Site-specific immobilization of Cysteinyl leukotriene receptor 1 through enzymatic DNA-protein conjugation strategy for lead screening.

Immobilization of functional protein, especially G protein-coupled receptors (GPCRs), is particularly significant in various fields such as the development of assays for diagnosis, lead compound screening, as well as drug-protein interaction analysis. However, there are still some challenges with the immobilized proteins such as undefined loads, orientations, and the loss of activity. Herein, we introduced a DNA conjugation strategy into the immobilization of Cysteinyl leukotriene receptor 1(CysLTR1) which enables exquisite molecular control and higher activity of the receptor. We used the bacterial relaxases VirD2 as an immobilized tag fused at the C terminus of CysLTR1. Tyrosine residue(Y29) at the core binding site of the VirD2 tag can react with the single-strand piece of DNA(T-DNA) in the form of a covalent bond. Inspired by this strategy, we developed a new immobilization method by mixing the T-DNA-modified silica gel with the cell lysate containing the expressed VirD2-tagged CysLTR1 for 1 hour. We found that the successful formation of DNA-protein conjugate enables the immobilization of CysLTR1 fast, site-specific, and with minimal loss of activity. The feasibility of the immobilized CysLTR1 was evaluated in drug-protein binding interaction by frontal analysis and adsorption energy distribution analysis. The binding of pranlukast, zafirlukast, and MK571 to the immobilized CysLTR1 was realized, and the association constants presented good agreement between the two methods. Rosmarinic acid was retained in the immobilized CysLTR1 column, and the in-vitro test revealed that the compound binds to the receptor in one type of binding site mode. Despite these results, we concluded that the DNA-protein conjugate strategy will probably open up the possibilities for capturing other functional proteins in covalent and site-specific modes from the complex matrices and the immobilized receptor preserves the potential in fishing out lead compounds from natural products.

Rapid pulmonary 129Xe ventilation MRI of discharged COVID-19 patients with zigzag sampling.

PURPOSE: To demonstrate the feasibility of zigzag sampling for 3D rapid hyperpolarized 129Xe ventilation MRI in human. METHODS: Zigzag sampling in one direction was combined with gradient-recalled echo sequence (GRE-zigzag-Y) to acquire hyperpolarized 129Xe ventilation images. Image quality was compared with a balanced SSFP (bSSFP) sequence with the same spatial resolution for 12 healthy volunteers (HVs). For another 8 HVs and 9 discharged coronavirus disease 2019 subjects, isotropic resolution 129Xe ventilation images were acquired using zigzag sampling in two directions through GRE-zigzag-YZ. 129Xe ventilation defect percent (VDP) was quantified for GRE-zigzag-YZ and bSSFP acquisitions. Relationships and agreement between these VDP measurements were evaluated using Pearson correlation coefficient (r) and Bland-Altman analysis. RESULTS: For 12 HVs, GRE-zigzag-Y and bSSFP required 2.2 s and 10.5 s, respectively, to acquire 129Xe images with a spatial resolution of 3.96 × 3.96 × 10.5 mm3. Structural similarity index, mean absolute error, and Dice similarity coefficient between the two sets of images and ventilated lung regions were 0.85 ± 0.03, 0.0015 ± 0.0001, and 0.91 ± 0.02, respectively. For another 8 HVs and 9 coronavirus disease 2019 subjects, 129Xe images with a nominal spatial resolution of 2.5 × 2.5 × 2.5 mm3 were acquired within 5.5 s per subject using GRE-zigzag-YZ. VDP provided by GRE-zigzag-YZ was strongly correlated (R2 = 0.93, p < 0.0001) with that generated by bSSFP with minimal biases (bias = -0.005%, 95% limit-of-agreement = [-0.414%, 0.424%]). CONCLUSION: Zigzag sampling combined with GRE sequence provides a way for rapid 129Xe ventilation imaging.

Survival outcome and optimal candidates of primary tumor resection for patients with metastatic medullary thyroid cancer.

CONTEXT: Medullary thyroid cancer (MTC) often exhibits aggressive growth with distant organ metastasis, leading to poor survival. OBJECTIVE: The question of whether primary tumor resection (PTR) is beneficial for patients with metastatic MTC remains a subject of debate. In this study, we evaluated the prognostic significance of organ-specific metastases and the number of metastatic organs in these patients, and we also conducted an analysis to determine the therapeutic value of PTR in managing this rare malignancy. MATERIALS AND METHODS: Patients initially diagnosed with metastatic MTC were identified within the Surveillance, Epidemiology, and End Results (SEER) database. Univariable and multivariable Cox proportional hazards regression models were performed to identify survival predictors. Survival outcomes were calculated using the Kaplan-Meier method and compared using the log-rank tests. RESULTS: A total of 186 patients with metastatic MTC at initial diagnosis from 2010 to 2020 were included. Bone, lung and liver were the most common metastatic organs. Patients with brain metastasis had significantly worse overall survival (OS) (p = 0.007) and cancer-specific survival (CSS) (p = 0.0013). Among all patients, 105 (56.45%) underwent PTR, and this group showed reduced overall mortality (OM) and cancer-specific mortality (CSM) (all p < 0.05). When analyzing different metastatic patterns, PTR significantly lowered the risk of OM and CSM for patients with bone, lung, liver, or distant lymph node (DLN) involvement (all p < 0.05). Additionally, among patients with one or two metastases, those undergoing surgical resection were significantly associated with favorable OS (p = 0.008) and CSS (p = 0.0247). CONCLUSIONS: PTR may confer therapeutic benefits for carefully selected individuals with metastatic MTCs. To integrate these insights into clinical decision-making settings, it is imperative to undertake multicenter prospective studies in the future.

Suicidal ideation in Chinese patients with advanced breast cancer: a multi-center mediation model study.

PURPOSE: The pathways underpinning suicide ideation (SI) and certain physical and psychological factors in patients with advanced breast cancer remain unclear. This study develops and validates a mediation model that delineates the associations between several multidimensional variables and SI in Chinese patients with advanced breast cancer. METHODS: Patients with advanced breast cancer (n = 509) were recruited as study participants from 10 regional cancer centers across China from August 2019 to December 2020. Participants were required to complete five questionnaires using an electronic patient-reported outcomes (ePRO) system: 9 item- Patient Health Questionnaire (PHQ-9), Hospital Anxiety and Depression Scale (HADS), Insomnia Severity Index (ISI), 5-level EQ-5D (EQ-5D-5L), and MD Anderson Symptom Inventory (MDASI). Risk factors for SI were identified using multivariable logistic regression, and inputted into serial multiple mediation models to elucidate the pathways linking the risk factors to SI. RESULTS: SI prevalence was 22.8% (116/509). After adjusting for covariates, depression (odds ratio [OR] = 1.384), emotional distress (OR = 1.107), upset (OR = 0.842), and forgetfulness (OR = 1.236) were identified as significant independent risk factors (all p < 0.05). The ORs indicate that depression and distress have the strongest associations with SI. Health status has a significant indirect effect (OR=-0.044, p = 0.005) and a strong total effect (OR=-0.485, p < 0.001) on SI, mediated by insomnia severity and emotional distress. CONCLUSIONS: There is a high SI prevalence among Chinese patients with advanced breast cancer. Our analysis revealed predictive pathways from poor health to heightened SI, mediated by emotional distress and insomnia. Regular management of distress and insomnia can decrease suicide risk in this vulnerable population.

Zinc hybrid polyester barrier membrane accelerates guided tissue regeneration.

Barrier membranes play a pivotal role in the success of guided periodontal tissue regeneration. The biodegradable barriers predominantly used in clinical practice often lack sufficient barrier strength, antibacterial properties, and bioactivity, frequently leading to suboptimal regeneration outcomes. Although with advantages in mechanical strength, biodegradability and plasticity, bioinert aliphatic polyesters as barrier materials are usually polymerized via toxic catalysts, hard to be functionalized and lack of antibacterial properties. To address these challenges, we propose a new concept that controlled release of bioactive substance on the whole degradation course can give a bioinert aliphatic polyester bioactivity. Thus, a Zn-based catalytic system for polycondensation of dicarboxylic acids and diols is created to prepare zinc covalent hybrid polyester (PBS/ZnO). The atomically-dispersed Zn2+ ions entering main chain of polyester molecules endow PBS/ZnO barrier with antibacterial properties, barrier strength, excellent biocompatibility and histocompatibility. Further studies reveal that relying on long-term controlled release of Zn2+ ions, the PBS/ZnO membrane greatly expedites osteogenetic effect in guided tissue regeneration (GTR) by enhancing the mitochondrial function of macrophages to induce M2 polarization. These findings show a novel preparation strategy of bioactive polyester biomaterials based on long term controlled release of bioactive substance that integrates catalysis, material structures and function customization.

Physical symptoms and anxiety and depression in older patients with advanced cancer in China: a network analysis.

BACKGROUND: Little is understood about the association between psychosomatic symptoms and advanced cancer among older Chinese patients. METHODS: This secondary analysis was part of a multicenter cross-sectional study based on an electronic patient-reported outcome platform. Patients with advanced cancer were included between August 2019 and December 2020 in China. Participants (over 60 years) completed the MD Anderson Symptom Inventory (MDASI) and Hospital Anxiety and Depression Scale (HADS) to measure symptom burden. Network analysis was also conducted to investigate the network structure, centrality indices (strength, closeness, and betweenness) and network stability. RESULTS: A total of 1022 patients with a mean age of 66 (60-88) years were included; 727 (71.1%) were males, and 295 (28.9%) were females. A total of 64.9% of older patients with advanced cancer had one or more symptoms, and up to 80% had anxiety and depression. The generated network indicated that the physical symptoms, anxiety and depression symptom communities were well connected with each other. Based on an evaluation of the centrality indices, 'distress/feeling upset' (MDASI 5) appears to be a structurally important node in all three networks, and 'I lost interest in my own appearance' (HADS-D4) had the lowest centrality indices. The network stability was relatively high (> 0.7). CONCLUSION: The symptom burden remains high in older patients with advanced cancer in China. Psychosomatic symptoms are highly interactive and often present as comorbidities. This network can be used to provide targeted interventions to optimize symptom management in older patients with advanced cancer in China. TRIAL REGISTRATION: Chinese Clinical Trial Registry (ChiCTR1900024957), registered on 06/12/2020.

Relationship between circulating metabolites and diabetic retinopathy: a two-sample Mendelian randomization analysis.

Diabetic retinopathy (DR) is the most frequent microvascular complication of diabetes mellitus, however, its underlying biological mechanisms remain poorly understood. We examined single nucleotide polymorphisms linked to 486 blood metabolites through extensive genome-wide association studies conducted on individuals of European ancestry. The FinnGen Biobank database served as a reference to define DR. Two-sample MR analysis was conducted to reveal the association between the levels of genetically predicted circulating metabolites and the susceptibility to DR. To validate the robustness of the obtained findings, sensitivity analyses with weighted median, weighted mode, and MR-Egger were conducted. 1-oleoylglycerophosphoethanolamine (odds ratio [OR] (OR per one standard deviation [SD] increase) = 0.414; 95% confidence interval [CI] 0.292-0.587; P = 7.613E-07, PFDR = 6.849E-06), pyroglutamine (OR per one SD increase = 0.414; 95% confidence interval [CI] 0.292-0.587; P = 8.31E-04, PFDR = 0.007), phenyllactate (PLA) (OR per one SD increase = 0.591; 95% confidence interval [CI] 0.418-0.836; P = 0.003, PFDR = 0.026), metoprolol acid metabolite (OR per one SD increase = 0.978; 95% confidence interval [CI] 0.962-0.993; P = 0.005, PFDR = 0.042), 10-undecenoate (OR per one SD increase = 0.788; 95% confidence interval [CI] 0.667-0.932; P = 0.005, PFDR = 0.049), erythritol (OR per one SD increase = 0.691; 95% confidence interval [CI] 0.513-0.932; P = 0.015, PFDR = 0.034), 1-stearoylglycerophosphoethanolamine (OR per one SD increase = 0.636; 95% confidence interval [CI] 0.431-0.937; P = 0.022, PFDR = 0.099), 1-arachidonoylglycerophosphoethanolamine (OR per one SD increase = 0.636; 95% confidence interval [CI] 0.431-0.937; P = 0.030, PFDR = 0.099) showed a significant causal relationship with DR and could have protective effects. stachydrine (OR per one SD increase = 1.146; 95% confidence interval [CI] 1.066-1.233; P = 2.270E-04, PFDR = 0.002), butyrylcarnitine (OR per one SD increase = 1.117; 95% confidence interval [CI] 1.023-1.219; P = 0.014, PFDR = 0.062), 5-oxoproline (OR per one SD increase = 1.569; 95% confidence interval [CI] 1.056-2.335; P = 0.026, PFDR = 0.082), and kynurenine (OR = 1.623; 95% CI 1.042-2.526; P = 0.041, PFDR = 0.097) were significantly associated with an increased risk of DR. This study identified metabolites have the potential to be considered prospective compounds for investigating the underlying mechanisms of DR and for selecting appropriate drug targets.

Encoding Enhanced Complex CNN for Accurate and Highly Accelerated MRI.

Magnetic resonance imaging (MRI) using hyperpolarized noble gases provides a way to visualize the structure and function of human lung, but the long imaging time limits its broad research and clinical applications. Deep learning has demonstrated great potential for accelerating MRI by reconstructing images from undersampled data. However, most existing deep convolutional neural networks (CNN) directly apply square convolution to k-space data without considering the inherent properties of k-space sampling, limiting k-space learning efficiency and image reconstruction quality. In this work, we propose an encoding enhanced (EN2) complex CNN for highly undersampled pulmonary MRI reconstruction. EN2 complex CNN employs convolution along either the frequency or phase-encoding direction, resembling the mechanisms of k-space sampling, to maximize the utilization of the encoding correlation and integrity within a row or column of k-space. We also employ complex convolution to learn rich representations from the complex k-space data. In addition, we develop a feature-strengthened modularized unit to further boost the reconstruction performance. Experiments demonstrate that our approach can accurately reconstruct hyperpolarized 129Xe and 1H lung MRI from 6-fold undersampled k-space data and provide lung function measurements with minimal biases compared with fully sampled images. These results demonstrate the effectiveness of the proposed algorithmic components and indicate that the proposed approach could be used for accelerated pulmonary MRI in research and clinical lung disease patient care.

High-efficiency Electroreduction of O2 into H2 O2 over ZnCo Bimetallic Triazole Frameworks Promoted by Ligand Activation.

Co-based metal-organic frameworks (MOFs) as electrocatalysts for two-electron oxygen reduction reaction (2e- ORR) are highly promising for H2 O2 production, but suffer from the intrinsic activity-selectivity trade-off. Herein, we report a ZnCo bimetal-triazole framework (ZnCo-MTF) as high-efficiency 2e- ORR electrocatalysts. The experimental and theoretical results demonstrate that the coordination between 1,2,3-triazole and Co increases the antibonding-orbital occupancy on the Co-N bond, promoting the activation of Co center. Besides, the adjacent Zn-Co sites on 1,2,3-triazole enable an asymmetric "side-on" adsorption mode of O2 , favoring the reduction of O2 molecules and desorption of OOH* intermediate. By virtue of the unique ligand effect, the ZnCo-MTF exhibits a 2e- ORR selectivity of ≈100 %, onset potential of 0.614 V and H2 O2 production rate of 5.55 mol gcat -1 h-1 , superior to the state-of-the-art zeolite imidazole frameworks. Our work paves the way for the design of 2e- ORR electrocatalysts with desirable coordination and electronic structure.

Complementation-reinforced network for integrated reconstruction and segmentation of pulmonary gas MRI with high acceleration.

BACKGROUND: Hyperpolarized (HP) gas MRI enables the clear visualization of lung structure and function. Clinically relevant biomarkers, such as ventilated defect percentage (VDP) derived from this modality can quantify lung ventilation function. However, long imaging time leads to image quality degradation and causes discomfort to the patients. Although accelerating MRI by undersampling k-space data is available, accurate reconstruction and segmentation of lung images are quite challenging at high acceleration factors. PURPOSE: To simultaneously improve the performance of reconstruction and segmentation of pulmonary gas MRI at high acceleration factors by effectively utilizing the complementary information in different tasks. METHODS: A complementation-reinforced network is proposed, which takes the undersampled images as input and outputs both the reconstructed images and the segmentation results of lung ventilation defects. The proposed network comprises a reconstruction branch and a segmentation branch. To effectively exploit the complementary information, several strategies are designed in the proposed network. Firstly, both branches adopt the encoder-decoder architecture, and their encoders are designed to share convolutional weights for facilitating knowledge transfer. Secondly, a designed feature-selecting block discriminately feeds shared features into decoders of both branches, which can adaptively pick suitable features for each task. Thirdly, the segmentation branch incorporates the lung mask obtained from the reconstructed images to enhance the accuracy of the segmentation results. Lastly, the proposed network is optimized by a tailored loss function that efficiently combines and balances these two tasks, in order to achieve mutual benefits. RESULTS: Experimental results on the pulmonary HP 129 Xe MRI dataset (including 43 healthy subjects and 42 patients) show that the proposed network outperforms state-of-the-art methods at high acceleration factors (4, 5, and 6). The peak signal-to-noise ratio (PSNR), structural similarity (SSIM), and Dice score of the proposed network are enhanced to 30.89, 0.875, and 0.892, respectively. Additionally, the VDP obtained from the proposed network has good correlations with that obtained from fully sampled images (r = 0.984). At the highest acceleration factor of 6, the proposed network promotes PSNR, SSIM, and Dice score by 7.79%, 5.39%, and 9.52%, respectively, in comparison to the single-task models. CONCLUSION: The proposed method effectively enhances the reconstruction and segmentation performance at high acceleration factors up to 6. It facilitates fast and high-quality lung imaging and segmentation, and provides valuable support in the clinical diagnosis of lung diseases.

Reconstruction of the anterior maxillary defect using a vascularized bone flap with residual teeth in the posterior maxilla.

BACKGROUND: Microsurgical bone reconstruction is challenging in cases of anterior maxillary defects because of the presence of residual teeth. The study analyzed the method and feasibility of using vascularized bone flaps to reconstruct anterior maxillary defects. METHODS: We retrospectively analyzed 15 patients treated at the Department of Oral and Maxillofacial Surgery, Peking University School, and Hospital of Stomatology between November 2017 and January 2023. RESULTS: A total of 14 patients were successfully reconstructed using the digital technique: 6 deep circumflex iliac artery (DCIA) flaps and 8 fibular free flaps. Palatal and buccal pedicle paths were used in 4 and 10 cases, respectively, for vascular anastomosis. The implant coverage rates of the DCIA and fibular free flaps were 87.2% and 92.6%, respectively (p > 0.05). CONCLUSION: Anterior maxillary defects reconstructed with the DCIA and fibular free flaps are reliable methods. Furthermore, the palatal and buccal paths are recommended for vascular anastomosis.

PEB-DDI: A Task-Specific Dual-View Substructural Learning Framework for Drug-Drug Interaction Prediction.

Adverse drug-drug interactions (DDIs) pose potential risks in polypharmacy due to unknown physicochemical incompatibilities between co-administered drugs. Recent studies have utilized multi-layer graph neural network architectures to model hierarchical molecular substructures of drugs, achieving excellent DDI prediction performance. While extant substructural frameworks effectively encode interactions from atom-level features, they overlook valuable chemical bond representations within molecular graphs. More critically, given the multifaceted nature of DDI prediction tasks involving both known and novel drug combinations, previous methods lack tailored strategies to address these distinct scenarios. The resulting lack of adaptability impedes further improvements to model performance. To tackle these challenges, we propose PEB-DDI, a DDI prediction learning framework with enhanced substructure extraction. First, the information of chemical bonds is integrated and synchronously updated with the atomic nodes. Then, different dual-view strategies are selected based on whether novel drugs are present in the prediction task. Particularly, we constructed Molecular fingerprint-Molecular graph view for transductive task, and Bipartite graph-Molecular graph view for inductive task. Rigorous evaluations on benchmark datasets underscore PEB-DDI's superior performance. Notably, on DrugBank, it achieves an outstanding accuracy rate of 98.18% when predicting previously unknown interactions among approved drugs. Even when faced with novel drugs, PEB-DDI consistently exhibits outstanding generalization capabilities with an accuracy rate of 88.06%, attributing to the proper migrating of molecular basic structure learning.

Perilipin 5 protects the mitochondrial oxidative functions and improves the alcoholic liver injury in mice.

BACKGROUND AND AIMS: Alcohol consumption is a well-established risk factor for the onset and progression of hepatic steatosis. Perilipin 5 (Plin5), a lipid droplet protein, is an important protective factor against hepatic lipotoxicity induced by excessive lipolysis, but its role and molecular mechanism in alcoholic liver disease (ALD) are not fully elucidated. METHODS: The optimized National Institute on Alcohol Abuse and Alcoholism model was used to construct ALD model mice. Automatic biochemical analyser was used for Biochemical Parameters. The primary hepatocytes and Plin5-overexpressed HepG2 cells (including full-length Plin5 and Plin5 deleting 444-464 aa) were used for in vitro experiment. Haematoxylin and Eosin staining, Oil Red O staining, Bodipy 493/503 staining, Periodic Acid-Schiff staining, immunohistochemistry and JC-1 staining were used to evaluate cell morphology, lipids, glycogen, inflammation and membrane potential. Commercially kits are used to detect glycolipid metabolites, such as triglycerides, glycogen, glucose, reactive oxygen species, lactic acids, ketone bodies. Fluorescently labelled deoxyglucose, NBDG, was used for glucose intake. An XF96 extracellular flux analyser was used to determinate oxygen consumption rate in hepatocytes. The morphological and structural damage of mitochondria was evaluated by electron microscopy. Classical ultracentrifugation is used to separate the subcellular organelles of tissues and cells. Immunoblotting and qPCR were used to detect changes in mRNA and protein levels of related genes. RESULTS: Our results showed that the expression of Plin5 in mouse livers was enhanced by alcohol intake, and Plin5 deficiency aggravated the alcohol-induced liver injury. To clarify the mechanism, we found that Plin5 deficiency significantly elevated the hepatic NADH levels and ketone body production in the alcohol-treated mice. As NADH elevation could promote the reduction of pyruvate into lactate and then inhibit the gluconeogenesis, alcohol-treated Plin5-deficient mice exhibited more lactate production and severer hypoglycemia. These results implied that Plin5 deficiency impaired the mitochondrial oxidative functions in the presence of alcohol. In addition, we demonstrated that Plin5 could be recruited onto mitochondria by alcohol, while Plin5 without mitochondrial targeting sequences lost its mitochondrial protection functions. CONCLUSION: Collectively, this study demonstrated that the mitochondrial Plin5 could protect the alcohol-induced mitochondrial injury, which provides an important new insight on the roles of Plin5 in highly oxidative tissues.

Distribution and major driving elements of antibiotic resistance genes in the soil-vegetable system under microplastic stress.

Microplastics (MPs) and antibiotic resistance genes (ARGs) are both enriched in soil-vegetable systems as a consequence of the prolonged use of agricultural mulches. MPs can form unique bacterial communities and provide potential hosts for ARGs. Therefore, MPs stress may promote the spread of ARGs from soil to crops. Increasing ARGs pollution in soil-vegetable system. In our research, we investigated the distribution and major driving elements of antibiotic resistance genes in the soil-vegetable system under microplastic stress. The results showed that MPs treatment decreased the relative abundance of ARGs in non-rhizosphere soil. High concentrations of MPs promoted the enrichment of tetracycline antibiotic resistance genes in rhizosphere soil. MPs treatment promoted the enrichment of ARGs and mobile genetic elements (MGEs) in lettuce tissues, and the overall abundance of ARGs in root after 0.5 %, 1 %, and 2 % (w/w, dry weight) polyethylene (PE) administration was considerably higher compared to that in the untreated group (p < 0.05). At the same time, high PE concentrations promoted the spread of sulfa ARGs from root to leaf. MPs also impacted the bacterial communities in the soil-plant system, and the changes in ARGs as well as MGEs in each part of the soil-vegetable system were significantly correlated with the bacterial diversity index (p < 0.05). Correlation analysis and network analysis showed that bacterial communities and MGEs were the main drivers of ARGs variation in soil-lettuce systems.

Gas Dispersion Coefficient Test System and Dimensionless Inversion Method for Porous Media.

Due to the complex porous media structure of the longwall gob area, it has been difficult to determine the gas dispersion coefficient of oxygen when studying spontaneous coal combustion in the gob area. In this work, we first designed an experimental device for testing the gas diffusion coefficient of porous media. Then, the distribution law of gas concentration in porous media under different particle size conditions was obtained by experiments. Subsequently, we established a dimensionless mathematical model of gas dispersion in porous media and developed a corresponding numerical simulator based on the finite volume method (FVM). The influence of the dimensionless gas dispersion coefficient on the gas concentration distribution was analyzed, and then a dimensionless inversion method of the gas dispersion coefficient was summarized and put forward. Finally, we obtained the values of the gas dispersion coefficient in the experimental device under different particle size conditions by inversion and discussed its effect on the gas dispersion behavior in porous media. The results show that (1) the distribution of gas concentration obtained from the experimental test and numerical simulation is consistent, which verifies the reliability of our work; (2) the dimensionless gas concentration is the highest near the injection point and gradually decreases along the depth and both sides of the test container; (3) with the increase of the dimensionless gas dispersion coefficient, the distance required for uniform gas mixing in the test container is gradually shortened and the gas dispersion coverage is wider; and (4) the larger pore space facilitates the dispersion behavior of the gas, and the gas dispersion coefficient shows a parabolic trend with the increase of porous medium particle size.

Neuronal MeCP2 in the dentate gyrus regulates mossy fiber sprouting of mice with temporal lobe epilepsy.

Sprouting of mossy fibers, one of the most consistent findings in tissue from patients with mesial temporal lobe epilepsy, exhibits several uncommon axonal growth features and has been considered a paradigmatic example of circuit plasticity that occurs in the adult brain. Clarifying the mechanisms responsible may provide new insight into epileptogenesis as well as axon misguidance in the central nervous system. Methyl-CpG-binding protein 2 (MeCP2) binds to methylated genomic DNA to regulate a range of physiological functions implicated in neuronal development and adult synaptic plasticity. However, exploring the potential role of MeCP2 in the documented misguidance of axons in the dentate gyrus has not yet been attempted. In this study, a status epilepticus-induced decrease of neuronal MeCP2 was observed in the dentate gyrus (DG). An essential regulatory role of MeCP2 in the development of functional mossy fiber sprouting (MFS) was confirmed through stereotaxic injection of a recombinant adeno-associated virus (AAV) to up- or down-regulate MeCP2 in the dentate neurons. Chromatin immunoprecipitation sequencing (ChIP-seq) was performed to identify the binding profile of native MeCP2 using micro-dissected dentate tissues. In both dentate tissues and HT22 cell lines, we demonstrated that MeCP2 could act as a transcription repressor on miR-682 with the involvement of the DNA methylation mechanism. Further, we found that miR-682 could bind to mRNA of phosphatase and tensin homolog (PTEN) in a sequence specific manner, thus leading to the suppression of PTEN and excessive activation of mTOR. This study therefore presents a novel epigenetic mechanism by identifying MeCP2/miR-682/PTEN/mTOR as an essential signal pathway in regulating the formation of MFS in the temporal lobe epileptic (TLE) mice. SIGNIFICANCE STATEMENT: Understanding the mechanisms that regulate axon guidance is important for a better comprehension of neural disorders. Sprouting of mossy fibers, one of the most consistent findings in patients with mesial temporal lobe epilepsy, has been considered a paradigmatic example of circuit plasticity in the adult brain. Although abnormal regulation of DNA methylation has been observed in both experimental rodents and humans with epilepsy, the potential role of DNA methylation in this well-documented example of sprouting of dentate axon remains elusive. This study demonstrates an essential role of methyl-CpG-binding protein 2 in the formation of mossy fiber sprouting. The underlying signal pathway has been also identified. The data hence provide new insight into epileptogenesis as well as axon misguidance in the central nervous system.

Advances in the Study of Selenium-Enriched Probiotics: From the Inorganic Se into Se Nanoparticles.

Selenium (Se) is a momentous metallic element that plays an irreplaceable role in biochemical activities. Se deficiency remains a nutritional challenge across the world. Organic Se supplementation is the most effective treatment means for Se deficiency. Organic Se transformed from Se-enriched probiotics show outstanding excellent properties in antibacteria, anti-oxidation, anti-inflammation, and immunoregulation. Studying the influencing factors for Se enrichment capacity and enrichment mechanisms of Se-enriched probiotics is conducive to the exploit of more potent Se-enriched probiotics. Se-enriched probiotics transform inorganic Se into Se nanoparticles (SeNPs), which have been widely used in animal husbandry and biomedical field. In this paper, the novel development of Se-enriched probiotics is reviewed, and the bioactivities of SeNPs are assessed, so as to display their potential application prospects. The excellent role of SeNPs in anti-oxidation is summarized, and the mechanism by which SeNPs improve Se deficiency and boost animal health is explained.

Identification of signature of tumor-infiltrating CD8 T lymphocytes in prognosis and immunotherapy of colon cancer by machine learning.

BACKGROUND: To explore the specific marker of CD8+ T cell subsets which are closely related to the prognosis and immunotherapy of patients with colon cancer. METHODS: 18 kinds of immune cell expression profile data sets were obtained from GEO database. Compared with other immune cell types, the specific markers of CD8 (+) T cells (TI-CD8) in colorectal cancer were screened. Regression analyses were used to further screen prognostic related genes and construct a prognostic evaluation model. The patients were stratified and analyzed according to the risk scores, KRAS mutation status, stage, lymphatic infiltration and other indicators. The landscape of infiltration level, mutation and copy number variation of immune subsets in high and low TI-CD8Sig score groups were compared and analyzed. The difference of drug response between high and low TI-CD8Sig score groups was analyzed. Differential expression of the model genes was verified by the HPA database. RESULTS: Six prognostic-related CD8T cell-specific gene targets were further screened, and the prognostic evaluation model was constructed. The AUC value of the model is >0.75. FAT3 and UNC13C showed a high mutation state in the low-risk group, while USH2A, MUC5B et al. specifically showed a high mutation state in the high-risk group. Compared with the low-risk group, the high-risk group had lower effective rate of drug response. The expression of PD-1 gene was positively correlated with the level of TI-CD8Sig score. CONCLUSION: The risk assessment model based on CD8T cell-specific marker genes can effectively predict the prognosis and the drug response of patients with CRC.

Taok1 haploinsufficiency leads to autistic-like behaviors in mice via the dorsal raphe nucleus.

Strong evidence from human genetic studies associates the thousand and one amino acid kinase 1 (TAOK1) gene with autism spectrum disorder (ASD). In this work, we discovered a de novo frameshifting mutation in TAOK1 within a Chinese ASD cohort. We found that Taok1 haploinsufficiency induces autistic-like behaviors in mice. Importantly, we observed a significant enrichment of Taok1 in the dorsal raphe nucleus (DRN). The haploinsufficiency of Taok1 considerably restrained the activation of DRN neurons during social interactions, leading to the aberrant phosphorylation of numerous proteins. Intriguingly, the genetic deletion of Taok1 in VGlut3-positive neurons of DRN resulted in mice exhibiting autistic-like behaviors. Ultimately, reintroducing wild-type Taok1, but not its kinase-dead variant, into the DRN of adult mice effectively mitigated the autistic-like behaviors associated with Taok1 haploinsufficiency. This work suggests that Taok1, through its influence in the DRN, regulates social interaction behaviors, providing critical insights into the etiology of ASD.