Dynamic contrast-enhanced MRI of ocular biotransport in normal and hypertensive eyes

Proceedings of the IEEE Engineering in Medicine and Biology Society Conference, 2008, p. 835-838This study aims to employ in vivo dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to evaluate the ocular transport following an induction of ocular hypertension in a rat model of chronic glaucoma. Upon systemic administration of Gd-DTPA solution, T1-weighted signal increase was observed in the vitreous body of the glaucomatous eye but not the control eye. This increase occurred earlier in the anterior vitreous body than the preretinal vitreous. Further, there was an earlier Gd-DTPA transport into the anterior chamber in the majority of glaucomatous eyes. Our DCE-MRI findings revealed the leakage of Gd-DTPA at the aqueous-vitreous interface, which was likely resulted from increased permeability of blood-aqueous or aqueous-vitreous barrier. These may explain the sources of changing biochemical compositions in the chamber components, which may implicate the neurodegenerative processes in the glaucomatous visual components. © 2008 IEEE.published_or_final_versio

Combined effect of brain-derived neurotrophic factor and LINGO-1 fusion protein on long-term survival of retinal ganglion cells in chronic glaucoma

Glaucoma is a progressive neuropathy characterized by loss of vision as a result of retinal ganglion cell (RGC) death. There are no effective neuroprotectants to treat this disorder. Brain-derived neurotrophic factor (BDNF) is well known to transiently delay RGC death in ocular hypertensive eyes. The CNS-specific leucine-rich repeat protein LINGO-1 contributes to the negative regulation to some trophic pathways. We thereby examined whether BDNF combined with LINGO-1 antagonists can promote long-term RGC survival after ocular hypertension. In this study, intraocular pressure was elevated in adult rats using an argon laser to photocoagulate the episcleral and limbal veins. BDNF alone shows slight neuroprotection to RGCs after a long-term progress of 4 weeks following the induction of ocular hypertension. However, combination of BDNF and LINGO-1-Fc prevents RGC death in the same condition. We further identified that (1) LINGO-1 was co-expressed with BDNF receptor, TrkB in the RGCs, and (2) BDNF combined with LINGO-1-Fc activated more TrkB in the injured retina compared to BDNF alone. These results indicate that the combination of BDNF with LINGO-1 antagonist can provide long-term protection for RGCs in a chronic ocular hypertension model. TrkB may be the predominant mediator of this neuroprotection. © 2009 IBRO.postprin

miR-375 suppresses IGF1R expression and contributes to inhibition cell progression in laryngeal squamous cell carcinoma

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EZH2 protein: A promising immunomarker for the detection of hepatocellular carcinomas in liver needle biopsies

Background and aims: A previous study of ours indicated that enhancer of zeste homologue 2 (EZH2) plays an important role in hepatocellular carcinoma (HCC) tumorigenesis. The aim of the present study was to investigate the potential diagnostic utility of EZH2 in HCC. Methods: Immunohistochemistry was performed to examine the expression dynamics of EZH2 in two independent surgical cohorts of HCC and non-malignant liver tissues to develop a diagnostic yield of EZH2, HSP70 and GPC3 for HCC detection. The diagnostic performances of EZH2 and a three-marker panel in HCC were re-evaluated by using an additional biopsy cohort. Results: Immunohistochemistry analysis demonstrated that the sensitivity and specificity of EZH2 for HCC detection was 95.8% and 97.8% in the testing cohort. Similar results were confirmed in the validation cohort. For diagnosis of well-differentiated HCCs, the sensitivity and specificity were 68.9% and 91.5% for EZH2, 62.5% and 98.5% for HSP70, 50.0% and 92.1% for GPC3, and 75.0% and 100% for a three-marker panel. In biopsies, positive cases for at least one marker increased from large regenerative nodule and hepatocellular adenoma (0/12) to focal nodular hyperplasia (2/20), dysplastic nodule (7/25), well-differentiated HCC (16/18) and moderately and poorly differentiated HCC (54/54). When at least two positive markers were considered, regardless of their identity, the positive cases were detected in 0/12 large regenerative nodules and hepatocellular adenomas, 0/20 focal nodular hyperplasias, 0/25 dysplastic nodules, 11/18 well-differentiated HCCs, 32/37 moderately differentiated HCCs and 15/17 poorly differentiated HCCs. Conclusion: Our findings suggest that EZH2 protein, as examined by immunohistochemistry, may serve as a promising diagnostic biomarker of HCCs, and the use of a three-marker panel (EZH2, HSP70 and GPC3) can improve the rate of detection of HCCs in liver biopsy tissues.published_or_final_versio

Targeted Skipping of Human Dystrophin Exons in Transgenic Mouse Model Systemically for Antisense Drug Development

Antisense therapy has recently been demonstrated with great potential for targeted exon skipping and restoration of dystrophin production in cultured muscle cells and in muscles of Duchenne Muscular Dystrophy (DMD) patients. Therapeutic values of exon skipping critically depend on efficacy of the drugs, antisense oligomers (AOs). However, no animal model has been established to test AO targeting human dystrophin exon in vivo systemically. In this study, we applied Vivo-Morpholino to the hDMD/mdx mouse, a transgenic model carrying the full-length human dystrophin gene with mdx background, and achieved for the first time more than 70% efficiency of targeted human dystrophin exon skipping in vivo systemically. We also established a GFP-reporter myoblast culture to screen AOs targeting human dystrophin exon 50. Antisense efficiency for most AOs is consistent between the reporter cells, human myoblasts and in the hDMD/mdx mice in vivo. However, variation in efficiency was also clearly observed. A combination of in vitro cell culture and a Vivo-Morpholino based evaluation in vivo systemically in the hDMD/mdx mice therefore may represent a prudent approach for selecting AO drug and to meet the regulatory requirement

Prediction of migratory routes of the invasive fall armyworm in eastern China using a trajectory analytical approach

This is the author accepted manuscript. The final version is available from Wiley via the DOI in this record BACKGROUND: The fall armyworm (FAW), an invasive pest from the Americas, is rapidly spreading through the Old World, and has recently invaded the Indochinese Peninsula and southern China. In the Americas, FAW migrates from winter-breeding areas in the south into summer-breeding areas throughout North America where it is a major pest of corn. Asian populations are also likely to evolve migrations into the corn-producing regions of eastern China, where they will pose a serious threat to food security. RESULTS: To evaluate the invasion risk in eastern China, the rate of expansion and future migratory range was modelled by a trajectory simulation approach, combined with flight behavior and meteorological data. Our results predict that FAW will migrate from its new year-round breeding regions into the two main corn-producing regions of eastern China (Huang-Huai-Hai Summer Corn and Northeast Spring Corn Regions), via two pathways. The western pathway originates in Myanmar and Yunnan, and FAW will take four migration steps (i.e. four generations) to reach the Huang-Huai-Hai Region by July. Migration along the eastern pathway from Indochina and southern China progresses faster, with FAW reaching the Huang-Huai-Hai Region in three steps by June and reaching the Northeast Spring Region in July. CONCLUSION: Our results indicate that there is a high risk that FAW will invade the major corn-producing areas of eastern China via two migration pathways, and cause significant impacts to agricultural productivity. Information on migration pathways and timings can be used to inform integrated pest management strategies for this emerging pest.Biotechnology & Biological Sciences Research Council (BBSRC)CABI Bioscienc

Superlattice in austenitic Ni-Mn-Ga shape memory microwires

The link between microstructure evolution, micromodulated domain and the structure transformation of Ni-Mn-Ga shape memory microwires prepared with rapid solidification is studied systematically by TEM and HRTEM. Multiple microdomain structures are determined according to the corresponding diffraction spots. The domain structure with a periodic distortion is a kind of characteristic of premartensitic phase. When cooling below the martensitic transformation temperature, the austenitic phase transforms to modulated 5M martensite, and the sequence of phase transformation can finally be confirmed from austenite to premartensite to 5M martensite during cooling. The characterization of micromodulated domain and the structure characteristics of austenite at atomic scale provide comprehensive understanding on the martensitic phase transformation route. (C) 2018 Published by Elsevier B.V.</p

Notch signaling during human T cell development

Notch signaling is critical during multiple stages of T cell development in both mouse and human. Evidence has emerged in recent years that this pathway might regulate T-lineage differentiation differently between both species. Here, we review our current understanding of how Notch signaling is activated and used during human T cell development. First, we set the stage by describing the developmental steps that make up human T cell development before describing the expression profiles of Notch receptors, ligands, and target genes during this process. To delineate stage-specific roles for Notch signaling during human T cell development, we subsequently try to interpret the functional Notch studies that have been performed in light of these expression profiles and compare this to its suggested role in the mouse

XIAP impairs Smac release from the mitochondria during apoptosis

X-linked inhibitor of apoptosis protein (XIAP) is a potent inhibitor of caspases 3, 7 and 9, and mitochondrial Smac (second mitochondria-derived activator of caspase) release during apoptosis inhibits the activity of XIAP. In this study we show that cytosolic XIAP also feeds back to mitochondria to impair Smac release. We constructed a fluorescent XIAP-fusion protein by labelling NH2- and COOH-termini with Cerulean fluorescent protein (C-XIAP-C). Immunoprecipitation confirmed that C-XIAP-C retained the ability to interact with Smac and impaired extrinsically and intrinsically activated apoptosis in response to tumour necrosis factor-related apoptosis-inducing ligand/cycloheximide and staurosporine. In C-XIAP-C-expressing cells, cytochrome c release from mitochondria proceeded normally, whereas Smac release was significantly prolonged and incomplete. In addition, physiological expression of native XIAP prolonged or limited Smac release in HCT-116 colon cancer cells and primary mouse cortical neurons. The Smac-binding capacity of XIAP, but not caspase inhibition, was central for mitochondrial Smac retention, as evidenced in experiments using XIAP mutants that cannot bind to Smac or effector caspases. Similarly, the release of a Smac mutant that cannot bind to XIAP was not impaired by C-XIAP-C expression. Full Smac release could however be provoked by rapid cytosolic C-XIAP-C depletion upon digitonin-induced plasma membrane permeabilization. Our findings suggest that although mitochondria may already contain pores sufficient for cytochrome c release, elevated amounts of XIAP can selectively impair and limit the release of Smac

Generation of Germline-Competent Rat Induced Pluripotent Stem Cells

Recent progress in rat pluripotent stem cell technology has been remarkable. Particularly salient is the demonstration that embryonic stem cells (ESCs) in the rat (rESCs) can contribute to germline transmission, permitting generation of gene-modified rats as is now done using mouse ESCs (mESCs) or mouse induced pluripotent stem cells (iPSCs; miPSCs). However, determinations of whether rat iPSCs (riPSCs) can contribute to germ cells are not published. Here we report the germline competency of riPSCs.We generated riPSCs by transducing three mouse reprogramming factors (Oct3/4, Klf4, and Sox2) into rat somatic cells, followed by culture in the presence of exogenous rat leukemia inhibitory factor (rLIF) and small molecules that specifically inhibit GSK3, MEK, and FGF receptor tyrosine kinases. We found that, like rESCs, our riPSCs can contribute to germline transmission. Furthermore we found, by immunostaining of testis from mouse-rat interspecific chimeras with antibody against mouse vasa homolog, that riPSCs can contribute to embryonic development with chimera formation in mice (rat-mouse interspecific chimeras) and to interspecific germlines.Our data clearly demonstrate that using only three reprogramming factors (Oct3/4, Klf4, and Sox2) rat somatic cells can be reprogrammed into a ground state. Our generated riPSCs exhibited germline transmission in either rat-rat intraspecific or mouse-rat interspecific chimeras