows that our system exhibits superior adaptation to complex surfaces compared to the laser line profiler.

High Plant Protein Diet Ameliorated Hepatic Lipid Accumulation Through the Modulation of Gut Microbiota.

SCOPE: Substituting plant protein for animal protein has emerged as a promising strategy for managing atherogenic lipids. However, the impact of long-term intake of a high plant protein diet (HPD) on hepatic lipid disorder remains unclear. METHODS AND RESULTS: Eight-week-old apolipoprotein E deficient (apoE-/- ) mice are fed with either a normal protein diet (NCD) or HPD for 12 weeks. HPD intervention results in decreased body weight accompanied by increased energy expenditure, with no significant effect on glycemic control. Long-term intake of HPD improves the serum and hepatic lipid and cholesterol accumulation by suppressing hepatic squalene epoxidase (SQLE) expression, a key enzyme in cholesterol biosynthesis. Integrated analysis of 16S rDNA sequencing and metabolomics profiling reveals that HPD intervention increases the abundance of the Lachnospiraece family and serum levels of 12,13-DiHOME. Furthermore, in vivo studies demonstrate that 12,13-DiHOME significantly inhibits lipid accumulation, as well as SQLE expression induced by oleic acid in HepG2 cells. CONCLUSION: Diet rich in plant protein diet alleviates hyperlipidemia via increased microbial production of 12,13-DiHOME.