Changes in amplitude-integrated electroencephalography, neuron-specific enolase, and S100B in neonates with brain injury induced by neonatal hyperbilirubinemia and their significance.

OBJECTIVE: To explore the changes in amplitude-integrated electroencephalography (aEEG), neuron-specific enolase (NSE), and S100B in neonates with brain injury induced by neonatal hyperbilirubinemia (NHB). METHODS: 67 neonates with brain injury induced by NHB admitted to our hospital from March 2016 to October 2018 were included in a brain injury group (BIG), and 82 neonates with NHB but without brain injury in our hospital during the same period were included in a non-BIG. The two groups were compared regarding the rates of normal and abnormal aEEG results. RESULTS: The proportion of normal aEEG results in the BIG was significantly lower than that in the non-BIG, and the proportion of moderately and severely abnormal aEEG results in the BIG were both significantly higher than those in the non-BIG. The BIG showed significantly higher NSE and S100B levels than those of the non-BIG. The ROC curve for predicting prognosis showed that the AUC of aEEG, NSE, S100B, and the combined detection are 0.780, 0.754, 0.743, 0.788. The AUC > 0.700 indicated a good predictive value for the prognosis. CONCLUSION: The combination of aEEG, NSE, and S100B has good value in diagnosing injury induced by NHB and can predict prognosis moderately well.

Transcriptomic Data Analyses Reveal a Reprogramed Lipid Metabolism in HCV-Derived Hepatocellular Cancer.

Reprograming lipid metabolism, one of the major metabolic alterations in cancer, is believed to play an essential role in cancer development, but the exact molecular mechanism remains elusive. Here, we present a computational study of transcriptomic data of HCC with HCV etiology to investigate how lipid metabolism alters during HCC progression. Our analyses reveal that: (1) cancer tissue cells tend to synthesize fatty acids de novo and its phospholipid derivatives; (2) lipid catabolism and fatty acid oxidation are remarkably down-regulated in HCC; (3) the lipid metabolism in HCC is largely independent of lipids in blood circulation; (4) stage-specific co-expression networks for lipid metabolic genes were identified during HCC progression; and (5) the expression levels of several lipid metabolic genes that are differentially expressed or co-expressed specifically at the HCC stage have a strong correlation with cancer survival. Overall, the results provide detailed information about the reprogramed lipid metabolism in HCV-derived HCC.

Accumulation of synovial fluid CD19+CD24hiCD27+ B cells was associated with bone destruction in rheumatoid arthritis.

Regulatory CD19+CD24hiCD27+ B cells were proved to be numerically decreased and functionally impaired in the peripheral blood (PB) from rheumatoid arthritis (RA), with the potential of converting into osteoclast-priming cells. However, the distribution and function of CD19+CD24hiCD27+ B cells in RA synovial fluid (SF) were unclear. In this study, we investigated whether RA SF CD19+CD24hiCD27+ B cells were increased and associated with bone destruction. We found that the proportion of RA SF CD19+CD24hiCD27+ B cells was increased significantly, and was positively correlated with swollen joint counts, tender joint counts and disease activity. CXCL12, CXCL13, CCL19 contributed to the recruitment of CD19+CD24hiCD27+ B cells in RA SF. Notably, CD19+CD24hiCD27+ B cells in the SF from RA expressed significantly more RANKL compared to OA and that in the PB from RA. Critically, RA CD19+CD24hiCD27+ B cells promoted osteoclast (OC) differentiation in vitro, and the number of OCs was higher in cultures with RA SF CD19+CD24hiCD27+ B cells than in those derived from RA PB. Collectively, these findings revealed the accumulation of CD19+CD24hiCD27+ B cells in SF and their likely contribution to joint destruction in RA. Modulating the status of CD19+CD24hiCD27+ B cells might provide novel therapeutic strategies for RA.

Dynamic Alternative Splicing During Mouse Preimplantation Embryo Development.

The mechanism of alternative pre-mRNA splicing (AS) during preimplantation development is largely unknown. In order to capture the dynamic changes of AS occurring during embryogenesis, we carried out bioinformatics analysis based on scRNA-seq data over the time-course preimplantation development in mouse. We detected numerous previously-unreported differentially expressed genes at specific developmental stages and investigated the nature of AS at both minor and major zygotic genome activation (ZGA). The AS and differential AS atlas over preimplantation development were established. The differentially alternatively spliced genes (DASGs) are likely to be key splicing factors (SFs) during preimplantation development. We also demonstrated that there is a regulatory cascade of AS events in which some key SFs are regulated by differentially AS of their own gene transcripts. Moreover, 212 isoform switches (ISs) during preimplantation development were detected, which may be critical for decoding the mechanism of early embryogenesis. Importantly, we uncovered that zygotic AS activation (ZASA) is in conformity with ZGA and revealed that AS is coupled with transcription during preimplantation development. Our results may provide a deeper insight into the regulation of early embryogenesis.

Remission assessment of rheumatoid arthritis in daily practice in China: a cross-sectional observational study.

The objective of this study is to evaluate the remission rate and describe the current use of medication in a large cohort of rheumatoid arthritis (RA) patients under routine clinical care in China. RA patients were recruited from 40 large teaching hospitals nationwide in China. Data regarding RA disease activity, medication treatment, and adverse events were recorded using a standardized clinical data questionnaire. RA remission was evaluated by the 28 Joint Disease Activity Score DAS28-ESR Clinical Disease Activity Index (CDAI), Simplified Disease Activity Index (SDAI), and American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) remission criteria. A total of 1945 patients with RA were included in the study. The proportions of patients who fulfilled the DAS28-ESR, CDAI, SDAI, and ACR/EULAR remission criteria were 10.90%, 6.17%, 5.04% , and 1.75%, respectively. Most patients had taken at least one disease-modifying anti-rheumatic drug (DMARD), and the most common prescriptions included leflunomide (LEF) and methotrexate (MTX). DMARD combined with botanics were the most common and dominant strategy for RA management (29.16%). Overall, 433 patients (22.27%) had at least one adverse event. Gastrointestinal adverse events (41.27%) were the most frequently reported events. The incidence of side effects in patients using biologics DMARDs (bDMARDs) was significantly lower than that in those taking MTX, LEF, or sulfasalazine (SSZ). The remission rate of RA disease activity, as assessed in Chinese clinical practice, was very low. Adverse effects of the medicine occurred in approximately one in five RA patients, with bDMARDs were demonstrated to be the medication with the lowest side effects.

Evolutionary direction of processed pseudogenes.

While some pseudogenes have been reported to play important roles in gene regulation, little is known about the possible relationship between pseudogene functions and evolutionary process of pseudogenes, or about the forces responsible for the pseudogene evolution. In this study, we characterized human processed pseudogenes in terms of evolutionary dynamics. Our results show that pseudogenes tend to evolve toward: lower GC content, strong dinucleotide bias, reduced abundance of transcription factor binding motifs and short palindromes, and decreased ability to form nucleosomes. We explored possible evolutionary forces that shaped the evolution pattern of pseudogenes, and concluded that mutations in pseudogenes are likely determined, at least partially, by neighbor-dependent mutational bias and recombination-associated selection.

MiasDB: A Database of Molecular Interactions Associated with Alternative Splicing of Human Pre-mRNAs.

Alternative splicing (AS) is pervasive in human multi-exon genes and is a major contributor to expansion of the transcriptome and proteome diversity. The accurate recognition of alternative splice sites is regulated by information contained in networks of protein-protein and protein-RNA interactions. However, the mechanisms leading to splice site selection are not fully understood. Although numerous databases have been built to describe AS, molecular interaction databases associated with AS have only recently emerged. In this study, we present a new database, MiasDB, that provides a description of molecular interactions associated with human AS events. This database covers 938 interactions between human splicing factors, RNA elements, transcription factors, kinases and modified histones for 173 human AS events. Every entry includes the interaction partners, interaction type, experimental methods, AS type, tissue specificity or disease-relevant information, a simple description of the functionally tested interaction in the AS event and references. The database can be queried easily using a web server (http://47.88.84.236/Miasdb). We display some interaction figures for several genes. With this database, users can view the regulation network describing AS events for 12 given genes.

Combinations of Histone Modifications for Pattern Genes.

Histone post-translational modifications play important roles in transcriptional regulation. It is known that multiple histone modifications can act in a combinatorial manner. In this study, we investigated the effects of multiple histone modifications on expression levels of five gene categories (four kinds of pattern genes and non-pattern genes) in coding regions. The combinatorial patterns of modifications for the five gene categories were also studied in the regions. Our results indicated that the differences in the expression levels between any two gene categories were significant. There were some corresponding differences in multiple histone modification levels among the five gene categories. Multiple histone modifications jointly impacted expression levels of every gene category. Four mutual combinations of histone modifications were found and analyzed.

GSK-3ß controls autophagy by modulating LKB1-AMPK pathway in prostate cancer cells.

BACKGROUND: Glycogen synthase kinase 3ß (GSK3B, GSK-3ß) is a multi-functional protein kinase involved in various cellular processes and its activity elevates after serum deprivation. We have shown that inhibition of GSK-3ß activity triggered a profound autophagic response and subsequent necrotic cell death after serum deprivation in prostate cancer cells. In this study, we dissected the mechanisms involved in GSK-3ß inhibition-triggered autophagy. METHODS: Prostate cancer PC-3 and DU145 cells were used in the study. Multiple GSK-3ß specific inhibitors were used including small chemicals TDZD8, Tideglusib, TWS119, and peptide L803-mts. Western blot assay coupled with phospho-specific antibodies were used in detecting signal pathway activation. ATP levels were assessed with ATPLite kit and HPLC methods. Autophagy response was determined by evaluating Microtubule-associated proteins 1A/1B light chain 3B (LC3B) processing and p62 protein stability in Western blot assays. Immunofluorescent microscopy was used to detect LKB1 translocation. RESULTS: Inhibition of GSK-3ß activity resulted in a significant decline of cellular ATP production, leading to a significant increase of AMP/ATP ratio, a strong trigger of AMP-activated protein kinase (AMPK) activation in prostate cancer PC-3 cells. In parallel with increased LC-3B biosynthesis and p62 protein reduction, the classical sign of autophagy induction, AMPK was activated after inhibition of GSK-3ß activity. Further analysis revealed that Liver kinase B1 (LKB1) but not Calcium/calmodulin-dependent protein kinase kinase ß (CaMKKß) is involved in AMPK activation and autophagy induction triggered by GSK-3ß inhibition. Meanwhile, GSK-3ß inhibition promoted LKB1 translocation from nuclear to cytoplasmic compartment and enhanced LKB1 interaction with its regulatory partners Mouse protein-25 (MO25) and STE20-related adaptor (STRAD). CONCLUSIONS: In conclusion, our data suggest that GSK-3ß plays an important role in controlling autophagy induction by modulating the activation of LKB1-AMPK pathway after serum deprivation.

Influence factors on the correlations between expression levels of neighboring pattern genes.

Some genes tend to cluster and be co-expressed. Multiple factors affect gene co-expression. In this study, we investigated the relationships between multiple factors and the correlations of expression levels of neighboring genes, which were divided into four kinds of pattern genes and one type of non-pattern gene. Our results indicate that the correlation between expression levels of neighboring non-pattern genes is related to multiple factors with the exception of transcriptional orientations of neighboring genes. The correlation between expression levels of neighboring specific genes or neighboring repressed genes is likely to be dependent on the co-functions of neighboring genes. The correlation between expression levels of neighboring housekeeping genes is associated with histone modifications in intergenic regions.

[Application of three kinds of non-invasive positive pressure ventilation as a primary mode of ventilation in premature infants with respiratory distress syndrome: a randomized controlled trial].

OBJECTIVE: Non-invasive positive pressure ventilation has increasingly been chosen as the primary ventilation mode in respiratory distress syndrome (RDS) in preterm infants. In order to further understand the application of various non-invasive positive pressure ventilation modes, we compared the advantages and disadvantages of three modes as a primary mode of ventilation in premature infants with RDS. METHOD: From December 2011 to March 2013, 107 preterm infants with RDS who received intubation-pulmonary surfactant (PS) -extubation in our NICU were randomly divided (by means of random number table) into three groups based on the primary mode of ventilation: nasal continuous positive airway pressure [NCPAP, n = 39, male/female ratio was 27/12, mean gestational age (GA) was (32.0 ± 2.1)weeks, mean birth weight (BW) was (1752 ± 457)g], bi-level positive airway pressure [BiPAP, n = 35, male/female ratio was 25/10, GA was (31.4 ± 2.0) weeks, BW was (1530 ± 318) g], and synchronized bi-level positive airway pressure [SBiPAP, n = 33, male/female rate was 25/8, GA was (31.5 ± 2.2) weeks, BW was (1622 ± 447) g]. Ventilation settings including FiO(2) were adjusted according to transcutaneous SPO(2) monitoring or blood gas analysis. Various settings and adverse events were recorded as well. The main parameter was the FiO(2) at 24 h post-positive-pressure ventilation. Statistical analyses were performed using χ(2) test, rank sum test, one-way analysis of variance for least-significant difference value, paired-sample t-test, two related sample Wilcoxon signed rank sum test and Logistic regression. RESULT: The PaCO(2) (mmHg, 1 mmHg = 0.133 kPa), oxygen index (OI) at 12-24 h, and FiO(2) at 24 h post-ventilation in BiPAP and SBiPAP groups were lower than that in NCPAP groups with significant difference (44 ± 9 and 45 ± 9 vs. 50 ± 9, 2.76 ± 0.96 and 2.79 ± 0.60 vs. 3.24 ± 0.72, 0.34 ± 0.10 and 0.35 ± 0.07 vs. 0.39 ± 0.07; F = 4.456, 5.146 and 4.123; P = 0.014, 0.007 and 0.019, respectively). There was no significant difference between BiPAP and SBiPAP groups. There was no significant difference among three groups (all P > 0.05) in the following events: respiratory index (RI) at 12-24 h post-ventilation, abdominal distension, period of non-invasive ventilation, ratio of intubation for invasive ventilation if failed noninvasive ventilation, air-leak syndrome, neonatal necrotizing enterocolitis, periventricular-intraventricular haemorrhage, bronchopulmonary dysplasia, retinopathy of prematurity, mortality rate after 36 h of age or rate of abandon for discharge. The independent risk factors for failure of non-invasive positive pressure ventilation were gender, gestational age, antepartum steroid at 24 h before birth to 7 d, and birth weight, with the OR (95% confidence interval) being 14.120 (1.135, 175.662), 2.862 (1.479, 5.535), 61.084 (3.115, 1 198.031), and 8.306 (1.488, 46.383), respectively. CONCLUSION: As the primary mode of ventilation in premature infants with RDS, both BiPAP and SBiPAP are more beneficial than NCPAP in improving oxygenation and reducing CO(2) retention without increasing the incidence of adverse events.

Sequence-dependent prediction of recombination hotspots in Saccharomyces cerevisiae.

Meiotic recombination does not occur randomly across the genome, but instead occurs at relatively high frequencies in some genomic regions (hotspots) and relatively low frequencies in others (coldspots). Hotspots and coldspots would shed light on the mechanism of recombination, but the accurate prediction of hot/cold spots is still an open question. In this study, we presented a model to predict hot/cold spots in yeast using increment of diversity combined with quadratic discriminant analysis (IDQD) based on sequence k-mer frequencies. 5-fold cross validation showed a total prediction accuracy of 80.3%. Compared with other machine-learning algorithms, IDQD approach is as powerful as random forest (RF) and outperforms support vector machine (SVM) in identifying hotspots and coldspots. We also predicted increased recombination rates in the upstream regions of transcription start sites and in the downstream regions of transcription termination sites. Additionally, genome-wide recombination map in yeast obtained by IDQD model is in close agreement with the experimentally generated map, especially for the Peak locations, although some fine-scale differences exist. Our results highlight the sequence dependency of recombination.

Combinatorial patterns of histone modifications in Saccharomyces cerevisiae.

Histone modification is an important subject of epigenetics that plays an intrinsic role in transcriptional regulation. It has been suggested that multiple histone modifications act in a combinatorial fashion to form a 'histone code'. In this study, the combinatorial patterns of histone modifications were studied by using a Bayesian network at the level of individual nucleosomes in S. cerevisiae. Our results indicated that there were 23 combinatorial patterns for 12 histone modifications investigated when a general Bayesian network was constructed. Meanwhile, different networks were also constructed for the genes with high transcript levels (H-network) and low transcript levels (L-network), respectively. Comparison among the general network, H-network and L-network illustrated four conserved combinations: H2BK16Ac → H3K4me3; H3K14Ac → H3K4me3; H2AK7Ac → H3K14Ac; and H4K12Ac → H3K18Ac. The detailed analysis for some combinations demonstrated that the combinations were ascribed to some histone-modifying enzymes.

Cordyceps sinensis extract suppresses hypoxia-induced proliferation of rat pulmonary artery smooth muscle cells.

OBJECTIVE: To investigate the effects of a Chinese herb Cordyceps sinensis (C. sinensis) extract on hypoxia-induced proliferation and the underlying mechanisms involved. METHODS: This prospective study was carried out at the Central Laboratory of Yichang Central People's Hospital, Yichang, China from March 2008 to April 2010. The C. sinensis was extracted from the Chinese herb C. sinensis using aqueous alcohol extraction techniques. Forty healthy adult male Sprague Dawley rats were used in the study. The proliferation of pulmonary artery smooth muscle cells (PASMCs) was measured using 3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and cell viability was determined by trypan blue exclusion. Cell cycles were analyzed using FACSort flow cytometric analysis. The expression of proliferating cell nuclear antigen (PCNA), c-jun, and c-fos in rat PASMCs was determined by immunohistochemistry. RESULTS: We found an increased proliferation of PASMCs and increased expression of transcription factors, c-jun and c-fos in PASMCs cultured under hypoxic conditions. The C. sinensis extract significantly inhibited hypoxia-induced cell proliferation in a dose-dependent manner. In addition, C. sinensis extract also significantly inhibited the expression of PCNA, c-jun, and c-fos in these PASMCs. CONCLUSION: Our results indicated that C. sinensis extract inhibits hypoxia-induced proliferation of rat PASMCs, probably by suppressing the expression of PCNA, c-fos, c-jun, and decreasing the percentage of cells in synthesis phase, second gap phase, and mitotic phase in cell cycle (S+G2/M) phase. Our results therefore, provided novel evidence that C. sinensis extract may be used as a therapeutic reagent in the treatment of hypoxic pulmonary hypertension.