Publications by authors named "Minhua Wang"

32 Publications

Fine-Needle Aspiration Biopsy of Intraocular Mass-like Lesions.

Am J Clin Pathol 2021 Feb 20. Epub 2021 Feb 20.

Department of Pathology, Yale University School of Medicine, New Haven, CT, USA.

Objectives: The purpose of this study was to evaluate the diagnostic performance of fine-needle aspiration (FNA) biopsy for intraocular mass-like lesions and its contributing factors.

Methods: Intraocular FNA cases were retrieved and reviewed along with histopathologic follow-ups, if available. The effects of rapid on-site evaluation (ROSE), repeated biopsy, and adjunct immunocytochemical studies on cytologic diagnoses were analyzed.

Results: Of 72 FNA biopsies from 63 patients, nondiagnostic biopsy was seen in 17 cases (24%), whereas a definitive diagnosis was rendered in 39 cases (54%). The cytologic diagnoses correlated well with histopathologic follow-ups with a concordance rate of 61%. Almost all nondiagnostic biopsies (16/17, 94%) were seen in cases in which ROSE was not performed. Of the 7 patients in whom biopsy was repeated, a definitive diagnosis was rendered in 4 cases (57%). Immunocytochemistry was performed in the majority of cases with a malignant diagnosis, especially in metastatic tumors (75%).

Conclusions: Our data demonstrates that FNA is an effective tool for the diagnosis of intraocular tumors. ROSE, repeated biopsy, and adjunct immunocytochemistry can help reduce the nondiagnostic rate and/or enhance diagnosis of malignancy, further improving FNA diagnostic performance.
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http://dx.doi.org/10.1093/ajcp/aqaa235DOI Listing
February 2021

Formation environments and mechanisms of multistage paleokarst of Ordovician carbonates in Southern North China Basin.

Sci Rep 2021 Jan 12;11(1):819. Epub 2021 Jan 12.

Department of Geology and Hydrogeology, Huaihe Energy Holding Group Co., Ltd., Huainan, 232001, China.

With the reduction of oil and gas reserves and the increase of mining difficulty in Northern China, the carbonate rocks in Southern North China Basin are becoming a significant exploration target for carbonate reservoirs. However, the development characteristics, formation stages, formation environments and mechanisms of the carbonate reservoirs in Southern North China Basin are still unclear, which caused the failures of many oil and gas exploration wells. This study focused on addressing this unsolved issue from the Ordovician carbonate paleokarst in the Huai-Fu Basin, which is located in the southeast of Southern North China Basin and one of the key areas for oil and gas exploration. Based on petrology, mineralogy and geochemical data, pore types, distribution characteristics, and formation stages of the Ordovician paleokarst were analyzed. Then, in attempt to define the origins of porosity development, the formation environments and mechanisms were illustrated. The results of this study showed that pore types of the Ordovician carbonates in the Huai-Fu Basin are mainly composed of intragranular pores, intercrystalline (intergranular) pores, dissolution pores (vugs), fractures, channels, and caves, which are usually in fault and fold zones and paleoweathering crust. Furthermore, five stages and five formation environments of the Ordovician paleokarst were identified. Syngenetic karst, eogenetic karst, and paleoweathering crust karst were all developed in a relatively open near-surface environment, and their formations are mainly related to meteoric water dissolution. Mesogenetic karst was developed in a closed buried environment, and its formation is mainly related to the diagenesis of organic matters and thermochemical sulfate reduction in the Permian-Carboniferous strata. Hydrothermal (water) karst was developed in a deep-buried and high-temperature environment, where hydrothermal fluids (waters) migrated upward through structures such as faults and fractures to dissolve carbonate rocks and simultaneously deposited hydrothermal minerals and calcites. Lastly, a paleokarst evolution model, combined with the related porosity evolution processes, nicely revealed the Ordovician carbonate reservoir development. This study provides insights and guidance for further oil and gas exploration in the Southern North China Basin, and also advances our understanding of the genesis of carbonate paleokarst around the world.
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http://dx.doi.org/10.1038/s41598-020-80878-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804134PMC
January 2021

Standardized Method for Defining a 1-mm2 Region of Interest for Calculation of Mitotic Rate on Melanoma Whole Slide Images.

Arch Pathol Lab Med 2021 Jan 8. Epub 2021 Jan 8.

From the Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston.

Context.—: Mitotic rate counting is essential in pathologic evaluations in melanoma. The American Joint Committee on Cancer recommends reporting the number of mitotic figures (MFs) in a 1-mm2 area encompassing the "hot spot." There is currently no standard procedure for delineating a 1-mm2 region of interest for MF counting on a digital whole slide image (WSI) of melanoma.

Objective.—: To establish a standardized method to enclose a 1-mm2 region of interest for MF counting in melanoma based on WSIs and assess the method's effectiveness.

Design.—: Whole slide images were visualized using the ImageScope viewer (Aperio). Different monitors and viewing magnifications were explored and the annotation tools provided by ImageScope were evaluated. For validation, we compared mitotic rates obtained from WSIs with our method and those from glass slides with traditional microscopy with 30 melanoma cases.

Results.—: Of the monitors we examined, a 32-inch monitor with 3840 × 2160 resolution was optimal for counting MFs within a 1-mm2 region of interest in melanoma. When WSIs were viewed in the ImageScope viewer, ×10 to ×20 magnification during screening could efficiently locate a hot spot and ×20 to ×40 magnification during counting could accurately identify MFs. Fixed-shape annotations with 500 × 500-μm squares or circles can precisely and efficiently enclose a 1-mm2 region of interest. Our method on WSIs was able to produce a higher mitotic rate than with glass slides.

Conclusions.—: Whole slide images may be used to efficiently count MFs. We recommend fixed-shape annotation with 500 × 500-μm squares or circles for routine practice in counting MFs for melanoma.
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http://dx.doi.org/10.5858/arpa.2020-0137-OADOI Listing
January 2021

Pitfalls of FNA diagnosis of thymic tumors.

Cancer Cytopathol 2020 01 19;128(1):57-67. Epub 2019 Nov 19.

Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Background: Fine-needle aspiration (FNA), a minimally invasive and cost-effective procedure, often is used in the initial diagnosis of thymic lesions. However, the diagnosis can be challenging. Knowledge of the diagnostic pitfalls is important to improve diagnostic accuracy.

Methods: The authors retrospectively searched the pathology database of The University of Texas MD Anderson Cancer Center for FNA cases using the keywords "thymoma" or "thymic" in cytologic diagnoses or in corresponding final histologic diagnoses rendered from January 2002 to June 2018. The authors reviewed the FNA diagnostic accuracy and pitfalls in comparison with the final histologic diagnoses.

Results: A total of 118 FNA cases were identified from 115 patients. The FNA diagnoses were concordant with the final pathologic diagnoses in 110 cases (93.2%), including thymoma (97 cases), atypical thymoma (5 cases), and thymic carcinoma (8 cases). Discrepant FNA and final diagnoses were noted in 8 tumors (6.8%): thymoma versus atypical thymoma/thymic carcinoma (3 tumors), thymoma versus lymphoma (2 tumors), suspicious for lymphoma versus thymoma (1 tumor), and T-lymphoblastic lymphoma versus thymoma (2 tumors). Factors contributing to misinterpretation included intrinsic limitations of the FNA sample (sampling error and a lack of histologic architecture information) and similarities of the cytologic and immunophenotypic features of lymphocyte-rich thymoma and T-lymphoblastic lymphoma.

Conclusions: An accurate FNA diagnosis of thymic tumors can be rendered in the majority of cases. Diagnostic pitfalls can be encountered in rare cases. It is important to handle each case carefully to avoid erroneous diagnoses that may lead to inappropriate treatment.
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http://dx.doi.org/10.1002/cncy.22211DOI Listing
January 2020

Expression of Epithelial-Mesenchymal Transition Markers in Treated Pancreatic Ductal Adenocarcinoma.

Pancreas 2019 Nov/Dec;48(10):1367-1372

From the Departments of Anatomical Pathology.

Objectives: Epithelial-mesenchymal transition (EMT) plays an important role in the progression, metastasis, and chemoresistance of pancreatic duct adenocarcinoma (PDAC); however, the expression of EMT markers and their clinical significance in PDAC patients who received neoadjuvant therapy (NAT) are unclear.

Methods: We examined the expression of EMT markers, including Zeb-1 (zinc finger E-box-binding homeobox 1), E-cadherin, and vimentin by immunohistochemistry in 120 PDAC patients who received NAT and pancreatectomy from 1999 to 2007. The results were correlated with clinicopathologic parameters and survival.

Results: Among 120 cases, 45 (37.5%) and 14 (11.7%) were positive for Zeb-1 and vimentin, respectively, and 25 (20.8%) were E-cadherin-low. The median overall survival and disease-free survival were 35.3 (standard deviation [SD], 2.8) and 15.9 (SD, 3.6) months, respectively, in vimentin-negative group compared with 16.1 (SD, 1.1) (P = 0.03) and 7.0 (SD, 1.1) months (P = 0.02) in the vimentin-positive group. In multivariate analysis, vimentin expression was an independent predictor of shorter disease-free survival (hazard ratio, 2.50; 95% confidence interval, 1.31-4.78; P = 0.016) and overall survival (hazard ratio, 2.55; 95% confidence interval, 1.33-4.89; P = 0.01).

Conclusions: Epithelial-mesenchymal transition markers are frequently expressed in treated PDAC. Vimentin expression is a prognostic biomarker for survival in PDAC patients who received NAT.
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http://dx.doi.org/10.1097/MPA.0000000000001432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944196PMC
September 2020

Study on eccentricity effects of the rod-pinch diode radiography source.

Rev Sci Instrum 2019 Feb;90(2):023304

Institute of Fluid Physics, China Academy of Engineering Physics, Mian Yang 621999, China and Key Laboratory of Pulsed Power, Institute of Fluid Physics, Mian Yang 621999, China.

The rod pinch diode (RPD) is a cylindrical pinched beam diode that generates intense pulsed bremsstrahlung X-ray radiation with a small diameter. In practice, the anode and cathode structures of the RPD may be eccentric due to the mechanical deformation and mounting errors. In theory, this eccentricity changes the physical characteristics of the RPD, which in turn affects the X-ray production. To study the performance variation induced by eccentric electrodes, the electrode concentricity evaluation system is used to quantify the concentricity of the anode and cathode. Then a series of experiments are carried out with different concentricity deviations, and the electrical performance, the radiation dose, and the X-ray pulse signal among different shots are analyzed. These results have shown that, within a certain eccentricity range, the overall performances of the RPD, including the diode impedance and the X-ray production, change very little. Going beyond this range, the average impedance decay rate increases significantly, resulting in accelerated impedance collapse and shortened voltage pulse width. Consequently, X-ray dose distribution and the X-ray pulse width are both reduced. These results are helpful in understanding the RPD characteristics from a different perspective as well as providing a method to determine the designing and mounting criteria of the electrodes of rod-pinch diode.
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http://dx.doi.org/10.1063/1.5053739DOI Listing
February 2019

Mechanisms of PKA-Dependent Potentiation of Kv7.5 Channel Activity in Human Airway Smooth Muscle Cells.

Int J Mol Sci 2018 Jul 30;19(8). Epub 2018 Jul 30.

Department of Molecular Pharmacology & Therapeutics, Loyola University Chicago, Maywood, IL 60153, USA.

β-adrenergic receptor (βAR) activation promotes relaxation of both vascular and airway smooth muscle cells (VSMCs and ASMCs, respectively), though the signaling mechanisms have not been fully elucidated. We previously found that the activity of Kv7.5 voltage-activated potassium channels in VSMCs is robustly enhanced by activation of βARs via a mechanism involving protein kinase A (PKA)-dependent phosphorylation. We also found that enhancement of Kv7 channel activity in ASMCs promotes airway relaxation. Here we provide evidence that Kv7.5 channels are natively expressed in primary cultures of human ASMCs and that they conduct currents which are robustly enhanced in response to activation of the βAR/cyclic adenosine monophosphate (cAMP)/PKA pathway. MIT Scansite software analysis of putative PKA phosphorylation sites on Kv7.5 identified 8 candidate serine or threonine residues. Each residue was individually mutated to an alanine to prevent its phosphorylation and then tested for responses to βAR activation or to stimuli that elevate cAMP levels. Only the mutation of serine 53 (S53A), located on the amino terminus of Kv7.5, significantly reduced the increase in Kv7.5 current in response to these stimuli. A phospho-mimic mutation (S53D) exhibited characteristics of βAR-activated Kv7.5. Serine-to-alanine mutations of 6 putative PKA phosphorylation sites on the Kv7.5 C-terminus, individually or in combination, did not significantly reduce the enhancement of the currents in response to forskolin treatment (to elevate cAMP levels). We conclude that phosphorylation of S53 on the amino terminus of Kv7.5 is essential for PKA-dependent enhancement of channel activity in response to βAR activation in vascular and airway smooth muscle cells.
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http://dx.doi.org/10.3390/ijms19082223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6121446PMC
July 2018

Growth Hormone Mediates Its Protective Effect in Hepatic Apoptosis through Hnf6.

PLoS One 2016 9;11(12):e0167085. Epub 2016 Dec 9.

Department of Surgery/Pediatric Surgery, U of Illinois College of Medicine, Peoria, IL, United States of America.

Background And Aims: Growth hormone (GH) not only supports hepatic metabolism but also protects against hepatocyte cell death. Hnf6 (or Oc1) belonging to the Onecut family of hepatocyte transcription factors known to regulate differentiated hepatic function, is a GH-responsive gene. We evaluate if GH mediates Hnf6 activity to attenuate hepatic apoptotic injury.

Methods: We used an animal model of hepatic apoptosis by bile duct ligation (BDL) with Hnf6 -/- (KO) mice in which hepatic Hnf6 was conditionally inactivated. GH was administered to adult wild type WT and KO mice for the 7 days of BDL to enhance Hnf6 expression. In vitro, primary hepatocytes derived from KO and WT liver were treated with LPS and hepatocyte apoptosis was assessed with and without GH treatment.

Results: In WT mice, GH treatment enhanced Hnf6 expression during BDL, inhibited Caspase -3, -8 and -9 responses and diminished hepatic apoptotic and fibrotic injury. GH-mediated upregulation of Hnf6 expression and parallel suppression of apoptosis and fibrosis in WT BDL liver were abrogated in KO mice. LPS activated apoptosis and suppressed Hnf6 expression in primary hepatocytes. GH/LPS co-treatment enhanced Hnf6 expression with corresponding attenuation of apoptosis in WT-derived hepatocytes, but not in KO hepatocytes. ChiP-on-ChiP and electromobility shift assays of KO and WT liver nuclear extracts identified Ciap1 (or Birc2) as an Hnf6-bound target gene. Ciap1 expression patterns closely follow Hnf6 expression in the liver and in hepatocytes.

Conclusion: GH broad protective actions on hepatocytes during liver injury are effected through Hnf6, with Hnf6 transcriptional activation of Ciap1 as an underlying molecular mediator.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0167085PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5147851PMC
July 2017

Metastatic colon cancer from extrahepatic cholangiocarcinoma presenting as painless jaundice: case report and literature review.

J Gastrointest Oncol 2016 Apr;7(2):E25-30

1 Department of Surgery, 2 Department of Pathology, University at Buffalo School of Medicine, 3 Department of Gastroenterology, Buffalo General Medical Center, Buffalo, NY, USA ; 4 Department of Surgery, Jersey Shore University Medical Center, Neptune, NJ 07753, USA.

Cholangiocarcinoma (CCA) is a rare cancer of the biliary epithelium comprising only about 3% of all gastrointestinal malignancies. It is a highly aggressive malignancy and confers a dismal prognosis with majority of patients presenting with metastatic disease. Metastatic CCA to the colon is extremely rare with only few cases reported in the literature. We present a 61-year-old patient with incidental synchronous metastatic colonic adenocarcinoma from extra-hepatic CCA. Laboratory data revealed significant indirect hyperbilirubinemia and transaminitis. Imaging study showed intrahepatic bile ducts prominence without mass lesions. Incidentally, there was diffuse colonic thickening without mass lesions or obstruction. Endoscopic retrograde cholangiopancreatography (ERCP) showed a common bile duct stricture. Brushings were consistent with CCA. Screening colonoscopy identified nodularity and biopsy and immunostaining were consistent with CCA metastasis to colon. The patient elected for palliative and comfort care. Metastatic CCA to the colon is a rare pattern of distant spread that may pose a diagnostic challenge. Some salient characteristics may assist in the differentiation of primary colon cancer and metastatic colon cancer from CCA. Little remains known about the pathogenic behavior of metastatic secondary colorectal cancer. And more so, the management approach to such metastatic cancer still remains to be defined. Screening colonoscopy in patients presenting with resectable CCA may alter management. Furthermore, whether patients with history of resected CCA may benefit from a more frequent screening colonoscopy remains to be validated.
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http://dx.doi.org/10.3978/j.issn.2078-6891.2015.119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4783741PMC
April 2016

Requirement for Microglia for the Maintenance of Synaptic Function and Integrity in the Mature Retina.

J Neurosci 2016 Mar;36(9):2827-42

Unit on Neuron-Glia Interactions in Retinal Disease,

Unlabelled: Microglia, the principal resident immune cell of the CNS, exert significant influence on neurons during development and in pathological situations. However, if and how microglia contribute to normal neuronal function in the mature uninjured CNS is not well understood. We used the model of the adult mouse retina, a part of the CNS amenable to structural and functional analysis, to investigate the constitutive role of microglia by depleting microglia from the retina in a sustained manner using genetic methods. We discovered that microglia are not acutely required for the maintenance of adult retinal architecture, the survival of retinal neurons, or the laminar organization of their dendritic and axonal compartments. However, sustained microglial depletion results in the degeneration of photoreceptor synapses in the outer plexiform layer, leading to a progressive functional deterioration in retinal light responses. Our results demonstrate that microglia are constitutively required for the maintenance of synaptic structure in the adult retina and for synaptic transmission underlying normal visual function. Our findings on constitutive microglial function are relevant in understanding microglial contributions to pathology and in the consideration of therapeutic interventions that reduce or perturb constitutive microglial function.

Significance Statement: Microglia, the principal resident immune cell population in the CNS, has been implicated in diseases in the brain and retina. However, how they contribute to the everyday function of the CNS is unclear. Using the model of the adult mouse retina, we examined the constitutive role of microglia by depleting microglia from the retina. We found that in the absence of microglia, retinal neurons did not undergo overt cell death or become structurally disorganized in their processes. However, connections between neurons called synapses begin to break down, leading to a decreased ability of the retina to transmit light responses. Our results indicate that retinal microglia contribute constitutively to the maintenance of synapses underlying healthy vision.
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http://dx.doi.org/10.1523/JNEUROSCI.3575-15.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879218PMC
March 2016

[Genome-wide analysis of HSP70 superfamily in Gossypium raimondii and the expression of orthologs in Gossypium hirsutum].

Yi Chuan 2014 Sep;36(9):921-33

The Key Laboratory for Quality Improvement of Agricultural Products of Zhejiang Province, School of Agriculture and Food Science, Zhejiang Agricultural and Forestry University, Lin'an 311300, China; Institute of Cotton Research, Chinese Academy of Agricultural Sciences, State Key Laboratory of Cotton Biology, Anyang 455000, China.

Heat shock 70 (HSP70) proteins are highly conserved molecular chaperones widely existed in the plant kingdom which are involved in cellular protein folding process. In this study, comprehensive evolutionary analyses of the Gossypium raimondii HSP70 gene family members are conducted and 30 HSP70 genes are identified. The gene structure, chromosome distribution, gene duplication and phylogenic evolution of this family are further analyzed. The results reveal that HSP70 family genes can be clustered into several major subgroups based on their sub-cellular locations, and the gene structures are relatively conserved in each subgroup. Both tandem duplications and chromosome segmental duplications are found to contribute to the expansion of HSP70 gene family. Evolutionary analysis of HSP70s in diverse species reveals that the differentiation of HSP70 subgroups occurred before the multi-cell and single-cell differentiation, with the cytoplasmic HSP70s multiple amplified. The expression pattern of HSP70 genes under series of fiber development stages indicates that many HSP70 genes may participate in fiber development processes including fiber initiation and elongation. This study provides the complete profiles of cotton HSP70 family genes for future study on their functions related to the molecular mechanisms of fiber development.
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http://dx.doi.org/10.3724/SP.J.1005.2014.0921DOI Listing
September 2014

Genome-wide investigation and transcriptome analysis of the WRKY gene family in Gossypium.

Mol Genet Genomics 2015 Feb 5;290(1):151-71. Epub 2014 Sep 5.

The Key Laboratory for Quality Improvement of Agricultural Products of Zhejiang Province, School of Agriculture and Food Science, Zhejiang A&F University, Linan, Hangzhou, 311300, Zhejiang, China.

WRKY transcription factors play important roles in various stress responses in diverse plant species. In cotton, this family has not been well studied, especially in relation to fiber development. Here, the genomes and transcriptomes of Gossypium raimondii and Gossypium arboreum were investigated to identify fiber development related WRKY genes. This represents the first comprehensive comparative study of WRKY transcription factors in both diploid A and D cotton species. In total, 112 G. raimondii and 109 G. arboreum WRKY genes were identified. No significant gene structure or domain alterations were detected between the two species, but many SNPs distributed unequally in exon and intron regions. Physical mapping revealed that the WRKY genes in G. arboreum were not located in the corresponding chromosomes of G. raimondii, suggesting great chromosome rearrangement in the diploid cotton genomes. The cotton WRKY genes, especially subgroups I and II, have expanded through multiple whole genome duplications and tandem duplications compared with other plant species. Sequence comparison showed many functionally divergent sites between WRKY subgroups, while the genes within each group are under strong purifying selection. Transcriptome analysis suggested that many WRKY genes participate in specific fiber development processes such as fiber initiation, elongation and maturation with different expression patterns between species. Complex WRKY gene expression such as differential Dt and At allelic gene expression in G. hirsutum and alternative splicing events were also observed in both diploid and tetraploid cottons during fiber development process. In conclusion, this study provides important information on the evolution and function of WRKY gene family in cotton species.
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http://dx.doi.org/10.1007/s00438-014-0904-7DOI Listing
February 2015

Microglia-Müller cell interactions in the retina.

Adv Exp Med Biol 2014 ;801:333-8

Unit on Neuron-Glia Interactions in Retinal Diseases, National Eye Institute, National Institutes of Health, 6 Center Drive, 6/215, 20892, Bethesda, MD, USA,

Microglia and Müller cells are cell types that feature prominently in responses to disease and injury in the retina. However, their mutual interactions have not been investigated in detail. Here, we review evidence that indicate that these two cell populations exchange functionally significant signals under uninjured conditions and during retinal inflammation. Under normal conditions, Müller cells constitute a potential source of extracellular ATP that mediates the activity-dependent regulation of microglial dynamic process motility. Following microglial activation in inflammation, microglia can signal to Müller cells, influencing their morphological, molecular, and functional responses. Microglia-Müller cell interactions appear to be a mode of bi-directional communications that help shape the overall injury response in the retina.
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http://dx.doi.org/10.1007/978-1-4614-3209-8_42DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4685688PMC
July 2014

Macroglia-microglia interactions via TSPO signaling regulates microglial activation in the mouse retina.

J Neurosci 2014 Mar;34(10):3793-806

Unit on Neuron-Glia Interactions in Retinal Disease, Mechanism of Retinal Diseases Section, Laboratory of Retinal Cell and Molecular Biology, and Biological Imaging Core, National Eye institute, National Institutes of Health, Bethesda, Maryland 20892.

Chronic retinal inflammation in the form of activated microglia and macrophages are implicated in the etiology of neurodegenerative diseases of the retina, including age-related macular degeneration, diabetic retinopathy, and glaucoma. However, molecular biomarkers and targeted therapies for immune cell activation in these disorders are currently lacking. To address this, we investigated the involvement and role of translocator protein (TSPO), a biomarker of microglial and astrocyte gliosis in brain degeneration, in the context of retinal inflammation. Here, we find that TSPO is acutely and specifically upregulated in retinal microglia in separate mouse models of retinal inflammation and injury. Concomitantly, its endogenous ligand, diazepam-binding inhibitor (DBI), is upregulated in the macroglia of the mouse retina such as astrocytes and Müller cells. In addition, we discover that TSPO-mediated signaling in microglia via DBI-derived ligands negatively regulates features of microglial activation, including reactive oxygen species production, TNF-α expression and secretion, and microglial proliferation. The inducibility and effects of DBI-TSPO signaling in the retina reveal a mechanism of coordinated macroglia-microglia interactions, the function of which is to limit the magnitude of inflammatory responses after their initiation, facilitating a return to baseline quiescence. Our results indicate that TSPO is a promising molecular marker for imaging inflammatory cell activation in the retina and highlight DBI-TSPO signaling as a potential target for immodulatory therapies.
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http://dx.doi.org/10.1523/JNEUROSCI.3153-13.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3942591PMC
March 2014

A novel p38 mitogen-activated protein kinase/Elk-1 transcription factor-dependent molecular mechanism underlying abnormal endothelial cell proliferation in plexogenic pulmonary arterial hypertension.

J Biol Chem 2013 Sep 26;288(36):25701-25716. Epub 2013 Jul 26.

From the Departments of Pharmacology and Medicine, Vascular Biology, and Pulmonary and Critical Care Medicine, Rush University Medical Center, Chicago, Illinois 60612,. Electronic address:

Plexiform lesions (PLs), the hallmark of plexogenic pulmonary arterial hypertension (PAH), contain phenotypically altered, proliferative endothelial cells (ECs). The molecular mechanism that contributes to EC proliferation and formation of PLs is poorly understood. We now show that a decrease in intersectin-1s (ITSN-1s) expression due to granzyme B (GrB) cleavage during inflammation associated with PAH and the high p38/Erk1/2(MAPK) activity ratio caused by the GrB/ITSN cleavage products lead to EC proliferation and selection of a proliferative/plexiform EC phenotype. We used human pulmonary artery ECs of PAH subjects (EC(PAH)), paraffin-embedded and frozen human lung tissue, and animal models of PAH in conjunction with microscopy imaging, biochemical, and molecular biology approaches to demonstrate that GrB cleaves ITSN-1s, a prosurvival protein of lung ECs, and generates two biologically active fragments, an N-terminal fragment (GrB-EH(ITSN)) with EC proliferative potential and a C-terminal product with dominant negative effects on Ras/Erk1/2. The proliferative potential of GrB-EH(ITSN) is mediated via sustained phosphorylation of p38(MAPK) and Elk-1 transcription factor and abolished by chemical inhibition of p38(MAPK). Moreover, lung tissue of PAH animal models and human specimens and EC(PAH) express lower levels of ITSN-1s compared with controls and the GrB-EH(ITSN) cleavage product. Moreover, GrB immunoreactivity is associated with PLs in PAH lungs. The concurrent expression of the two cleavage products results in a high p38/Erk1/2(MAPK) activity ratio, which is critical for EC proliferation. Our findings identify a novel GrB-EH(ITSN)-dependent pathogenic p38(MAPK)/Elk-1 signaling pathway involved in the poorly understood process of PL formation in severe PAH.
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http://dx.doi.org/10.1074/jbc.M113.502674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3764778PMC
September 2013

Impaired caveolae function and upregulation of alternative endocytic pathways induced by experimental modulation of intersectin-1s expression in mouse lung endothelium.

Biochem Res Int 2012 26;2012:672705. Epub 2012 Feb 26.

Department of Pharmacology, Rush University, 1735 W Harrison, Chicago, IL 60612, USA.

Intersectin-1s (ITSN-1s), a protein containing five SH3 (A-E) domains, regulates via the SH3A the function of dynamin-2 (dyn2) at the endocytic site. ITSN-1s expression was modulated in mouse lung endothelium by liposome delivery of either a plasmid cDNA encoding myc-SH3A or a specific siRNA targeting ITSN-1 gene. The lung vasculature of SH3A-transduced and ITSN-1s- deficient mice was perfused with gold albumin (Au-BSA) to analyze by electron microscopy the morphological intermediates and pathways involved in transendothelial transport or with dinitrophenylated (DNP)-BSA to quantify by ELISA its transport. Acute modulation of ITSN-1s expression decreased the number of caveolae, impaired their transport, and opened the interendothelial junctions, while upregulating compensatory nonconventional endocytic/transcytotic structures. Chronic inhibition of ITSN-1s further increased the occurrence of nonconventional intermediates and partially restored the junctional integrity. These findings indicate that ITSN-1s expression is required for caveolae function and efficient transendothelial transport. Moreover, our results demonstrate that ECs are highly adapted to perform their transport function while maintaining lung homeostasis.
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http://dx.doi.org/10.1155/2012/672705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3299393PMC
August 2012

Regulation of microglia by ionotropic glutamatergic and GABAergic neurotransmission.

Neuron Glia Biol 2011 Feb 14;7(1):41-6. Epub 2011 Dec 14.

Unit on Neuron-Glia Interactions in Retinal Diseases, National Eye Institute, National Institute of Health, Bethesda, MD 20892, USA.

Recent studies have indicated that constitutive functions of microglia in the healthy adult central nervous system (CNS) involve immune surveillance, synapse maintenance and trophic support. These functions have been related to the ramified structure of 'resting' microglia and the prominent motility in their processes that provide extensive coverage of the entire extracellular milleu. In this review, we examine how external signals, and in particular, ionotropic neurotransmission, regulate features of microglial morphology and process motility. Current findings indicate that microglial physiology in the healthy CNS is constitutively and reciprocally regulated by endogenous ionotropic glutamatergic and GABAergic neurotransmission. These influences do not act directly on microglial cells but indirectly via the activity-dependent release of ATP, likely through a mechanism involving pannexin channels. Microglia in the 'resting' state are not only dynamically active, but also constantly engaged in ongoing communication with neuronal and macroglial components of the CNS in a functionally relevant way.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694585PMC
http://dx.doi.org/10.1017/S1740925X11000123DOI Listing
February 2011

Adaptive Müller cell responses to microglial activation mediate neuroprotection and coordinate inflammation in the retina.

J Neuroinflammation 2011 Dec 7;8:173. Epub 2011 Dec 7.

Unit on Neuron-Glia Interactions in Retinal Diseases, Office of the Scientific Director, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.

Purpose: Microglia and Müller cells are prominent participants in retinal responses to injury and disease that shape eventual tissue adaptation or damage. This investigation examined how microglia and Müller cells interact with each other following initial microglial activation.

Methods: Mouse Müller cells were cultured alone, or co-cultured with activated or unactivated retinal microglia, and their morphological, molecular, and functional responses were evaluated. Müller cell-feedback signaling to microglia was studied using Müller cell-conditioned media. Corroborative in vivo analyses of retinal microglia-Müller cell interactions in the mouse retina were also performed.

Results: Our results demonstrate that Müller cells exposed to activated microglia, relative to those cultured alone or with unactivated microglia, exhibit marked alterations in cell morphology and gene expression that differed from those seen in chronic gliosis. These Müller cells demonstrated in vitro (1) an upregulation of growth factors such as GDNF and LIF, and provide neuroprotection to photoreceptor cells, (2) increased pro-inflammatory factor production, which in turn increased microglial activation in a positive feedback loop, and (3) upregulated chemokine and adhesion protein expression, which allowed Müller cells to attract and adhere to microglia. In vivo activation of microglia by intravitreal injection of lipopolysaccharide (LPS) also induced increased Müller cell-microglia adhesion, indicating that activated microglia may translocate intraretinally in a radial direction using Müller cell processes as an adhesive scaffold.

Conclusion: Our findings demonstrate that activated microglia are able to influence Müller cells directly, and initiate a program of bidirectional microglia-Müller cell signaling that can mediate adaptive responses within the retina following injury. In the acute aftermath following initial microglia activation, Müller cell responses may serve to augment initial inflammatory responses across retinal lamina and to guide the intraretinal mobilization of migratory microglia using chemotactic cues and adhesive cell contacts. Understanding adaptive microglia-Müller cell interactions in injury responses can help discover therapeutic cellular targets for intervention in retinal disease.
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http://dx.doi.org/10.1186/1742-2094-8-173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3251543PMC
December 2011

Pro-inflammatory endothelial cell dysfunction is associated with intersectin-1s down-regulation.

Respir Res 2011 Apr 12;12:46. Epub 2011 Apr 12.

Pulmonary and Critical Care Medicine, Rush University Medical Center, 1750 W, Harrison Street, 297 Jelke, Chicago, IL 60612, USA.

Background: The response of lung microvascular endothelial cells (ECs) to lipopolysaccharide (LPS) is central to the pathogenesis of lung injury. It is dual in nature, with one facet that is pro-inflammatory and another that is cyto-protective. In previous work, overexpression of the anti-apoptotic Bcl-XL rescued ECs from apoptosis triggered by siRNA knockdown of intersectin-1s (ITSN-1s), a pro-survival protein crucial for ECs function. Here we further characterized the cyto-protective EC response to LPS and pro-inflammatory dysfunction.

Methods And Results: Electron microscopy (EM) analyses of LPS-exposed ECs revealed an activated/dysfunctional phenotype, while a biotin assay for caveolae internalization followed by biochemical quantification indicated that LPS causes a 40% inhibition in biotin uptake compared to controls. Quantitative PCR and Western blotting were used to evaluate the mRNA and protein expression, respectively, for several regulatory proteins of intrinsic apoptosis, including ITSN-1s. The decrease in ITSN-1s mRNA and protein expression were countered by Bcl-XL and survivin upregulation, as well as Bim downregulation, events thought to protect ECs from impending apoptosis. Absence of apoptosis was confirmed by TUNEL and lack of cytochrome c (cyt c) efflux from mitochondria. Moreover, LPS exposure caused induction and activation of inducible nitric oxide synthase (iNOS) and a mitochondrial variant (mtNOS), as well as augmented mitochondrial NO production as measured by an oxidation oxyhemoglobin (oxyHb) assay applied on mitochondrial-enriched fractions prepared from LPS-exposed ECs. Interestingly, expression of myc-ITSN-1s rescued caveolae endocytosis and reversed induction of iNOS expression.

Conclusion: Our results suggest that ITSN-1s deficiency is relevant for the pro-inflammatory ECs dysfunction induced by LPS.
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http://dx.doi.org/10.1186/1465-9921-12-46DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3096597PMC
April 2011

Microglial morphology and dynamic behavior is regulated by ionotropic glutamatergic and GABAergic neurotransmission.

PLoS One 2011 Jan 25;6(1):e15973. Epub 2011 Jan 25.

Unit on Neuron-Glia Interactions in Retinal Disease, National Eye Institute, National Institutes of Health, Bethesda, Maryland, United States of America.

Purpose: Microglia represent the primary resident immune cells in the CNS, and have been implicated in the pathology of neurodegenerative diseases. Under basal or "resting" conditions, microglia possess ramified morphologies and exhibit dynamic surveying movements in their processes. Despite the prominence of this phenomenon, the function and regulation of microglial morphology and dynamic behavior are incompletely understood. We investigate here whether and how neurotransmission regulates "resting" microglial morphology and behavior.

Methods: We employed an ex vivo mouse retinal explant system in which endogenous neurotransmission and dynamic microglial behavior are present. We utilized live-cell time-lapse confocal imaging to study the morphology and behavior of GFP-labeled retinal microglia in response to neurotransmitter agonists and antagonists. Patch clamp electrophysiology and immunohistochemical localization of glutamate receptors were also used to investigate direct-versus-indirect effects of neurotransmission by microglia.

Results: Retinal microglial morphology and dynamic behavior were not cell-autonomously regulated but are instead modulated by endogenous neurotransmission. Morphological parameters and process motility were differentially regulated by different modes of neurotransmission and were increased by ionotropic glutamatergic neurotransmission and decreased by ionotropic GABAergic neurotransmission. These neurotransmitter influences on retinal microglia were however unlikely to be directly mediated; local applications of neurotransmitters were unable to elicit electrical responses on microglia patch-clamp recordings and ionotropic glutamatergic receptors were not located on microglial cell bodies or processes by immunofluorescent labeling. Instead, these influences were mediated indirectly via extracellular ATP, released in response to glutamatergic neurotransmission through probenecid-sensitive pannexin hemichannels.

Conclusions: Our results demonstrate that neurotransmission plays an endogenous role in regulating the morphology and behavior of "resting" microglia in the retina. These findings illustrate a mode of constitutive signaling between the neural and immune compartments of the CNS through which immune cells may be regulated in concert with levels of neural activity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0015973PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3026789PMC
January 2011

Regulation of dynamin-2 assembly-disassembly and function through the SH3A domain of intersectin-1s.

J Cell Mol Med 2011 Nov;15(11):2364-76

Department of Pharmacology, Rush University Medical Center, Medical College, Vascular Biology Section, Chicago, IL 60612, USA.

Intersectin-1s (ITSN-1s), a five Src homology 3 (SH3) domain-containing protein, is critically required for caveolae and clathrin-mediated endocytosis (CME), due to its interactions with dynamin (dyn). Of the five SH3A-E domains, SH3A is unique because of its high affinity for dyn and potent inhibition of CME. However, the molecular mechanism by which SH3A integrates in the overall function of ITSN-1s to regulate the endocytic process is not understood. Using biochemical and functional approaches as well as high-resolution electron microscopy, we show that SH3A exogenously expressed in human lung endothelial cells caused abnormal endocytic structures, distorted caveolae clusters, frequent staining-dense rings around the caveolar necks and 60% inhibition of caveolae internalization. In vitro studies further revealed that SH3A, similar to full-length ITSN-1s stimulates dyn2 oligomerization and guanosine triphosphatase (GTP)ase activity, effects not detected when other SH3 domains of ITSN-1s were used as controls. Strikingly, in the presence of SH3A, dyn2-dyn2 interactions are stabilized and despite continuous GTP hydrolysis, dyn2 oligomers cannot disassemble. SH3A may hold up caveolae release from the plasma membrane and formation of free-transport vesicles, by prolonging the lifetime of assembled dyn2. Altogether, our results indicate that ITSN-1s, via its SH3A has the unique ability to regulate dyn2 assembly-disassembly and function during endocytosis.
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http://dx.doi.org/10.1111/j.1582-4934.2010.01226.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3072443PMC
November 2011

Retinal pathway origins of the pattern ERG of the mouse.

Exp Eye Res 2009 Jun 27;89(1):49-62. Epub 2009 Feb 27.

University of Houston, College of Optometry, 4901 Calhoun Road, Houston, TX 77204-2020, USA.

This study investigated contributions from the retinal On and Off pathways, and the spiking and nonspiking activity of neurons in those pathways to the pattern ERG of the mouse. Light-adapted pattern and ganzfeld ERGs were recorded from anesthetized C57BL/6 mice 3-4 months of age. Recordings were made before and after intravitreal injections of PDA (cis-2,3-piperidine-dicarboxylic acid) to block transmission to hyperpolarizing 2nd order and all 3rd order neurons, TTX (tetrodotoxin) to block Na(+)-dependent spiking, APB (2-amino-4-phosphonobutyric acid) to block synapses between photoreceptors and ON-bipolar cells, and APB + TTX and PDA + TTX cocktails. The pattern stimuli consisted of 0.05 cy/deg gratings reversing in contrast at 1 Hz, presented at various contrasts (50-90%) and a rod saturating mean luminance. For flash ERGs, brief green ganzfeld flashes were presented on a rod-suppressing green background. Recordings were made 39-42 days after unilateral optic nerve crush (ONC) in a subset of animals in which ganglion cell degeneration was subsequently confirmed in retinal sections. Pattern ERGs were similar in waveform for all contrasts, with a positive wave (P1) peak for 90% contrast around 60 ms on average and maximum trough for a negative wave (N2) around 132 ms after each contrast reversal; amplitudes were greatest for 90% contrast which became the standard stimulus. ONC eliminated or nearly eliminated the pattern ERG but did not affect the major waves of the flash ERG. PDA and TTX both delayed P1 and N2 waves of the pattern ERG, and reduced their amplitudes, with effects of PDA on N2 greater than those of TTX. In the flash ERG, PDA reduced a-wave amplitudes, removed OPs but hardly affected b-wave amplitudes. In contrast, TTX reduced b-wave amplitudes substantially, as previously observed in rat. APB removed P1 of the pattern ERG, but left a negative wave of similar timing and amplitude to N2. In the flash ERG, APB removed the b-wave, producing a negative ERG. Addition of TTX to the APB injection removed most of N2 of the pattern ERG, while other waves of the pattern and flash ERG resembled those after APB alone. Addition of TTX to the PDA injection had little effect on the pattern ERG beyond that of PDA alone, but it prolonged the b-wave of the flash ERG. In conclusion, this study confirmed that a selective lesion of ganglion cells will practically eliminate the pattern ERG. The study also showed that P1 of the mouse pattern ERG is dominated by contributions, mainly spiking, from ON pathway neurons, whereas N2 reflects substantial spiking activity from the OFF pathway as well as nonspiking contributions from both pathways.
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http://dx.doi.org/10.1016/j.exer.2009.02.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2739005PMC
June 2009

Intracellular delivery of proteins into mouse Müller glia cells in vitro and in vivo using Pep-1 transfection reagent.

J Neurosci Methods 2009 Mar 17;177(2):403-19. Epub 2008 Nov 17.

College of Optometry, University of Houston, 4901 Calhoun, 505 JD Armistead Bldg Rm. 2143, Houston, TX 77204-2020, United States.

Direct protein transfection is a potentially valuable tool for studying protein function in basic and clinical research. A major challenge is to enable a sufficiently large amount of protein to penetrate the plasma membrane of the transfected cells. Pep-1, a protein transfection reagent, was evaluated for its ability and efficiency in delivering proteins and antibodies into mouse Müller cells in vitro and in vivo. Pep-1 delivered active beta-galactosidase enzyme and antibodies (non-specific IgG and Cy3-conjugated anti-vimentin) into cultured Müller cells with high efficiency. Transfection efficiency increased with increasing concentration of the protein in the complex and with incubation time. Following intravitreal injection of Pep-1/IgG complexes in vivo, retinal histology was preserved and immunostaining showed that the antibodies were distributed widely across the retinal surface, with the most intense staining located near the retino-vitreal border. For complexes using non-specific IgG, double staining with anti-glutamine synthetase identified many IgG-positive cells as Müller glia. IgG immunoreactivity was also detected in the cytoplasm and occasionally in the nuclei of inner retinal neurons. Dark-adapted flash electroretinogram (ERG) recordings from injected eyes were nearly identical to ERG recordings from control eyes, suggesting that injection of Pep-1/IgG complex has minimal effects on retinal function. Therefore, Pep-1 is a useful tool for intracellular delivery of antibodies to study the role of proteins in living cells.
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http://dx.doi.org/10.1016/j.jneumeth.2008.10.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2681185PMC
March 2009

Transcriptional activation by growth hormone of HNF-6-regulated hepatic genes, a potential mechanism for improved liver repair during biliary injury in mice.

Am J Physiol Gastrointest Liver Physiol 2008 Aug 29;295(2):G357-66. Epub 2008 May 29.

RUSH Univ. Medical Center, Depts. of Pediatrics and Surgery, 1725 W. Harrison St., Suite 718, Chicago, IL, USA.

Growth hormone (GH) function is mediated through multiple endocrine pathways. In the liver, GH also transcriptionally activates hepatocyte nuclear factor-6 (HNF-6; OC-1), a liver-enriched transcription factor that regulates the expression of genes essential to hepatic function. We hypothesize that GH modulates hepatic function in the normal and injured liver through HNF-6 and HNF-6 target genes. CD1 mice received PBS or GH for the 1-, 7-, and 28-day course of Sham operation or bile duct ligation (BDL). Proliferation-, metabolic-, and profibrotic-specific hepatic functions were assessed with a focus on candidate HNF-6 transcriptional target genes. Confirmation of HNF-6 regulation was done by analysis of target gene expression in liver infected with recombinant adenovirus AdHNF-6 expression vectors. GH administration upregulated HNF-6 expression throughout the course of liver injury. This was associated with increased expression of HNF-6 proliferative target genes cyclin D1 and metabolic gene Cyp7A1 and downregulation of profibrogenic TGFb2R. Hepatic function improved such as enhanced hepatocyte proliferation, higher cholesterol clearance throughout the course of injury, and attenuated fibrogenic response at day 28 of BDL. GH treatment also transcriptionally increased albumin expression in an HNF-6-independent manner. This was associated with enhanced serum albumin levels. In conclusion, the GH/HNF-6 axis is a potential in vivo mechanism underlying GH diverse function in the liver to modulate the liver repair response to BDL.
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http://dx.doi.org/10.1152/ajpgi.00581.2007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2519853PMC
August 2008

Near complete loss of retinal ganglion cells in the math5/brn3b double knockout elicits severe reductions of other cell types during retinal development.

Dev Biol 2008 Apr 26;316(2):214-27. Epub 2008 Jan 26.

Department of Biochemistry and Molecular Biology, The University of Texas-Houston, Houston, TX 77030, USA.

Retinal ganglion cells (RGCs) are the first cell type to differentiate during retinal histogenesis. It has been postulated that specified RGCs subsequently influence the number and fate of the remaining progenitors to produce the rest of the retinal cell types. However, several genetic knockout models have argued against this developmental role for RGCs. Although it is known that RGCs secrete cellular factors implicated in cell proliferation, survival, and differentiation, until now, limited publications have shown that reductions in the RGC number cause significant changes in these processes. In this study, we observed that Math5 and Brn3b double null mice exhibited over a 99% reduction in the number of RGCs during development. This severe reduction of RGCs is accompanied by a drastic loss in the number of all other retinal cell types that was never seen before. Unlike Brn3b null or Math5 null animals, mice null for both alleles lack an optic nerve and have severe retinal dysfunction. Results of this study support the hypothesis that RGCs play a pivotal role in the late phase of mammalian retina development.
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http://dx.doi.org/10.1016/j.ydbio.2008.01.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2483850PMC
April 2008

Repression of Six3 by a corepressor regulates rhodopsin expression.

Proc Natl Acad Sci U S A 2007 Aug 31;104(32):13128-33. Epub 2007 Jul 31.

Department of Molecular and Cellular Oncology, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.

Here, we provide gain-of-function, loss-of function, and molecular evidence supporting genetic interactions between metastasis associated protein 1 (MTA1) and Six3 and between Six3 and rhodopsin. We discovered that MTA1 physically interacts with the Six3 chromatin in a histone deacetylase-dependent manner, leading to transcriptional suppression of the Six3 gene. MTA1 is also a Six3-interacting corepressor that contributes to a self-negative regulation of Six3 transcription by Six3. In contrast, deletion of the MTA1 alleles in murine embryonic fibroblasts or its knockdown in rat retinal ganglion cells stimulates Six3 expression. MTA1 inactivation in the MTA1-null mice results in an elevated Six3 level and proliferation of the retina cells with no obvious abnormities in eye formation. However, unexpectedly, we discovered an enhanced recruitment of Six3 to the rhodopsin chromatin in retina from the MTA1-null mice; Six3's homeodomain interacts with specific DNA elements in the rhodopsin promoter to stimulate its transcription, resulting in increased rhodopsin expression. Further, in holoprosencephaly patients, Six3 protein with a naturally occurring deletion mutation in the helix 3 of the homeodomain does not bind to rhodopsin DNA or stimulate rhodopsin transcription, implying a potential defective rhodopsin pathway in the affected holoprosencephaly patients. Further Six3 cooperates with Crx or NRL in stimulating transcription from the rhodopsin-luc. These findings reveal a previously unrecognized role for the MTA1 as an upstream modifier of Six3 and indicate that Six3 is a direct stimulator of rhodopsin expression, thus revealing a putative role for the MTA1/Six3/rhodopsin pathway in vertebrate eye.
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http://dx.doi.org/10.1073/pnas.0705878104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1941821PMC
August 2007

[The study of the therapeutic application of PV contact lens].

Yan Ke Xue Bao 2005 Jun;21(2):67-9, 81

Department of Optometry, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.

Purpose: To evaluate the indications and effects of continuously wearing the Bausch & Lomb Pure-Vision (PV)Contact Lens.

Method: Twenty-nine patients (31 eyes) who required therapeutic contact lens wear were selected non-randomly from Zhongshan Ophthalmic Center for wearing (Pure Vision, PV) contact lens. Therapeutic indications included pain and irritation relief, corneal protection, and enhancement of corneal wound healing. Simultaneously antibiotics and artificial tears were used according to the ocular diseases. And then, the effect of treatment, anterior segment of eyes, contact lens fitting characteristics, lens deposits and the presence of contact lens-relative complications were evaluated.

Results: The duration of PV contact lens wear on 31 eyes were 3-57 days, averagely 20.9 days. Patients included bullous keratopathy (6 cases, 6 eyes), keratitis incorporated with descemetocele (5 cases, 5 eyes), chemical burns with epithelial abrasions (6 cases, 7 eyes), post-keratoplasty (3 cases, 3 eyes), filamentary keratitis (3 cases, 3 eyes), corneal epithelial erosion syndrome (2 cases, 3 eyes), repetitive corneal epithelial stripping syndrome (1 case, 1 eye), corneal lamellar laceration and epithelial coloboma (1 case, 1 eye), post-extraction of traumatic cataract with durative corneal ulcer (1 case, 1 eye), post-limbal & amnia transplantation (1 case, 1 eye). For the treatment of pain and irritation relief (21 patients, 22 eyes), all patients had complete or partial relief. For corneal healing (20 patients, 22 eyes), full healing was noted in 15 patients (16 eyes) (72.7%), partial healing occurred in 4 patients (5 eyes) (22.7%). For corneal protection (21 patients, 23 eyes), lens wear was fully protective in all cases, except one case of loosely fitting. Our result shows that PV Contact Lens exhibits prominent efficiency in

Conclusion: treating corneal diseases and ocular surface diseases, as well as corneal protection, corneal healing and pain relief. The lens has increased oxygen transmissibility and good anti-deposit quality, reducing the risk of ocular complications. As a result of these, PV Contact Lens is the ideal bandage therapeutic lens.
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June 2005

Asymmetrical vertical phorias in normal subjects: the influence of unbalanced illumination.

Strabismus 2005 Sep;13(3):123-8

College of Optometry, University of Houston, 505 J. Davis Armistead Building, Houston, TX 77204, USA.

Purpose: One goal of this investigation was to determine whether asymmetrical vertical hetereophorias, which are qualitatively similar to a dissociated vertical deviation (DVD), occur commonly in normal people. A second goal was to establish whether the magnitude or direction of vertical phoria depends on the illumination of the occluded eye, as would be expected if vertical eye position were influenced by a dorsal light reflex.

Methods: Vertical phorias were estimated in 30 normal subjects using a Maddox rod in conjunction with a dark and an illuminated occluder.

Results: On average, subjects exhibited a hypophoria of less than 1 min arc with both the dark and the illuminated occluder. Asymmetrical vertical phorias that were consistent with previously published criteria for a minute DVD were found in eight subjects when a dark occluder was used and in four subjects when an illuminated occluder was used. The proportions of subjects whose vertical phorias were consistent with a DVD did not differ significantly under the two conditions of occlusion.

Conclusions: Asymmetrical vertical phorias that mimic a minute DVD do not occur commonly in normal people. Our finding that vertical phorias do not change systematically when an illuminated instead of a dark occluder is used suggests that normal subjects exhibit little or no vestige of the dorsal light reflex.
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http://dx.doi.org/10.1080/09273970500216465DOI Listing
September 2005

Studies on the effects of the immunosuppressant FK-506 on the high-risk corneal graft rejection.

Yan Ke Xue Bao 2002 Sep;18(3):160-4

Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510060, China.

Purpose: To evaluate the clinical efficacy of FK-506 on suppressing high-risk cornea transplantation rejection.

Methods: In a randomized controlled clinical trial, 56 eyes of 56 patients with high-risk keratoplasty (including total corneal transplantation TCT, total corneal transplantation with circular lamellar sclera CST, vascularization corneal transplantation and corneal retransplantation) were divided into the experimental group and the control group (each with 28 eyes). The experimental group was treated by FK-506 eyedrops (0.5 mg/ml) and TobraDex eyedrops, compared with the control group that was treated by 1% CsA eyedrops and TobraDex eyedrops. In the average 8.1-month follow-up period, the visual acuity, graft transparent duration and Rejection Index (RI) of grafts were observed.

Results: In the follow-up period, the graft rejection rate of the experimental and the control group was 63.6% and 95.2% respectively (chi2 = 4.72, P < 0.05) with significant difference.

Conclusions: The local application of FK-506 suppressed effectively the graft rejection of corneal transplantation of the patients at high risk.
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September 2002