SEanalysis 2.0: a comprehensive super-enhancer regulatory network analysis tool for human and mouse.

Super-enhancers (SEs) play an essential regulatory role in various biological processes and diseases through their specific interaction with transcription factors (TFs). Here, we present the release of SEanalysis 2.0 (http://licpathway.net/SEanalysis), an updated version of the SEanalysis web server for the comprehensive analyses of transcriptional regulatory networks formed by SEs, pathways, TFs, and genes. The current version added mouse SEs and further expanded the scale of human SEs, documenting 1 167 518 human SEs from 1739 samples and 550 226 mouse SEs from 931 samples. The SE-related samples in SEanalysis 2.0 were more than five times that in version 1.0, which significantly improved the ability of original SE-related network analyses ('pathway downstream analysis', 'upstream regulatory analysis' and 'genomic region annotation') for understanding context-specific gene regulation. Furthermore, we designed two novel analysis models, 'TF regulatory analysis' and 'Sample comparative analysis' for supporting more comprehensive analyses of SE regulatory networks driven by TFs. Further, the risk SNPs were annotated to the SE regions to provide potential SE-related disease/trait information. Hence, we believe that SEanalysis 2.0 has significantly expanded the data and analytical capabilities of SEs, which helps researchers in an in-depth understanding of the regulatory mechanisms of SEs.

IRF4-mediated Treg phenotype switching can aggravate hyperoxia-induced alveolar epithelial cell injury.

Bronchopulmonary dysplasia (BPD) is characterized by alveolar dysplasia, and evidence indicates that interferon regulatory factor 4 (IRF4) is involved in the pathogenesis of various inflammatory lung diseases. Nonetheless, the significance and mechanism of IRF4 in BPD remain unelucidated. Consequently, we established a mouse model of BPD through hyperoxia exposure, and ELISA was employed to measure interleukin-17 A (IL-17 A) and interleukin-6 (IL-6) expression levels in lung tissues. Western blotting was adopted to determine the expression of IRF4, surfactant protein C (SP-C), and podoplanin (T1α) in lung tissues. Flow cytometry was utilized for analyzing the percentages of FOXP3+ regulatory T cells (Tregs) and FOXP3+RORγt+ Tregs in CD4+ T cells in lung tissues to clarify the underlying mechanism. Our findings revealed that BPD mice exhibited disordered lung tissue structure, elevated IRF4 expression, decreased SP-C and T1α expression, increased IL-17 A and IL-6 levels, reduced proportion of FOXP3+ Tregs, and increased proportion of FOXP3+RORγt+ Tregs. For the purpose of further elucidating the effect of IRF4 on Treg phenotype switching induced by hyperoxia in lung tissues, we exposed neonatal mice with IRF4 knockout to hyperoxia. These mice exhibited regular lung tissue structure, increased proportion of FOXP3+ Tregs, reduced proportion of FOXP3+RORγt+ Tregs, elevated SP-C and T1α expression, and decreased IL-17 A and IL-6 levels. In conclusion, our findings demonstrate that IRF4-mediated Treg phenotype switching in lung tissues exacerbates alveolar epithelial cell injury under hyperoxia exposure.

Six-Membered Aromatic Nitrogen Heterocyclic Anti-Tumor Agents: Synthesis and Applications.

Cancer stands as a serious malady, posing substantial risks to human well-being and survival. This underscores the paramount necessity to explore and investigate novel antitumor medications. Nitrogen-containing compounds, especially those derived from natural sources, form a highly significant category of antitumor agents. Among these, antitumor agents with six-membered aromatic nitrogen heterocycles have consistently attracted the attention of chemists and pharmacologists. Accordingly, we present a comprehensive summary of synthetic strategies and clinical implications of these compounds in this review. This entails an in-depth analysis of synthesis pathways for pyridine, quinoline, pyrimidine, and quinazoline. Additionally, we explore the historical progression, targets, mechanisms of action, and clinical effectiveness of small molecule inhibitors possessing these structural features.

VARAdb: a comprehensive variation annotation database for human.

With the study of human diseases and biological processes increasing, a large number of non-coding variants have been identified and facilitated. The rapid accumulation of genetic and epigenomic information has resulted in an urgent need to collect and process data to explore the regulation of non-coding variants. Here, we developed a comprehensive variation annotation database for human (VARAdb, http://www.licpathway.net/VARAdb/), which specifically considers non-coding variants. VARAdb provides annotation information for 577,283,813 variations and novel variants, prioritizes variations based on scores using nine annotation categories, and supports pathway downstream analysis. Importantly, VARAdb integrates a large amount of genetic and epigenomic data into five annotation sections, which include 'Variation information', 'Regulatory information', 'Related genes', 'Chromatin accessibility' and 'Chromatin interaction'. The detailed annotation information consists of motif changes, risk SNPs, LD SNPs, eQTLs, clinical variant-drug-gene pairs, sequence conservation, somatic mutations, enhancers, super enhancers, promoters, transcription factors, chromatin states, histone modifications, chromatin accessibility regions and chromatin interactions. This database is a user-friendly interface to query, browse and visualize variations and related annotation information. VARAdb is a useful resource for selecting potential functional variations and interpreting their effects on human diseases and biological processes.

Diagnostic value of ROC curve evaluation of serum markers in acute cholecystitis with bacterial infection.

OBJECTIVE: To explore correlation of serum markers human neutrophil lipocalin and C-reactive protein with acute cholecystitis associated with bacterial infection, and to evaluate the diagnostic value of the markers. METHODS: The cross-sectional study was conducted from January 2018 to April 2020 at the Beijing Luhe Hospital, Capital Medical University, Beijing, China, and comprised acute cholecystitis patients who were divided into bacterial infection group A and non-bacterial infection group B. Serum human neutrophil lipocalin and C-reactive protein were measured for both the groups. Receiver operating characteristic curve was used to evaluate the diagnostic value of the two markers in acute cholecystitis associated with bacterial infection. Data was analysed using SPSS 25. RESULTS: Of the 145 patients, 65(45%) were in group A; 36(55.38%) males and 29(44.62%) females with a mean age of 45.79±2.50 years. In group B there were 80(55%) subjects; 45(56.25%) males and 35(43.75%) females with a mean age of 46.16±2.52 years (p>0.05). In group A, there were 60(92.31%) cases of acute calculous cholecystitis, and 5(7.69%) had acute acalculous cholecystitis compared to 73(91.25%) and 7(8.75%), respectively, in group B (p>0.05). Serum human neutrophil lipocalin and C-reactive protein levels in group A were higher than group B (p<0.001). Serum human neutrophil lipocalin showed a high positive correlation with C-reactive protein in group A (r=0.800, p<0.001), and a moderate positive correlation in group B (r=0.683, p<0.001). Area under the curve of serum human neutrophil lipocalin associated with C-reactive protein was 0.901 (95% confidence interval: 0.850-0.953), which was higher than that of serum human neutrophil lipocalin and C-reactive protein alone, with sensitivity 95.40% and specificity 80%. CONCLUSIONS: The combined use of serum human neutrophil lipocalin and C-reactive protein may be used as an effective indicator for early diagnosis, identification and monitoring of acute cholecystitis with bacterial infection.

High repetition rate 102 W middle infrared ZnGeP2 master oscillator power amplifier system with thermal lens compensation.

We demonstrate a 102 W middle infrared ZnGeP2 (ZGP) optical parametric amplifier (OPA) pumped by a 2097-nm Q-switched Ho:YAG laser at a pulse repetition frequency of 10 kHz. The seed middle infrared laser was produced by a ZGP optical parametric oscillator. Its average power was 28.4 W pumped by a 50 W 2097-nm laser. By thermal lens compensation, the beam factor M2 reduced from 3.1 to 2.1. When the incident Ho pump power was 120 W, the middle infrared ZGP OPA yielded the maximum average output power of 102 W and slope efficiency of 61.7%. The overall optical conversion efficiency of 60% from Ho to middle infrared was obtained for the whole middle infrared laser system. In addition, at the maximum average output power, the beam quality factors of the middle infrared ZGP OPA were measured to be about 2.7 and 2.8 for horizontal and vertical directions, respectively.

Different responses of articular cartilage to strenuous running and joint immobilization.

OBJECTIVE: To compare the pathological changes in cartilage derived from rats that developed osteoarthritis either by joint immobilization or by strenuous treadmill running in order to better understand their respective pathomechanism. METHOD: A total of 24 male Wistar rats were randomly assigned to three groups: sedentary control (CON), immobilization (IM), and strenuous running (SR). For rats in the IM group, unilateral knee joint was immobilized in flexion. Rats in the SR group underwent treadmill running with high intensity. Eight weeks later, all animals were sacrificed. Femoral condyles were collected to take histological observation for cartilage characteristic and immunohistochemistry for collagen type II. In addition, cartilage samples were obtained to assess gene expression of aggrecan, collagen type II, biglycan, and fibromodulin by quantitative RT-PCR. RESULTS: Gross and histological observation showed osteoarthritic changes in groups SR and IM; however, more severe cartilage degradation was revealed in the latter. Proteoglycan and collagen II content decreased in groups SR and IM in comparison to group CON, with more loss in group IM. In group SR, mRNA levels in femoral cartilage were found to be unaltered for all the molecules measured. On the contrary, these molecules were significantly downregulated in group IM. CONCLUSION: Differences in gross observation, histological characteristics, and gene expression of proteoglycans and collagen II suggest that both knee immobilization and strenuous running would lead to degenerative change of cartilage, but at different stages of the degenerative process.

[In vitro anticoagulant activity of different processed products of Whitmania pigra by water extraction and bionic extraction].

In order to determine the scientificalness of traditionally processed Whitmania pigra, water extraction method and bionic extraction method were used respectively to extract the anticoagulating active components in W. pigra hanging dry products, talcum powder fried products and wine immersing-baked products. Activated partial thromboplastin time (APTT), prothrombin time (PT), thrombin time (TT), and antithrombin activity were selected as the activity indexes to evaluate the anticoagulant activities of different processed W. pigra. Then the contents of protein in different processed W. pigra were measured by Coomassie brilliant blue method to preliminarily explain the reason of anticoagulant activity changes. When water extraction method was used, the results of APTT, PT, TT and antithrombin activity showed that the anticoagulant activities of W. pigra were decreased both in talcum powder fried products and wine immersing-baked products, and the activity order was as follows: hanging dried products> wine immersing-baked products>talcum powder fried products. This order was same as the protein content order. While when bionic extraction was used, APTT was shortened in talcum powder fried products, but all the other results indicated the anticoagulant activities of W. pigra processed products were increased, and the activity order was as follows: wine immersing-baked products>talcum powder fried products>hanging dry products. As compared with water extraction, the bionic extraction was more similar to the absorption process of W. pigra in human digestive system after oral administration and was more scientific. Therefore, the traditional processing method can not only modify the taste and smell, but also enhance the anticoagulant activity of W. pigra.

A 41-W ZnGeP2 optical parametric oscillator pumped by a Q-switched Ho:YAG laser.

We reported a high-power ZnGeP2 (ZGP) optical parametric oscillator (OPO) pumped by a Q-switched Ho:YAG laser. The maximum output power of the ZGP OPO was 41.2 W at 107.0 W incident Ho pump power, corresponding to a slope efficiency of 44.6%. The ZGP OPO produced 16-ns mid-IR pulse laser in the 3.74-3.98 µm and 4.38-4.76 µm spectral regions simultaneously. The beam quality was measured to be M²<4.37. The continuous wave maximum average output power of the Ho:YAG laser was 128 W, corresponding to a slope efficiency of 65.8%.

Immunoenhancement effect of cinobufagin on macrophages and the cyclophosphamide-induced immunosuppression mouse model.

Cinobufagin (CBG) is a natural active substance. Although its various pharmacological activities have been explored, the immunomodulatory activity of CBG remains unexplored. Therefore, this study aimed to investigate the anti-inflammatory and immunomodulatory activities of CBG ex vivo and in vivo. The immunomodulatory activity of CBG was investigated in RAW 264.7 cells. CBG showed no significant toxicity to cells. Additionally, 0.5-8 µg/mL CBG significantly increased the phagocytosis ability of macrophages and the secretion levels of IL-1ß and TNF-α. Thus, it exerted immunomodulatory effects. We established the immunosuppressive model induced by cyclophosphamide (CTX) in mice and studied the immunomodulatory activity of CBG in vivo. The experimental results showed that the intervention of CBG alleviated the CTX-induced weight loss, restored the lymphocyte nuclear cell number, and promoted the secretion and mRNA expression of cytokines IFN-γ, IL-4, IL-6, and IL-12. Moreover, CBG increased the immune organ index, protected the growth of the spleen and thymus, and improved the pathological changes in immunosuppressed mice. Western blot results showed that different concentrations of CBG upregulated the phosphorylation level of PI3K/Akt/mTOR in the spleen of CTX-induced immunosuppressed mice. This suggests that the immunomodulatory effect of CBG may be related to the regulation of PI3K/Akt/mTOR signaling pathway. This study provides a theoretical basis for developing CBG immune enhancers and opens up new ideas for the comprehensive utilization and development of CBG in factories.

1,3-diene-based AIEgens: Stereoselective synthesis and applications.

In recent years, significant advancements have been made in the synthesis and application of 1,3-dienes. This specific structural motif has garnered significant attention from researchers in materials science and biology due to its unique aggregation-induced emission (AIE) properties and extensive conjugation systems. The luminescent characteristics of these compounds are notably influenced by the geometry of the two double bonds. Therefore, it is essential to consolidate stereoselective synthetic strategies for 1,3-dienes. This comprehensive review seeks to elucidate the diverse techniques employed to attain stereo-control in the synthesis of 1,3-diene-based AIE luminogens (AIEgens). Particular emphasis is placed on comprehending the determinants of stereoselectivity and exploring the array of substrates amenable to these methods. Furthermore, the review underscores the AIE properties exhibited by these compounds and their extensive utility in organic light-emitting diodes (OLEDs), stimuli-responsive materials, sensors, bioimaging, and photodynamic therapy (PDT).

Pancreatic cancer environment: from patient-derived models to single-cell omics.

Pancreatic cancer (PC) is a highly malignant cancer characterized by poor prognosis, high heterogeneity, and intricate heterocellular systems. Selecting an appropriate experimental model for studying its progression and treatment is crucial. Patient-derived models provide a more accurate representation of tumor heterogeneity and complexity compared to cell line-derived models. This review initially presents relevant patient-derived models, including patient-derived xenografts (PDXs), patient-derived organoids (PDOs), and patient-derived explants (PDEs), which are essential for studying cell communication and pancreatic cancer progression. We have emphasized the utilization of these models in comprehending intricate intercellular communication, drug responsiveness, mechanisms underlying tumor growth, expediting drug discovery, and enabling personalized medical approaches. Additionally, we have comprehensively summarized single-cell analyses of these models to enhance comprehension of intercellular communication among tumor cells, drug response mechanisms, and individual patient sensitivities.

Risk Factors for Level-VII Lymph Node Metastases of Thyroid Neoplasms: A Meta-Analysis.

OBJECTIVE: The present study conducted a meta-analysis to forecast the risk factors associated with level-VII lymph node metastases in case of thyroid neoplasms, intending to assist in determining the requirement for level-VII lymph node lymphadenectomy during the surgery. METHODS: Electronic databases, PubMed, Embase, the Cochrane Library, CNKI, Wanfang Data, VIP, and CBM electronic databases were searched for studies focused on level-VII lymph node metastases in thyroid neoplasms, published up to April 2021. Stata 13.1 software was used for analyses. RESULTS: The literature search identified a total of 997 studies. Among these, 8 studies, involving 1813 patients, were included in the present case. All these studies were case-control studies. Results for meta-analysis showed that male (OR = 1.340, 95% CI: 1.018-1.764, P = .037), age < 45 years (OR = 4.178, 95% CI: 1.601-10.908, P = .003), tumor size ≥ 2.0 cm (OR = 1.960, 95% CI: 1.079-3.562, P = .027), extrathyroidal extension (OR = 2.037, 95% CI: 1.578-2.630, P < .001), distant metastasis (OR = 2.775, 95% CI: 2.005-3.840, P < .001), central lymph node metastasis (OR = 3.500, 95% CI: 1.127-10.874, P = .03), contralateral cervicolateral metastasis (OR = 2.119, 95% CI: 1.514-2.965, P < .001), and bilateral nodal metastasis (OR = 4.651, 95% CI: 2.697-8.020, P < .001) acted as risk factors for level-VII lymph node metastases. In addition to this, sensitivity analyses and bias test showed that the results of meta-analysis were reliable and stable and involved no publication bias. CONCLUSION: In the present study, male gender, age < 45 years, tumor size ≥ 2.0 cm, extrathyroidal extension, distant metastasis, central lymph node metastasis, contralateral cervicolateral metastasis, and bilateral nodal metastasis were identified as risk factors for level-VII lymph node metastases in case of thyroid neoplasms.

103 W in-band dual-end-pumped Ho:YAG laser.

An efficient 2 µm in-band pumped Ho:YAG laser was demonstrated. The resonator involves two Ho:YAG crystals, each of which was dual-end-pumped by two orthogonally polarized diode-pumped Tm:YLF lasers. The maximum continuous wave output power of 103 W was achieved, corresponding to a slope efficiency of 67.8% with respect to the incident pump power and an optical-to-optical conversion efficiency of 63.5%. Under Q-switched mode, we obtained 101 W laser output at 30 kHz, corresponding to a slope efficiency of 66.2%. The beam quality or M2 factor was found to be less than 2.

Resonantly pumped high efficiency Ho:YAG laser.

High-efficient CW and Q-switched Ho:YAG lasers resonantly dual-end-pumped by two diode-pumped Tm:YLF lasers at 1908 nm were investigated. A maximum slope efficiency of 74.8% in CW operation as well as a maximum output power of 58.7 W at 83.2 W incident pump power was achieved, which corresponded to an optical-to-optical conversion efficiency of 70.6%. The maximum pulse energy of 2.94 mJ was achieved, with a 31 ns FWHM pulse width and a peak power of approximately 94.7 kW.

High-efficiency resonantly pumped room temperature Ho:YVO4 laser.

An efficient 2 µm room temperature Ho:YVO(4) laser resonantly pumped by a 1.94 µm Tm:YAP laser is demonstrated, for the first time to our knowledge, in this Letter. Up to 8.58 W of laser output at 2053 nm is obtained with the optical-to-optical conversion efficiency as much as 41.2%. The output beam had quality of M2 factor with Mx(2) of 3.58 and My(2) of 1.76 at 8 W output level. In addition, we also obtained 4.18 W laser output at 2066 nm and 7.04 W at 2040 nm from the Ho:YVO(4) laser with conversion efficiency of 27.8% and 33.8%, respectively.

[Pulmonary pathology in fatal human influenza A (H1N1) infection].

OBJECTIVE: To study the pulmonary pathology in patients died of fatal human influenza A(H1N1) infection. METHODS: Eight cases of fatal human influenza A (H1N1) infection, including 2 autopsy cases and 6 paramortem needle puncture biopsies, were enrolled into the study. Histologic examination, immunohistochemitry, flow cytometry and Western blotting were carried out. RESULTS: The major pathologic changes included necrotizing bronchiolitis with surrounding inflammation, diffuse alveolar damage and pulmonary hemorrhage. Influenza viral antigen expression was detected in the lung tissue by Western blotting. Immunohistochemical study demonstrated the presence of nuclear protein and hemagglutinin virus antigens in parts of trachea, bronchial epithelium and glands, alveolar epithelium, macrophages and endothelium. Flow cytometry showed that the apoptotic rate of type II pneumocytes (32.15%, 78.15%) was significantly higher than that of the controls (1.93%, 3.77%). CONCLUSION: Necrotizing bronchiolitis, diffuse alveolar damage and pulmonary hemorrhage followed by pulmonary fibrosis in late stage are the major pathologic changes in fatal human influenza A (H1N1) infection.

The Application of Electrical Impedance Tomography During the Ventilator Weaning Process.

BACKGROUND: This study proposes the investigation of electrical impedance tomography (EIT) as a useful predictor for ventilator weaning. METHODS: The study design was a nested case-control study and patients who were admitted to the intensive care unit and underwent their first tracheal intubation were enrolled. Those who successfully completed ventilator weaning and extubation after the first spontaneous breathing trial (SBT) were included in the weaning success group, while those who did not pass the SBT or received secondary intubation within 48 hours were included in the weaning failure group. In both groups, EIT was adopted to record the monitoring data in three phases: before the SBT (pre-SBT), during the SBT (SBT), and after the SBT (post-SBT). RESULTS: A total of 53 patients were enrolled, including 41 cases in the weaning success group and 12 cases in the weaning failure group. The logistic regression analysis showed that the pre-SBT global impedance (GI) and the SBT region of interest 2 (ROI2) were significantly higher in the weaning success group than in the weaning failure group (p = 0.0001 and p = 0.002). The pre-SBT GI predicted weaning success with a sensitivity of 0.524, a specificity of 0.818, a p-value of 0.0496, and a 95% confidence interval (CI) of 0.001-0.978. The sensitivity, specificity, p-value, and 95% CI for the SBT ROI2 were 1, 0.595, 0.0164, and 1.010-1.108, respectively. CONCLUSION: For patients without contraindications to EIT, the application of EIT is recommended to be added to the existing evaluation system for ventilator weaning, as it could help improve the weaning success rate. Further cohort studies are needed to investigate the actual efficacy of EIT after it has been added to the evaluation system.

Comparison of Pharmacokinetics and Tissue Distribution Characteristics of Three Diterpenoid Esters in Crude and Prepared Semen Euphorbiae.

BACKGROUND: Semen Euphorbiae (SE) and Semen Euphorbiae Pulveratum (SEP) have a long history of medicinal use. SEP is the processed product of SE; both ancient and modern studies have shown that SEP has a lower toxicity compared to SE. To clarify the influence of processing on the pharmacological properties of SE and SEP, a study was carried out to compare the pharmacokinetics and distribution characteristics of three active compounds after oral administration of SE and SEP extracts. METHODS: A UPLC-MS/MS method was established to simultaneously determine the contents of Euphorbia factors L1, L2, and L3 in rat plasma and mouse tissues after an oral administration of crude and processed SE with approximately the same dosage. Plasma and heart, liver, spleen, lung, kidney, and colon tissue samples were treated with ethyl acetate and separated by gradient elution on a C18 column with a mobile phase of 0.1% formic acid and methanol. RESULTS: The established method had good selectivity, linear range, accuracy, precision, stability, matrix effect, and extraction recovery. The area under the concentration time curve, time to maximum concentration, maximum concentration, half-life of elimination, and mean retention time of plasma samples in SEP-treated group decreased, and the clearance in SEP-treated group increased. Moreover, the active component concentrations in colon, liver, and kidney tissues were more followed by those in the heart, lungs, and spleen. CONCLUSION: These results indicate that the processing could influence the pharmacokinetics and tissue distribution of Euphorbia factors L1, L2, and L3 after oral administration of crude and processed SE. The data obtained may lay a foundation for the clinical use of SE and for further study on the processing mechanism of SE.

Emergent right lobe adult-to-adult living-donor liver transplantation for high model for end-stage liver disease score severe hepatitis.

The aim of this study was to explore the feasibility of emergency right lobe adult-to-adult living-donor liver transplantation (LDLT) for high model for end-stage liver disease (MELD) score severe hepatitis. Consecutive 10 high MELD score severe hepatitis patients underwent emergency right lobe adult-to-adult LDLT in our hospital from April to December 2007. The MELD score was 34.50 +/- 2.088. The outcomes of these recipients were retrospectively analyzed. Among them, eight cases of ABO blood group were identical and two cases compatible, one case was Rh negative. Two recipients died and the rest of the recipients and all donors are safe; perioperative and 2-year survival rate was 80%. The mean graft-recipient weight ratio (GRWR) was 1.27% +/- 0.25%, and graft volume to recipient standard liver volume ratio (GV/ESLVR) was 56.7% +/- 6.75%. Of the 10 patients, three received right lobe grafts with middle hepatic vein (MHV), four without MHV, three without MHV but followed by V and VIII hepatic vein outflow reconstruction. An encouraging outcome was achieved in this group: elevated serum creatinine, serum endotoxin, decreased serum prothrombin activity, and Tbil returned to normal on postoperative days 3, 7, 14, and 28, respectively. One-year survival rate was 80%. Outcomes of emergency right lobe adult-to-adult LDLT for high MELD score severe hepatitis were fairly encouraging and acceptable. Emergency right lobe adult-to-adult LDLT is an effective and life-saving modality for high MELD score acute liver failure patients following severe hepatitis.