Angiogenesis plays a pivotal role in the aggressive proliferation of synovial cells in rheumatoid arthritis. We have previously reported the overexpression of inhibitor of DNA binding/differentiation ...(Id) in the endothelial cells within the synovial tissues of rheumatoid arthritis. In this study, we investigated the role of Id in inflammation and angiogenesis in an in vitro model using HUVECs. Vascular endothelial growth factor (VEGF) and TGFbeta induced the expression of Id1 and Id3 in HUVECs. Forced expression of Id induced proliferative activity in HUVECs accompanied by down-regulation of p16INK4a. Overexpression of Id enhanced expression of ICAM-1 and E-selectin, and induced angiogenic processes such as transmigration, matrix metalloproteinase-2 and -9 expression, and tube formation. In contrast, knockdown of Id1 and Id3 with RNA interference abolished proliferation, activation, and angiogenic processes of HUVECs induced by VEGF. These results indicated that Id plays a crucial role in VEGF-induced signals of endothelial cells by causing activation and potentiation of angiogenic processes. Based on these findings, it was proposed that inhibition of expression and/or function of Id1 and Id3 may potentially be of therapeutic value for conditions associated with pathological angiogenesis.
A prognostic system for acute liver failure (ALF) with a higher predictive value is urgently needed. The role of extracellular matrix (ECM) remodeling in ALF has not been fully elucidated. We ...hypothesized that serologic fibrosis markers, which reflect ECM remodeling, are predictive of ALF outcome at first presentation. This observational study included 110 patients with acute liver dysfunction, of which 73 had non‐acetaminophen‐associated ALF (NAA‐ALF). We evaluated serum levels of hyaluronic acid, 7S domain of type IV collagen (4COL7S), and Wisteria floribunda agglutinin‐positive Mac‐2‐binding protein at first presentation to a tertiary center. Serologic fibrosis markers were significantly higher in NAA‐ALF compared with acute hepatitis. Elevated hyaluronic acid and 4COL7S levels at first presentation correlated significantly with worse clinical outcomes. 4COL7S, along with age, ammonia, and the Model for End‐Stage Liver Disease (MELD) score, was a significant prognostic factor in multivariate analysis; 4COL7S correlated significantly with coagulopathy, decreased hepatic synthetic functions, advanced hepatic encephalopathy, and liver atrophy and also predicted 180‐day transplant‐free survival. Cox regression models incorporating 4COL7S with the MELD system had profoundly improved predictive values that significantly surpassed the MELD system alone. Conclusion: Elevation of serologic fibrosis markers reflecting ECM remodeling in NAA‐ALF predicted a worse clinical outcome. Incorporation of 4COL7S at first presentation to a transplant center improves the specificity while retaining the sensitivity of the MELD system. External validation of a fibrosis marker as part of a clinical prediction tool in ALF warrants further investigation.
ECM remodeling is a universal histological phenomenon in non‐acetaminophen‐associated acute liver failure. Elevation of serological fibrosis markers that reflect ECM remodeling predicts a worse clinical outcome.
Aim
Simeprevir (SMV) is a protease inhibitor which demonstrates good tolerability and high antiviral response in patients with hepatitis C. The clinical outcomes of triple therapy using simeprevir, ...pegylated interferon and ribavirin (SMV/PEG IFN/RBV) for recurrent hepatitis C after living donor liver transplantation (LDLT) have not been well reported. In this study, we assessed the outcomes of patients with recurrent hepatitis C (genotype 1) after LDLT who received triple therapy at our hospital.
Methods
SMV/PEG IFN/RBV was administrated for 12 weeks (triple therapy), followed by another 12 weeks or extended period of PEG IFN/RBV (dual therapy). Virological response, interaction with calcineurin inhibitors and adverse events were retrospectively analyzed.
Results
Ten patients with recurrent hepatitis C after LDLT completed 12 weeks of triple therapy. Nine patients achieved rapid or early virological response, and one patient was a non‐responder. The nine responders received subsequent dual therapy, and the duration of dual therapy was extended (24 to 36 weeks) in five cases. Although one patient was in relapse 8 weeks after completing the standard duration (12 weeks) of dual therapy, eight patients achieved sustained virological response for 12 weeks (SVR12). The SVR12 rate was 80%. Trough levels of calcineurin inhibitor did not show marked changes after introduction of SMV in all cases. There were no major adverse events associated with SMV.
Conclusion
SMV treatment may be a safe and effective option for recurrent hepatitis C after LDLT.
The genomes of more than 100 species have been sequenced, and the biological functions of encoded proteins are now actively being researched. Protein function is based on interactions between ...proteins and other molecules. One approach to assuming protein function based on genomic sequence is to predict interactions between an encoded protein and other molecules. As a data source for such predictions, knowledge regarding known protein-small molecule interactions needs to be compiled. We have, therefore, surveyed interactions between proteins and other molecules in Protein Data Bank (PDB), the protein three-dimensional (3D) structure database. Among 20,685 entries in PDB (April, 2003), 4,189 types of small molecules were found to interact with proteins. Biologically relevant small molecules most often found in PDB were metal ions, such as calcium, zinc, and magnesium. Sugars and nucleotides were the next most common. These molecules are known to act as cofactors for enzymes and/or stabilizers of proteins. In each case of interactions between a protein and small molecule, we found preferred amino acid residues at the interaction sites. These preferences can be the basis for predicting protein function from genomic sequence and protein 3D structures. The data pertaining to these small molecules were collected in a database named Het-PDB Navi., which is freely available at http://daisy.nagahama-i-bio.ac.jp/golab/hetpdbnavi.html and linked to the official PDB home page.
Understanding how neural systems encode and coordinate behavior requires the ability to record multi-neuronal activity in freely behaving animals. This dissertation focuses on developing advanced ...imaging techniques to overcome the challenges associated with imaging in unrestrained organisms, particularly in larval Drosophila melanogaster, whose deforming brains present unique challenges.A new tracking microscope is developed using acousto-optic deflectors (AODs) and an acoustic GRIN lens (TAG lens) to achieve axially resonant random access scanning. This microscope offers rapid axial scanning rates ( 70kHz) with a minimal latency of 0.1 ms. This technology facilitates the recording of neural activities across a range of neurons within the moving larval central nervous system (CNS) and ventral nerve cord (VNC). These encompass premotor neurons, bilateral visual interneurons, and descending command neurons. This technique allows for fast 3D tracking and scanning, providing valuable insights into the neural dynamics during behavior.This work also presents a method to compensate for the spatial and temporal dispersions introduced by AODs. This method only utilizes off-the-shelf components, including a transmission grating and a telescope. The compact design corrects for distortions by tuning the GDD based on the translation of the telescope without adjustment of any other elements.Furthermore, an alternative method is developed to expand the capabilities of the tracking microscope by incorporating two excitation beams. This approach enables simultaneous tracking and imaging of a volume of the brain, providing a comprehensive view of neural activity in densely labeled neurons and neuropils.The dissertation demonstrates the potential of these new tracking and imaging techniques in recording the activity of multiple neurons and neuropils in the squishy brain of small transparent animals. These advancements facilitate investigations into neural network activity and contribute to a deeper understanding of the neural correlates of behavior.
Spinel Li4Ti5O12 thin films were prepared by a mist CVD process, using an aqueous solution of lithium nitrate and a water-soluble titanium lactate complex as the source of Li and Ti, respectively. In ...this process, mist particles ultrasonically atomized from a source aqueous solution were transferred by nitrogen gas to a heating substrate to prepare thin films. Scanning electron microscopy observation showed that thin films obtained by this process were dense and smooth, and thin films with a thickness of about 500nm were obtained. In the X-ray diffraction analysis, formation of Li4Ti5O12 spinel phase was confirmed in the obtained thin film sintered at 700°C for 4h. The cell with the thin films as an electrode exhibited a capacity of about 110mAhg−1, and the cell showed good cycling performance during 10 cycles.
Alternative splicing is a molecular mechanism that produces multiple proteins from a single gene, and is thought to produce variety in proteins translated from a limited number of genes. Here we ...analyzed how alternative splicing produced variety in protein structure and function, by using human full-length cDNAs on the assumption that all of the alternatively spliced mRNAs were translated to proteins. We found that the length of alternatively spliced amino acid sequences, in most cases, fell into a size shorter than that of average protein domain. We evaluated comprehensively the presumptive three-dimensional structures of the alternatively spliced products to assess the impact of alternative splicing on gene function. We found that more than half of the products encoded proteins which were involved in signal transduction, transcription and translation, and more than half of alternatively spliced regions comprised interaction sites between proteins and their binding partners, including substrates, DNA/RNA, and other proteins. Intriguingly, 67% of the alternatively spliced isoforms showed significant alterations to regions of the protein structural core, which likely resulted in large conformational change. Based on those findings, we speculate that there are a large number of cases that alternative splicing modulates protein networks through significant alteration in protein conformation.
β‐Catenin, a multifunctional protein related to the adherens junction and to signal transduction, is a key molecule of cell proliferation, and it is central to epithelial architecture, regulating the ...polarity of cells and tissues. β‐Catenin stabilization may play a key role in epidermal signaling leading to hair development, and its aberrant activation may be implicated in formation of hair tumors. Several investigators have shown that pilomatricomas are frequently associated with β‐catenin mutation. In this study, we confirmed β‐catenin gene (CTNNB1) mutation in human pilomatricomas (100% frequency) from which adequate DNA could be obtained for gene analysis. A novel mutation, D32N, was found in one case of pilomatricoma. A preliminary immunohistological study revealed prominent β‐catenin staining in basophilic cells of pilomatricomas, especially in nuclei. Benign tumors which were considered to be derived from hair matrix or hair follicles, and other benign skin tumors, were also investigated. β‐Catenin mutations were not detected in any of the these tumors. These results seem to indicate that hair matrix cells are key players in hair development. Investigation into gene abnormalities of hair‐follicle tumors may elucidate the cause of their neoplastic transformation, and may provide a suggestion for the mechanism of hair development.
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