Comparative study on the effects of anionic, cationic, and nonionic polyacrylamide surface modified magnetic micro-particles (MMP) for anaerobic digestion treatment of vegetable waste water (VWW).

Anaerobic digestion provides a solution for the treatment of vegetable waste water (VWW), but there are currently limited targeted treatment methods available. Building upon previous studies, this research investigated the effects of polyacrylamide-modified magnetic micro-particles (MMP) on anaerobic digestion (AD) of VWW. Three variations of these particles were created by grafting anionic, cationic, and non-ionic polyacrylamide (PAM) onto the MMPs' surfaces, resulting in aPAM-MMP, cPAM-MMP, and nPAM-MMP, respectively. In AD experiments, the addition of aPAM-MMP notably enhanced the degradation of chemical oxygen demand (COD) in VWW. COD decreased to 1290 mg/L in the reactor with aPAM-MMP by day 12 and remained low, while the other reactors had COD concentrations of 4137.5, 5510, and 3010 mg/L on the same day, decreasing thereafter. This modification also improved the production and utilization of hydrogen gas and volatile fatty acids (VFAs), along with the conversion of methane. When tested for bioaffinity using fluorescent GFP-E.coli bacteria, the aPAM-MMP, cPAM-MMP, and nPAM-MMP demonstrated increases in fluorescence intensity by 51.66%, 36.13%, and 37.02%, respectively, compared to unmodified MMP when attached with GFP-E.coli. Further analyses of microbial community revealed that the reactor with aPAM-MMP had the highest microbial richness and enriched bacteria capable of organic matter degradation, such as Bacteroidota, Synergistota, Chloroflexi, Halobacterota phyla, and Parabacteroides, Muribaculaceae, and Azotobacter genera. In conclusion, our experiment verifies that APAM-MMP promotes anaerobic treatment of VWW and provides a novel reference point for enhancing VWW degradation.

Evidence that the SARS-CoV-2 S protein undergoes a conformational change at the Golgi complex that leads to the formation of virus neutralising antibody binding epitopes in the S1 protein subunit.

Recombinant SARS-CoV-2 S protein expression was examined in Vero cells by imaging using the human monoclonal antibody panel (PD4, PD5, sc23, and sc29). The PD4 and sc29 antibodies recognised conformational specific epitopes in the S2 protein subunit at the Endoplasmic reticulum and Golgi complex. While PD5 and sc23 detected conformationally specific epitopes in the S1 protein subunit at the Golgi complex, only PD5 recognised the receptor binding domain (RBD). A comparison of the staining patterns of PD5 with non-conformationally specific antibodies that recognises the S1 subunit and RBD suggested the PD5 recognised a conformational structure within the S1 protein subunit. Our data suggests the antibody binding epitopes recognised by the human monoclonal antibodies formed at different locations in the secretory pathway during S protein transport, but a conformational change in the S1 protein subunit at the Golgi complex formed antibody binding epitopes that are recognised by virus neutralising antibodies.

Unraveling the Genetic Susceptibility of Irritable Bowel Syndrome: integrative genome-wide analyses in 845,492 individuals: a diagnostic study.

BACKGROUND: Irritable bowel syndrome (IBS) significantly impacts individuals due to its prevalence and negative effect on quality of life. Current genome-wide association studies (GWAS) have only identified a small number of crucial single nucleotide polymorphisms (SNPs), not fully elucidating IBS's pathogenesis. OBJECTIVE: To identify genomic loci at which common genetic variation influence IBS susceptibility. METHODS: Combining independent cohorts that in total comprise 65,840 cases of IBS and 788,652 controls, we performed a meta-analysis of genome-wide association studies (GWAS) of IBS. We also carried out gene mapping and pathway enrichment to gain insights into the underlying genes and pathways through which the associated loci contribute to disease susceptibility. Furthermore, we performed transcriptome analysis to deepen our understanding. IBS risk models were developed by combining clinical/lifestyle risk factors with polygenic risk scores (PRS) derived from the GWAS meta-analysis. We detect the phenotype association for IBS utilizing PRS-based phenome-wide association (PheWAS) analyses, linkage disequilibrium score regression, and Mendelian randomization. RESULTS: The GWAS meta-analysis identified 10 IBS risk loci, seven of which were novel (rs12755507, rs34209273, rs34365748, rs67427799, rs2587363, rs13321176, rs1546559). Multiple methods identified nine promising IBS candidate gene (PRRC2A, COP1, CADM2, LRP1B, SUGT1, MED12L, P2RY14, PHF2, SHISA6) at 10 GWAS loci. Transcriptome validation also revealed differential expression of these genes. Phenome-wide associations between PRS-IBS and nine traits (neuroticism, diaphragmatic hernia, asthma, diverticulosis, cholelithiasis, depression, insomnia, COPD, and BMI) were identified. The six diseases (asthma, diaphragmatic hernia, diverticulosis, insomnia major depressive disorder and neuroticism) were found to show genetic association with IBS and only major depressive disorder and neuroticism were found to show causality with IBS. CONCLUSION: We identified seven novel risk loci for IBS and highlight the substantial influence on genetic risk harboured. Our findings offer novel insights into aetiology and phenotypic association of IBS and lay the foundation for therapeutic targets and interventional strategies.

Template Role of Long Alkyl-Chain Amides in the Synthesis of Zeolitic Imidazolate Frameworks.

Organic amides as solvents and structure directing agents (SDAs) are crucial for synthesizing zeolitic imidazolate frameworks (ZIFs). However, current research focuses only on the use of short alkyl-chain amides as solvents/SDAs. Here, we investigate the role of amides with varying alkyl-chain lengths on the structures and topologies of Zn(Im)2 polymorphs. Using short alkyl-chain amides as solvents, the Zn(Im)2 topological structures are affected by the synthesis conditions, leading to "one SDA/multiple topological structures". In contrast, when long alkyl-chain amides are used as solvents, the Zn(Im)2 topological structures are essentially unaffected by other synthesis conditions. Thus, long alkyl-chain amides are shown for the first time to exhibit a significant template role, leading to "one template/one topological structure". Specifically, the use of long alkyl-chain N,N-dimethyl-Cn amides (abbreviated as DM-Cn amides, n = 3, 4, 6, 8, and 10) can lead to only DTF-type Zn(Im)2 frameworks under broad crystallization conditions. Single-crystal X-ray diffraction confirmed that the exquisite structural compatibility between long alkyl-chain DM-Cn amides and the DFT-type Zn(Im)2 framework results in a highly regular head-to-tail arrangement of amides along the (kaa-lov) n chain of the DFT framework. The template role for long alkyl-chain amides was further identified to be multiple C-H···π interactions between DM-Cn amides and Zn(Im)2 frameworks thanks to molecular simulations.

STING coordinates resolution of inflammation during wound repair by modulating macrophage trafficking through STAT3.

Efficient cutaneous wound healing requires a coordinated transition between inflammatory phases mediated by dynamic changes in leukocyte subset populations. Here, we identify STING as a key innate immune mediator governing timely resolution of inflammation by regulating macrophage dynamics during skin repair. Using a mouse model, we show STING deficiency caused delayed wound closure associated with abnormal persistence of TNF-α+ leukocytes. This resulted from the impaired macrophage recruitment. STING controlled the trafficking of bone marrow myeloid cells into blood and wounds, intrinsically enhancing macrophage migratory capacity through STAT3 activation. Specifically, STING modulated the production of monocyte chemokines and their receptors CCR2/CCR5 to enable efficient egress and wound infiltration. Consequently, disrupted systemic and local STING-STAT3-chemokine signaling combine to delay macrophage influx. This study elucidates STING as a critical rheostat tuning macrophage responses through STAT3 to orchestrate inflammatory resolution necessary for efficient wound healing. Our findings have broad implications for targeting STING therapeutically in both regenerative medicine and inflammatory disease contexts. STING regulates the macrophage trafficking through STAT3 in wound healing.

Evolution of the Structure and Morphology of Dual-Linker ZIF-301-eIm.

Few studies have reported on the continuous evolution of dual-linker zeolitic imidazolate frameworks' (ZIFs) structure and morphology during the crystal growth process. Herein, we report the synthesis of a novel ZIF material with CHA topology (ZIF-301-eIm) via the combination of a small-sized 2-ethylimidazole (eIm) with the large-sized 5-chlorobenzimidazole ligand. A series of derivative materials with distinct structures and morphologies were obtained via two pathways: (1) insufficient amount of eIm with prolonged crystallization time (pathway A) and (2) sufficient amount of eIm with prolonged crystallization time (pathway B). Various characterization techniques revealed the continuous evolution of structure and morphology during the crystal growth process. Insufficient amount of eIm and crystallization time (crystallization pathway A) led to ZIF-301-eIm derivatives with defective and open structures alongside an aggregated morphology of nanoparticles. Prolonging the crystallization time allowed small-sized eIm ligands to gradually fill into the framework, resulting in the formation of ZIF-301-eIm-A5 characterized by complete but dense structures with a perfect polyhedral morphology. Remarkably, a sufficient amount of eIm during synthesis (crystallization pathway B) formed ZIF-301-eIm-B1 with a similar structure and morphology to ZIF-301-eIm-A5 in just 1 day. ZIF-301-eIm-B3, with intact, dense structures, exhibits superior acetone/butanol separation performance compared to ZIF-301-eIm-A3 due to small pore windows and large cages facilitating selective adsorption of acetone through exclusion separation.

Diagnostic testing preferences can help inform future public health response efforts: Global insights from an international survey.

Public perception regarding diagnostic sample types as well as personal experiences can influence willingness to test. As such, public preferences for specific sample type(s) should be used to inform diagnostic and surveillance testing programs to improve public health response efforts. To understand where preferences lie, we conducted an international survey regarding the sample types used for SARS-CoV-2 tests. A Qualtrics survey regarding SARS-CoV-2 testing preferences was distributed via social media and email. The survey collected preferences regarding sample methods and key demographic data. Python was used to analyze survey responses. From March 30th to June 15th, 2022, 2,094 responses were collected from 125 countries. Participants were 55% female and predominantly aged 25-34 years (27%). Education and employment were skewed: 51% had graduate degrees, 26% had bachelor's degrees, 27% were scientists/researchers, and 29% were healthcare workers. By rank sum analysis, the most preferred sample type globally was the oral swab, followed by saliva, with parents/guardians preferring saliva-based testing for children. Respondents indicated a higher degree of trust in PCR testing (84%) vs. rapid antigen testing (36%). Preferences for self- or healthcare worker-collected sampling varied across regions. This international survey identified a preference for oral swabs and saliva when testing for SARS-CoV-2. Notably, respondents indicated that if they could be assured that all sample types performed equally, then saliva was preferred. Overall, survey responses reflected the region-specific testing experiences during the COVID-19. Public preferences should be considered when designing future response efforts to increase utilization, with oral sample types (either swabs or saliva) providing a practical option for large-scale, accessible diagnostic testing.

The mediating effect of blood biomarkers in the associations between inflammatory bowel disease and incident psychiatric disorders: a prospective cohort study.

BACKGROUND: Despite the growing evidence of an association between inflammatory bowel disease (IBD) and psychiatric disorders, there has been limited research exploring the underlying mediating role of blood biomarkers on the gut-brain axis. This study aimed to examine the association between IBD and the risk of incident psychiatric disorders and investigate whether and how blood biomarkers mediate this association. METHODS: This prospective cohort study using data from the UK Biobank included participants without psychiatric diagnoses at baseline. The case cohort consisted of participants with a hospital-based diagnosis of IBD at baseline. The primary outcome was all psychiatric disorders. Secondary outcomes included 11 major psychiatric disorders. Cox regression models estimated adjusted hazard ratios (HRs) for psychiatric outcomes. Causal mediation models investigated the potential mediation effects of blood biomarkers. RESULTS: Among 491,131 participants, patients with IBD exhibited higher risks of overall psychiatric disorders (HR 1.23 [95% CI 1.13-1.33]), substance misuse (1.23 [1.09-1.38]), depression (1.36 [1.22-1.52]), anxiety (1.15 [1.01-1.30]) and post-traumatic stress disorder (1.87 [1.00-3.51]) compared with non-IBD participants. The association with incident substance misuse was only among patients with Crohn's disease (CD, 1.47 [1.23-1.76]), but not ulcerative colitis (UC, 1.01 [0.84-1.21]). Mediation analysis revealed 16, 14, 15, and 6 biomarkers partially mediated the associations for all psychiatric disorders, substance misuse, depression, and anxiety, respectively. Six blood markers showed the strongest mediating effects: neutrophil count (12.04%), C-reactive protein (10.29%), systemic immune-inflammatory index (8.94%), erythrocyte distribution width (16.51%), erythrocyte count (9.76%), and albumin (9.15%). Moreover, several blood mediators of CD identified in association with incident substance misuse may explain the risk discrepancy between IBD subtype. CONCLUSION: The blood biomarkers of inflammation, blood oxygen-carrying capacity, and metabolism mediate the effect of IBD on the risk of psychiatric outcomes and could be considered as a therapeutic target.

The impact of the combat method on radiomics feature compensation and analysis of scanners from different manufacturers.

BACKGROUND: This study investigated whether the Combat compensation method can remove the variability of radiomic features extracted from different scanners, while also examining its impact on the subsequent predictive performance of machine learning models. MATERIALS AND METHODS: 135 CT images of Credence Cartridge Radiomic phantoms were collected and screened from three scanners manufactured by Siemens, Philips, and GE. 100 radiomic features were extracted and 20 radiomic features were screened according to the Lasso regression method. The radiomic features extracted from the rubber and resin-filled regions in the cartridges were labeled into different categories for evaluating the performance of the machine learning model. Radiomics features were divided into three groups based on the different scanner manufacturers. The radiomic features were randomly divided into training and test sets with a ratio of 8:2. Five machine learning models (lasso, logistic regression, random forest, support vector machine, neural network) were employed to evaluate the impact of Combat on radiomic features. The variability among radiomic features were assessed using analysis of variance (ANOVA) and principal component analysis (PCA). Accuracy, precision, recall, and area under the receiver curve (AUC) were used as evaluation metrics for model classification. RESULTS: The principal component and ANOVA analysis results show that the variability of different scanner manufacturers in radiomic features was removed (P˃0.05). After harmonization with the Combat algorithm, the distributions of radiomic features were aligned in terms of location and scale. The performance of machine learning models for classification improved, with the Random Forest model showing the most significant enhancement. The AUC value increased from 0.88 to 0.92. CONCLUSIONS: The Combat algorithm has reduced variability in radiomic features from different scanners. In the phantom CT dataset, it appears that the machine learning model's classification performance may have improved after Combat harmonization. However, further investigation and validation are required to fully comprehend Combat's impact on radiomic features in medical imaging.

High-performance grating-like SERS substrate based on machine learning for ultrasensitive detection of Zexie-Baizhu decoction.

Rapid, universal and accurate identification of chemical composition changes in multi-component traditional Chinese medicine (TCM) decoction is a necessary condition for elucidating the effectiveness and mechanism of pharmacodynamic substances in TCM. In this paper, SERS technology, combined with grating-like SERS substrate and machine learning method, was used to establish an efficient and sensitive method for the detection of TCM decoction. Firstly, the grating-like substrate prepared by magnetron sputtering technology was served as a reliable SERS sensor for the identification of TCM decoction. The enhancement factor (EF) of 4-ATP probe molecules was as high as 1.90 × 107 and the limit of detection (LOD) was as low as 1 × 10-10 M. Then, SERS technology combined with support vector machine (SVM), decision tree (DT), Naive Bayes (NB) and other machine learning algorithms were used to classify and identify the three TCM decoctions, and the classification accuracy rate was as high as 97.78 %. In summary, it is expected that the proposed method combining SERS and machine learning method will have a high development in the practical application of multi-component analytes in TCM.

Production of cleavage-resistant phytase transgenic pigs by handmade cloning.

With the rapid development of intensive animal husbandry in the livestock industry, large quantities of manure waste containing phytate phosphorus are being generated. Phytase can effectively solve the problem of high phosphorus pollution in the feces of monogastric animals. Enviropig, which produces phytase in the salivary glands and secretes the enzyme in the saliva, were first generated in 1999. However, phytase is easily inactivated during digestion. To address this problem, cleavage-resistant phytase transgenic pigs were generated using handmade cloning in this study. Transgene construction was improved and three cell lines carrying Cafp were obtained. In total, 810 blastocysts were generated and 712 good-quality were transferred into six recipients. Fourteen piglets were born, of which six survived after weaning. Polymerase chain reaction and sequencing results showed that seven (three live and four dead) of the fourteen piglets carried Cafp. Phytase activity in the saliva of the six live cloned pigs was tested at four months of age, and only one pig had 0.155 FTU/mL enzyme activity. The other five pigs may not have been activated in the transgenic parotid gland. Among all the transgenic pigs, the highest phosphorus digestion rate was 59.2% of intake, representing a 25.4% decrease in fecal emission compared to the average of controls. Immunohistochemical results on the three Cafp-positive pigs that died after six months of age showed that the transgene was only expressed in parotid glands, confirming tissue-specific gene expression. In conclusion, cleavage-resistant phytase transgenic pigs were successfully produced through handmade cloning. The cloned pigs offer a unique biological approach to managing phosphorus nutrition and environmental pollution in animal husbandry.

Prognostic Value of a Combined Nomogram Model Integrating 3-Dimensional Deep Learning and Radiomics for Head and Neck Cancer.

OBJECTIVE: The preoperative prediction of the overall survival (OS) status of patients with head and neck cancer (HNC) is significant value for their individualized treatment and prognosis. This study aims to evaluate the impact of adding 3D deep learning features to radiomics models for predicting 5-year OS status. METHODS: Two hundred twenty cases from The Cancer Imaging Archive public dataset were included in this study; 2212 radiomics features and 304 deep features were extracted from each case. The features were selected by univariate analysis and the least absolute shrinkage and selection operator, and then grouped into a radiomics model containing Positron Emission Tomography /Computed Tomography (PET/CT) radiomics features score, a deep model containing deep features score, and a combined model containing PET/CT radiomics features score +3D deep features score. TumorStage model was also constructed using initial patient tumor node metastasis stage to compare the performance of the combined model. A nomogram was constructed to analyze the influence of deep features on the performance of the model. The 10-fold cross-validation of the average area under the receiver operating characteristic curve and calibration curve were used to evaluate performance, and Shapley Additive exPlanations (SHAP) was developed for interpretation. RESULTS: The TumorStage model, radiomics model, deep model, and the combined model achieved areas under the receiver operating characteristic curve of 0.604, 0.851, 0.840, and 0.895 on the train set and 0.571, 0.849, 0.832, and 0.900 on the test set. The combined model showed better performance of predicting the 5-year OS status of HNC patients than the radiomics model and deep model. The combined model was shown to provide a favorable fit in calibration curves and be clinically useful in decision curve analysis. SHAP summary plot and SHAP The SHAP summary plot and SHAP force plot visually interpreted the influence of deep features and radiomics features on the model results. CONCLUSIONS: In predicting 5-year OS status in patients with HNC, 3D deep features could provide richer features for combined model, which showed outperformance compared with the radiomics model and deep model.

Multiomic study of the protective mechanism of Persicaria capitata (Buch.-Ham. ex D.Don) H.Gross against streptozotocin-induced diabetic nephropathy in Guizhou miniature pigs.

BACKGROUND: Persicaria capitata (Buch.-Ham. ex D.Don) H.Gross (P. capitata, PCB), a traditional drug of the Miao people in China, is potential traditional drug used for the treatment of diabetic nephropathy (DN). PURPOSE: The purpose of this study is to investigate the function of P. capitata and clarify its protective mechanism against DN. METHODS: We induced DN in the Guizhou miniature pig with injections of streptozotocin, and P. capitata was added to the pigs' diet to treat DN. In week 16, all the animals were slaughtered, samples were collected, and the relative DN indices were measured. 16S rRNA sequencing, metagenomics, metabolomics, RNA sequencing, and proteomics were used to explore the protective mechanism of P. capitata against DN. RESULTS: Dietary supplementation with P. capitata significantly reduced the extent of the disease, not only in term of the relative disease indices but also in hematoxylin-eosin-stained tissues. A multiomic analysis showed that two microbes (Clostridium baratii and Escherichia coli), five metabolites (oleic acid, linoleic acid, 4-phenylbutyric acid, 18-ß-glycyrrhetinic acid, and ergosterol peroxide), four proteins (ENTPD5, EPHX1, ARVCF and TREH), four important mRNAs (encoding ENTPD5, EPHX1, ARVCF, and TREH), six lncRNAs (TCONS_00024194, TCONS_00085825, TCONS_00006937, TCONS_00070981, TCONS_00074099, and TCONS_00097913), and two circRNAs (novel_circ_0001514 and novel_circ_0017507) are all involved in the protective mechanism of P. capitata against DN. CONCLUSIONS: Our results provide multidimensional theoretical support for the study and application of P. capitata.

Long-term risks of respiratory diseases in patients infected with SARS-CoV-2: a longitudinal, population-based cohort study.

Background: In the post-pandemic era, growing apprehension exists regarding the potential sequelae of COVID-19. However, the risks of respiratory diseases following SARS-CoV-2 infection have not been comprehensively understood. This study aimed to investigate whether COVID-19 increases the long-term risk of respiratory illness in patients with COVID-19. Methods: In this longitudinal, population-based cohort study, we built three distinct cohorts age 37-73 years using the UK Biobank database; a COVID-19 group diagnosed in medical records between January 30th, 2020 and October 30th, 2022, and two control groups, a contemporary control group and a historical control group, with cutoff dates of October 30th, 2022 and October 30th, 2019, respectively. The follow-up period of all three groups was 2.7 years (the median (IQR) follow-up time was 0.8 years). Respiratory outcomes diagnosed in medical records included common chronic pulmonary diseases (asthma, bronchiectasis, chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD), pulmonary vascular disease (PVD), and lung cancer. For the data analysis, we calculated hazard ratios (HRs) along with their 95% CIs using Cox regression models, following the application of inverse probability weights (IPTW). Findings: A total of 3 cohorts were included in this study; 112,311 individuals in the COVID-19 group with a mean age (±SDs) of 56.2 (8.1) years, 359,671 in the contemporary control group, and 370,979 in the historical control group. Compared with the contemporary control group, those infected with SARS-CoV-2 exhibited elevated risks for developing respiratory diseases. This includes asthma, with a HR of 1.49 and a 95% CI 1.28-1.74; bronchiectasis (1.30; 1.06-1.61); COPD (1.59; 1.41-1.81); ILD (1.81; 1.38-2.21); PVD (1.59; 1.39-1.82); and lung cancer (1.39; 1.13-1.71). With the severity of the acute phase of COVID-19, the risk of pre-described respiratory outcomes increases progressively. Besides, during the 24-months follow-up, we observed an increasing trend in the risks of asthma and bronchiectasis over time. Additionally, the HR of lung cancer for 0-6 month follow-up was 3.07 (CI 1.73-5.44), and the association of lung cancer with COVID-19 disease disappeared at 6-12 month follow-up (1.06; 0.43-2.64) and at 12-24 months (1.02; 0.45-2.34). Compared to those with one SARS-CoV-2 infection, reinfected patients were at a higher risk of asthma (3.0; 1.32-6.84), COPD (3.07; 1.42-6.65), ILD (3.61; 1.11-11.8), and lung cancer (3.20; 1.59-6.45). Similar findings were noted when comparing with a historical cohort serving as a control group, including asthma (1.31; 1.13-1.52); bronchiectasis (1.53; 1.23-1.89); COPD (1.41; 1.24-1.59); ILD (2.53; 2.05-3.13); PVD (2.30; 1.98-2.66); and lung cancer (2.23; 1.78-2.79). Interpretation: Our research suggests that patients with COVID-19 may have an increased risk of developing respiratory diseases, and the risk increases with the severity of infection and reinfection. Even during the 24-month follow-up, the risk of asthma and bronchiectasis continued to increase. Hence, implementing appropriate follow-up strategies for these individuals is crucial to monitor and manage potential long-term respiratory health issues. Additionally, the increased risk in lung cancer in the COVID-19 individuals was probably due to the diagnostic tests conducted and incidental diagnoses. Funding: The National Natural Science Foundation of China of China Regional Innovation and Development Joint Foundation; National Natural Science Foundation of China; Program for High-level Foreign Expert Introduction of China; Natural Science Foundation for Distinguished Young Scholars of Guangdong Province; Guangdong Basic and Applied Basic Research Foundation; Climbing Program of Introduced Talents and High-level Hospital Construction Project of Guangdong Provincial People's Hospital; VA Clinical Merit and ASGE clinical research funds.

[Effect of PFKFB3 on inflammatory activation of polymorphonuclear myeloid-derived suppressor cell in acute myocardial infarction].

OBJECTIVE: To investigate the correlation between 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3 (PFKFB3) and the inflammatory activation of polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) in acute myocardial infarction (AMI), and to evaluate the effect of intervention targeting PFKFB3 on the inflammatory activation of PMN-MDSC during AMI. METHODS: (1) Clinical trial section: a observational study was conducted. The patients with acute coronary syndrome (ACS) admitted to Zhenjiang Fourth People's Hospital were enrolled, and they were divided into AMI group and non-AMI group according to clinical diagnosis. The peripheral venous blood of the two groups was collected to detect the proportion of PMN-MDSC, and the expression of PFKFB3 gene in mononuclear cells was detected by real-time quantitative polymerase chain reaction (RT-qPCR). (2) Basic experiment section: a total of 30 male C57 mice (aged 6-8 weeks) were divided into normal control group (n = 5), Sham group (n = 5), AMI model group (n = 10) and PFKFB3 inhibitor PKF-15 intervention group (n = 10) according to random number table method. The AMI model of mice was reproduced by left anterior descending coronary artery (LADCA) ligation, and the mice in the Sham group did not attach the artery after thoracotomy. The PKF-15 intervention group was intraperitoneally injected with PKF-15 (20 µg/g) at the same time of LADCA ligation. Normal control mice did not receive any treatment. Peripheral venous blood and myocardial tissue of mice were collected 24 hours after modeling. Both the circulating PMN-MDSC ratio and the infiltration of PMN-MDSC in myocardial tissue were detected. After staining with hematoxylin-eosin (HE), the degree of inflammatory damage in mouse myocardial tissue was observed under light microscopy. PMN-MDSC were isolated from mice with flow cytometry, and the gene expressions of PFKFB3 and inflammatory factors were measured by RT-qPCR. RESULTS: (1) Clinical trial section: the circulating PMN-MDSC ratio of patients in the AMI group (n = 25) was significantly higher than that in the non-AMI group [n = 20; (8.53±0.96)% vs. (1.13±0.39)%, P < 0.01], and PFKFB3 gene expression in the peripheral blood mononuclear cells was also increased (2-ΔΔCt: 1.18±0.19 vs. 0.96±0.16, P < 0.01). Pearson correlation analysis showed that circulating PMN-MDSC ratio was positively correlated with PFKFB3 gene expression in mononuclear cells in AMI patients (r = 0.608, P = 0.001). (2) Basic experimental section: the circulating PMN-MDSC ratio and the infiltration of PMN-MDSC in myocardial tissue of AMI mice were significantly higher than those in the normal control group and Sham group. PFK-15 intervention could reduce the ratio of PMN-MDSC in the peripheral blood and myocardial tissue of AMI mice [(26.33±5.27)% vs. (75.12±5.02)% in peripheral blood, (20.87±2.97)% vs. (35.28±4.36)% in myocardial tissue, both P < 0.01]. Under light microscopy, the myocardial cells in the AMI modal group were disordered and a large number of inflammatory cells infiltrated. PFK-15 intervention could maintain a normal arrangement of cardiomyocytes and reduce the infiltration of inflammatory cells. The gene expression levels of PFKFB3 in the peripheral blood and myocardial tissue as well as the inflammatory factors in the myocardial tissue of AMI mice were significantly higher than those in the normal control group and Sham group. PKF-15 intervention could effectively reduce the gene expression levels of PFKFB3 in the peripheral blood and myocardial tissue as well as the inflammatory factors in the myocardial tissue of AMI mice [PFKFB3 mRNA (2-ΔΔCt): 1.01±0.09 vs. 1.40±0.12 in peripheral blood, 0.95±0.09 vs. 1.47±0.10 in myocardial tissue; myocardial tissue tumor necrosis factor-α (TNF-α) mRNA (2-ΔΔCt) was 14.55±3.99 vs. 29.66±3.90, interleukin-1ß (IL-1ß) mRNA (2-ΔΔCt) was 8.72±1.35 vs. 18.53±2.43, IL-6 mRNA (2-ΔΔCt) was 11.87±2.97 vs. 19.82±4.32, all P < 0.01]. CONCLUSIONS: The activation of PFKFB3 is closely related to the inflammatory activation of PMN-MDSC during AMI. Inhibition of PFKFB3 activity can inhibit the inflammatory activation of PMN-MDSC and reduce myocardial inflammatory injury.

First-in-Human Study of 18F-SynVesT-2: An SV2A PET Imaging Probe with Fast Brain Kinetics and High Specific Binding.

PET imaging of synaptic vesicle glycoprotein 2A allows for noninvasive quantification of synapses. This first-in-human study aimed to evaluate the kinetics, test-retest reproducibility, and extent of specific binding of a recently developed synaptic vesicle glycoprotein 2A PET ligand, (R)-4-(3-(18F-fluoro)phenyl)-1-((3-methylpyridin-4-yl)methyl)pyrrolidine-2-one (18F-SynVesT-2), with fast brain kinetics. Methods: Nine healthy volunteers participated in this study and were scanned on a High Resolution Research Tomograph scanner with 18F-SynVesT-2. Five volunteers were scanned twice on 2 different days. Five volunteers were rescanned with preinjected levetiracetam (20 mg/kg, intravenously). Arterial blood was collected to calculate the plasma free fraction and generate the arterial input function. Individual MR images were coregistered to a brain atlas to define regions of interest for generating time-activity curves, which were fitted with 1- and 2-tissue-compartment (1TC and 2TC) models to derive the regional distribution volume (V T). The regional nondisplaceable binding potential (BP ND) was calculated from 1TC V T, using the centrum semiovale (CS) as the reference region. Results: 18F-SynVesT-2 was synthesized with high molar activity (187 ± 69 MBq/nmol, n = 19). The parent fraction of 18F-SynVesT-2 in plasma was 28% ± 8% at 30 min after injection, and the plasma free fraction was high (0.29 ± 0.04). 18F-SynVesT-2 entered the brain quickly, with an SUVpeak of 8 within 10 min after injection. Regional time-activity curves fitted well with both the 1TC and the 2TC models; however, V T was estimated more reliably using the 1TC model. The 1TC V T ranged from 1.9 ± 0.2 mL/cm3 in CS to 7.6 ± 0.8 mL/cm3 in the putamen, with low absolute test-retest variability (6.0% ± 3.6%). Regional BP ND ranged from 1.76 ± 0.21 in the hippocampus to 3.06 ± 0.29 in the putamen. A 20-min scan was sufficient to provide reliable V T and BP ND Conclusion: 18F-SynVesT-2 has fast kinetics, high specific uptake, and low nonspecific uptake in the brain. Consistent with the nonhuman primate results, the kinetics of 18F-SynVesT-2 is faster than the kinetics of 11C-UCB-J and 18F-SynVesT-1 in the human brain and enables a shorter dynamic scan to derive physiologic information on cerebral blood flow and synapse density.

ZBTB7B is a permissive regulator of hepatocellular carcinoma initiation by repressing c-Jun expression and function.

Hepatocarcinogenesis is a multi-step process. However, the regulators of hepatocellular carcinoma (HCC) initiation are understudied. Adult liver-specific gene expression was globally downregulated in HCC. We hypothesize that adult liver-specific genes, especially adult liver-enriched transcription factors may exert tumor-suppressive functions in HCC. In this study, we identify ZBTB7B, an adult liver-enriched transcription factor as a permissive regulator of HCC initiation. ZBTB7B is highly expressed in hepatocytes in adult livers, compared to fetal livers. To evaluate the functions of ZBTB7B in hepatocarcinogenesis, we performed hepatocyte-specific ZBTB7B knockout in hydrodynamic oncogene transfer-induced mouse liver cancer models. Hepatocyte-specific knockout of ZBTB7B promotes activated Akt and N-Ras-induced HCC development. Moreover, ZBTB7B deficiency sensitizes hepatocytes to a single oncogene Akt-induced oncogenic transformation and HCC initiation, which is otherwise incompetent in inducing HCC. ZBTB7B deficiency accelerates HCC initiation by down-regulating adult liver-specific gene expression and priming livers to a fetal-like state. The molecular mechanism underlying ZBTB7B functions in hepatocytes was investigated by integrated transcriptomic, phosphoproteomic, and chromatin immunoprecipitation-sequencing analyses. Integrative multi-omics analyses identify c-Jun as the core signaling node in ZBTB7B-deficient liver cancer initiation. c-Jun is a direct target of ZBTB7B essential to accelerated liver cancer initiation in ZBTB7B-deficient livers. Knockdown of c-Jun expression or dominant negative c-Jun expression delays HCC development in ZBTB7B-deficient livers. In addition, ZBTB7B competes with c-Jun for chromatin binding. Ectopic ZBTB7B expression attenuates the tumor-promoting functions of c-Jun. Expression of ZBTB7B signature, composed of 140 genes co-regulated by ZBTB7B and c-Jun, is significantly downregulated in early-stage HCCs compared to adjacent normal tissues, correlates to liver-specific gene expression, and is associated with good prognosis in human HCC. Thus, ZBTB7B functions as a permissive regulator of HCC initiation by directly regulating c-Jun expression and function.

The regional pattern of age-related synaptic loss in the human brain differs from gray matter volume loss: in vivo PET measurement with [11C]UCB-J.

PURPOSE: Aging is a major societal concern due to age-related functional losses. Synapses are crucial components of neural circuits, and synaptic density could be a sensitive biomarker to evaluate brain function. [11C]UCB-J is a positron emission tomography (PET) ligand targeting synaptic vesicle glycoprotein 2A (SV2A), which can be used to evaluate brain synaptic density in vivo. METHODS: We evaluated age-related changes in gray matter synaptic density, volume, and blood flow using [11C]UCB-J PET and magnetic resonance imaging (MRI) in a wide age range of 80 cognitive normal subjects (21-83 years old). Partial volume correction was applied to the PET data. RESULTS: Significant age-related decreases were found in 13, two, and nine brain regions for volume, synaptic density, and blood flow, respectively. The prefrontal cortex showed the largest volume decline (4.9% reduction per decade: RPD), while the synaptic density loss was largest in the caudate (3.6% RPD) and medial occipital cortex (3.4% RPD). The reductions in caudate are consistent with previous SV2A PET studies and likely reflect that caudate is the site of nerve terminals for multiple major tracts that undergo substantial age-related neurodegeneration. There was a non-significant negative relationship between volume and synaptic density reductions in 16 gray matter regions. CONCLUSION: MRI and [11]C-UCB-J PET showed age-related decreases of gray matter volume, synaptic density, and blood flow; however, the regional patterns of the reductions in volume and SV2A binding were different. Those patterns suggest that MR-based measures of GM volume may not be directly representative of synaptic density.

Severe High-Voltage Electrical Injury: A Rare Case Report.

High-voltage electrical injury usually causes severe tissue damage and serious secondary complications. We report a case of treatment of severe high-voltage electrical injury. A series of personalized and effective treatment plans were created through repeated discussions, we successfully handled a series of acute and critical conditions, including severe limb damage, a very large area of full-thickness abdominal wall defect, abdominal viscera (stomach and liver) necrosis, abdominal infection, renal insufficiency, myocardial damage, and malignant arrhythmia (atrial fibrillation). Finally, the wounds were all closed, the functions of the abdominal organs were restored, and the course of the disease was successfully transitioned into the rehabilitation stage. It took a lot of twists and turns but ultimately saved the patient's life. The successful treatment of this patient provides an important reference for similar patients with serious electrical injury in the future.

Soluble epoxide hydrolase deficiency attenuates airway inflammation in COPD via IRE1α/JNK/AP-1 signaling pathway.

BACKGROUND: Soluble Epoxide Hydrolase (sEH) metabolizes anti-inflammatory epoxyeicosatrienoic acids and critically affects airway inflammation in chronic obstructive pulmonary disease (COPD). Considering the excessive endoplasmic reticulum stress is associated with the earlier onset of COPD. The role of sEH and endoplasmic reticulum stress in the pathogenesis of COPD remains unknown. METHOD: 16 weeks of cigarette-exposed mice were used to detect the relationship between sEH and endoplasmic reticulum stress in COPD. Human epithelial cells were used in vitro to determine the regulation mechanism of sEH in endoplasmic reticulum stress induced by cigarette smoke. RESULTS: sEH deficiency helps reduce emphysema formation after smoke exposure by alleviating endoplasmic reticulum stress response. sEH deficiency effectively reverses the upregulation of phosphorylation IRE1α and JNK and the nuclear expression of AP-1, alleviating the secretion of inflammatory factors induced by cigarette smoke extract. Furthermore, the treatment with endoplasmic reticulum stress and IRE1α inhibitor downregulated cigarette smoke extract-induced sEH expression and the secretion of inflammatory factors. CONCLUSION: sEH probably alleviates airway inflammatory response and endoplasmic reticulum stress via the IRE1α/JNK/AP-1 pathway, which might attenuate lung injury caused by long-term smoking and provide a new pharmacological target for preventing and treating COPD.