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  1. Article ; Online: Improved NOE fitting for flexible molecules based on molecular mechanics data - a case study with S-adenosylmethionine.

    Bame, Jessica / Hoeck, Casper / Carrington, Matthew J / Butts, Craig P / Jäger, Christof M / Croft, Anna K

    Physical chemistry chemical physics : PCCP

    2018  Volume 20, Issue 11, Page(s) 7523–7531

    Abstract: The use of molecular dynamics (MD) calculations to derive relative populations of conformers is highly sensitive to both timescale and parameterisation of the MD. Where these calculations are coupled with NOE data to determine the dynamics of a molecular ...

    Abstract The use of molecular dynamics (MD) calculations to derive relative populations of conformers is highly sensitive to both timescale and parameterisation of the MD. Where these calculations are coupled with NOE data to determine the dynamics of a molecular system, this can present issues if these populations are thus relied upon. We present an approach that refines the highly accurate PANIC NMR methodology combined with clustering approaches to generate conformers, but without restraining the simulations or considering the relative population distributions generated by MD. Combining this structural sampling with NOE fitting, we demonstrate, for S-adenosylmethionine (aqueous solution at pH 7.0), significant improvements are made to the fit of populations to the experimental data, revealing a strong overall preference for the syn conformation of the adenosyl group relative to the ribose ring, but with less discrimination for the conformation of the ribose ring itself.
    MeSH term(s) Magnetic Resonance Spectroscopy ; Mechanical Phenomena ; Molecular Conformation ; Molecular Dynamics Simulation ; S-Adenosylmethionine/chemistry
    Chemical Substances S-Adenosylmethionine (7LP2MPO46S)
    Language English
    Publishing date 2018-02-28
    Publishing country England
    Document type Journal Article
    ZDB-ID 1476244-4
    ISSN 1463-9084 ; 1463-9076
    ISSN (online) 1463-9084
    ISSN 1463-9076
    DOI 10.1039/c7cp07265a
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: The histone methyltransferase MLL1/KMT2A in monocytes drives coronavirus-associated coagulopathy and inflammation.

    Sharma, Sriganesh B / Melvin, William J / Audu, Christopher O / Bame, Monica / Rhoads, Nicole / Wu, Weisheng / Kanthi, Yogendra / Knight, Jason S / Adili, Reheman / Holinstat, Michael A / Wakefield, Thomas W / Henke, Peter K / Moore, Bethany B / Gallagher, Katherine A / Obi, Andrea T

    Blood

    2022  Volume 141, Issue 7, Page(s) 725–742

    Abstract: Coronavirus-associated coagulopathy (CAC) is a morbid and lethal sequela of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. CAC results from a perturbed balance between coagulation and fibrinolysis and occurs in conjunction with ... ...

    Abstract Coronavirus-associated coagulopathy (CAC) is a morbid and lethal sequela of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. CAC results from a perturbed balance between coagulation and fibrinolysis and occurs in conjunction with exaggerated activation of monocytes/macrophages (MO/Mφs), and the mechanisms that collectively govern this phenotype seen in CAC remain unclear. Here, using experimental models that use the murine betacoronavirus MHVA59, a well-established model of SARS-CoV-2 infection, we identify that the histone methyltransferase mixed lineage leukemia 1 (MLL1/KMT2A) is an important regulator of MO/Mφ expression of procoagulant and profibrinolytic factors such as tissue factor (F3; TF), urokinase (PLAU), and urokinase receptor (PLAUR) (herein, "coagulopathy-related factors") in noninfected and infected cells. We show that MLL1 concurrently promotes the expression of the proinflammatory cytokines while suppressing the expression of interferon alfa (IFN-α), a well-known inducer of TF and PLAUR. Using in vitro models, we identify MLL1-dependent NF-κB/RelA-mediated transcription of these coagulation-related factors and identify a context-dependent, MLL1-independent role for RelA in the expression of these factors in vivo. As functional correlates for these findings, we demonstrate that the inflammatory, procoagulant, and profibrinolytic phenotypes seen in vivo after coronavirus infection were MLL1-dependent despite blunted Ifna induction in MO/Mφs. Finally, in an analysis of SARS-CoV-2 positive human samples, we identify differential upregulation of MLL1 and coagulopathy-related factor expression and activity in CD14+ MO/Mφs relative to noninfected and healthy controls. We also observed elevated plasma PLAU and TF activity in COVID-positive samples. Collectively, these findings highlight an important role for MO/Mφ MLL1 in promoting CAC and inflammation.
    MeSH term(s) Animals ; Humans ; Mice ; COVID-19/complications ; Histone-Lysine N-Methyltransferase/genetics ; Histone-Lysine N-Methyltransferase/metabolism ; Histones/metabolism ; Inflammation/metabolism ; Monocytes/metabolism ; Myeloid-Lymphoid Leukemia Protein/genetics ; Myeloid-Lymphoid Leukemia Protein/metabolism ; SARS-CoV-2/metabolism ; Urokinase-Type Plasminogen Activator/metabolism
    Chemical Substances Histone-Lysine N-Methyltransferase (EC 2.1.1.43) ; Histones ; Myeloid-Lymphoid Leukemia Protein (149025-06-9) ; Urokinase-Type Plasminogen Activator (EC 3.4.21.73) ; KMT2A protein, human
    Language English
    Publishing date 2022-12-20
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural
    ZDB-ID 80069-7
    ISSN 1528-0020 ; 0006-4971
    ISSN (online) 1528-0020
    ISSN 0006-4971
    DOI 10.1182/blood.2022015917
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  3. Article: Heparanases: endoglycosidases that degrade heparan sulfate proteoglycans.

    Bame, K J

    Glycobiology

    2001  Volume 11, Issue 6, Page(s) 91R–98R

    Abstract: Heparanases are endoglycosidases that cleave the heparan sulfate glycosaminoglycans from proteoglycan core proteins and degrade them to small oligosaccharides. Inside cells, these enzymes are important for the normal catabolism of heparan sulfate ... ...

    Abstract Heparanases are endoglycosidases that cleave the heparan sulfate glycosaminoglycans from proteoglycan core proteins and degrade them to small oligosaccharides. Inside cells, these enzymes are important for the normal catabolism of heparan sulfate proteoglycans (HSPGs), generating glycosaminoglycan fragments that are then transported to lysosomes and completely degraded. When secreted, heparanases are thought to degrade basement membrane HSPGs at sites of injury or inflammation, allowing extravasion of immune cells into nonvascular spaces and releasing factors that regulate cell proliferation and angiogenesis. Heparanases have been described in a wide variety of tissues and cells, but because of difficulties in developing simple assays to follow activity, very little has been known about enzyme diversity until recently. Within the last 10 years, heparanases have been purified from platelets, placenta, and Chinese hamster ovary cells. Characterization of the enzymes suggests there may be a family of heparanase proteins with different substrate specificities and potential functions.
    MeSH term(s) Glucuronidase/metabolism ; Heparan Sulfate Proteoglycans/metabolism ; Substrate Specificity
    Chemical Substances Heparan Sulfate Proteoglycans ; heparanase (EC 3.2.1.-) ; Glucuronidase (EC 3.2.1.31)
    Language English
    Publishing date 2001-06
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 1067689-2
    ISSN 1460-2423 ; 0959-6658
    ISSN (online) 1460-2423
    ISSN 0959-6658
    DOI 10.1093/glycob/11.6.91r
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  4. Article ; Online: Coronavirus induces diabetic macrophage-mediated inflammation via SETDB2.

    Melvin, William J / Audu, Christopher O / Davis, Frank M / Sharma, Sriganesh B / Joshi, Amrita / DenDekker, Aaron / Wolf, Sonya / Barrett, Emily / Mangum, Kevin / Zhou, Xiaofeng / Bame, Monica / Ruan, Alex / Obi, Andrea / Kunkel, Steven L / Moore, Bethany B / Gallagher, Katherine A

    Proceedings of the National Academy of Sciences of the United States of America

    2021  Volume 118, Issue 38

    Abstract: COVID-19 induces a robust, extended inflammatory "cytokine storm" that contributes to an increased morbidity and mortality, particularly in patients with type 2 diabetes (T2D). Macrophages are a key innate immune cell population responsible for the ... ...

    Abstract COVID-19 induces a robust, extended inflammatory "cytokine storm" that contributes to an increased morbidity and mortality, particularly in patients with type 2 diabetes (T2D). Macrophages are a key innate immune cell population responsible for the cytokine storm that has been shown, in T2D, to promote excess inflammation in response to infection. Using peripheral monocytes and sera from human patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and a murine hepatitis coronavirus (MHV-A59) (an established murine model of SARS), we identified that coronavirus induces an increased Mφ-mediated inflammatory response due to a coronavirus-induced decrease in the histone methyltransferase, SETDB2. This decrease in SETDB2 upon coronavirus infection results in a decrease of the repressive trimethylation of histone 3 lysine 9 (H3K9me3) at NFkB binding sites on inflammatory gene promoters, effectively increasing inflammation. Mφs isolated from mice with a myeloid-specific deletion of SETDB2 displayed increased pathologic inflammation following coronavirus infection. Further, IFNβ directly regulates SETDB2 in Mφs via JaK1/STAT3 signaling, as blockade of this pathway altered SETDB2 and the inflammatory response to coronavirus infection. Importantly, we also found that loss of SETDB2 mediates an increased inflammatory response in diabetic Mϕs in response to coronavirus infection. Treatment of coronavirus-infected diabetic Mφs with IFNβ reversed the inflammatory cytokine production via up-regulation of SETDB2/H3K9me3 on inflammatory gene promoters. Together, these results describe a potential mechanism for the increased Mφ-mediated cytokine storm in patients with T2D in response to COVID-19 and suggest that therapeutic targeting of the IFNβ/SETDB2 axis in T2D patients may decrease pathologic inflammation associated with COVID-19.
    MeSH term(s) Animals ; COVID-19/immunology ; Coronavirus/metabolism ; Coronavirus Infections/genetics ; Coronavirus Infections/immunology ; Cytokine Release Syndrome ; Cytokines/metabolism ; Diabetes Mellitus, Type 2/genetics ; Diabetes Mellitus, Type 2/metabolism ; Female ; Histone-Lysine N-Methyltransferase/genetics ; Histone-Lysine N-Methyltransferase/metabolism ; Humans ; Inflammation/metabolism ; Inflammation/physiopathology ; Inflammation/virology ; Inflammation Mediators/metabolism ; Macrophages/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; NF-kappa B/metabolism ; SARS-CoV-2/metabolism ; Signal Transduction
    Chemical Substances Cytokines ; Inflammation Mediators ; NF-kappa B ; Histone-Lysine N-Methyltransferase (EC 2.1.1.43) ; SETDB2 protein, human (EC 2.1.1.43) ; Setdb2 protein, mouse (EC 2.1.1.43)
    Language English
    Publishing date 2021-08-19
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 209104-5
    ISSN 1091-6490 ; 0027-8424
    ISSN (online) 1091-6490
    ISSN 0027-8424
    DOI 10.1073/pnas.2101071118
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  5. Article: Release of heparan sulfate glycosaminoglycans from proteoglycans in Chinese hamster ovary cells does not require proteolysis of the core protein.

    Bame, K J

    The Journal of biological chemistry

    1993  Volume 268, Issue 27, Page(s) 19956–19964

    Abstract: ... pgsE-606 (Bame, K. J., and Esko, J. D. (1989) J. Biol. Chem. 264, 8059-8065), since the undersulfated ... proteins precedes heparanas cleavage (Yanagishita, M., and Hascall, V. C. (1992) J. Biol. Chem. 267, 9451 ...

    Abstract The initial steps in the catabolism of cell-associated heparan sulfate proteolgycans in Chinese hamster ovary (CHO) cells are similar to what has been observed in other cells, cell surface proteoglycans are internalized and the heparan sulfate glycosaminoglycans are released from core proteins and cleaved to small chains by intracellular heparanases. The mechanism of the release and cleavage reactions is unclear, since only intact proteoglycans and small, cleaved heparan sulfate chains are observed in pulse-chase experiments; however, it is thought that release of the glycosaminoglycans from core proteins precedes heparanas cleavage (Yanagishita, M., and Hascall, V. C. (1992) J. Biol. Chem. 267, 9451-9454). The relationship between these two steps were examined with the proteoglycan synthesis mutant pgsE-606 (Bame, K. J., and Esko, J. D. (1989) J. Biol. Chem. 264, 8059-8065), since the undersulfated heparan sulfate synthesized by the mutant is a poor substrate for heparanases. In addition to intact proteoglycans and small cleaved chains, a large glycosaminoglycan intermediate is present in pgsE-606 cells, suggesting that heparan sulfate is released from proteoglycans as large chains which are subsequently cleaved by heparanases. The catabolic intermediate in the mutant has been acted upon by heparanases, since it is smaller than the size of the heparan sulfate chains found on proteoglycans, raising the possibility that the glycosaminoglycans are first released from proteoglycans by an endoglycosidic cleavage of the chain before proteolysis of the core protein. To examine whether proteolysis of the core protein is required for endoglycosidic cleavage of the chain, heparan sulfate proteoglycans immobilized to Sepharose were incubated with CHO cell extracts in the presence of protease inhibitors. Heparan sulfate chains are released from the proteoglycans by heparanases in the cell extract, indicating that release of the glycosaminoglycans from core proteins is not a prerequisite for endoglycosidic cleavage of the chain. In addition, these studies indicate that there is a heparanase activity in CHO cells which can recognize and cleave sequences in the undersulfated heparan sulfate, but is unable to completely cleave the mutant glycosaminoglycan, suggesting that there may be multiple heparanase activities responsible for degrading the heparan sulfate chains.
    MeSH term(s) Animals ; CHO Cells ; Chromatography, Gel ; Chromatography, Ion Exchange ; Cricetinae ; Glucosamine/metabolism ; Glycosaminoglycans/isolation & purification ; Glycosaminoglycans/metabolism ; Heparan Sulfate Proteoglycans ; Heparitin Sulfate/isolation & purification ; Heparitin Sulfate/metabolism ; Kinetics ; Molecular Weight ; Proteoglycans/isolation & purification ; Proteoglycans/metabolism ; Radioisotope Dilution Technique ; Sulfates/metabolism ; Sulfur Radioisotopes ; Tritium
    Chemical Substances Glycosaminoglycans ; Heparan Sulfate Proteoglycans ; Proteoglycans ; Sulfates ; Sulfur Radioisotopes ; Tritium (10028-17-8) ; Heparitin Sulfate (9050-30-0) ; Glucosamine (N08U5BOQ1K)
    Language English
    Publishing date 1993-09-25
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, P.H.S.
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
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  6. Article ; Online: Leachate characteristics as influenced by application of anaerobic baffled reactor effluent to three soils: a soil column study.

    Bame, I B / Hughes, J C / Titshall, L W / Buckley, C A

    Chemosphere

    2013  Volume 93, Issue 9, Page(s) 2171–2179

    Abstract: ... contained plant nutrients such as P, S, Ca, Mg, and K. Results indicated that after application of 16 pore ...

    Abstract A soil column study was undertaken in the laboratory with three contrasting soil types namely a sandy soil (Longlands (Typic Plinthaquult), E horizon), an organic soil (Inanda (Rhodic Hapludox), A horizon) and a clayey soil (Sepane (Aquic Haplustalf), A horizon). Anaerobic baffled reactor (ABR) effluent was leached through the soil and distilled water was concurrently used as a control. The effluent was slightly basic (pH 7.4-7.6), had heavy metal concentrations below permissible limits for irrigation purposes and contained plant nutrients such as P, S, Ca, Mg, and K. Results indicated that after application of 16 pore volumes, the concentrations of Ca(2+) and Mg(2+) were lower in the leachates than in the original effluent indicating adsorption by the soils and Mg(2+) was preferentially adsorbed to Ca(2+). Phosphorus was strongly adsorbed in all soils. While its adsorption in the Inanda could be attributed to organic matter and the presence of iron oxides and oxyhydroxides, the clay type and amount in the Sepane was likely responsible for P adsorption. The NO3(-)-N, which was initially low in the effluent, increased as leaching progressed while the NH4-N decreased. A chemical balance to ascertain loss or gain of major elements from the effluent application indicated P to be strongly immobilised from the effluent representing 41, 6 and 10 fold the fertilizer needs for maize in the Inanda, Longlands and Sepane, respectively. Results obtained indicated that the chemical composition of ABR effluent is significantly altered when leached through soils with distinct properties.
    MeSH term(s) Agriculture ; Anaerobiosis ; Bioreactors ; Environmental Monitoring ; Hydrogen-Ion Concentration ; Metals, Heavy/analysis ; Metals, Heavy/chemistry ; Models, Chemical ; Phosphorus/analysis ; Phosphorus/chemistry ; Soil/chemistry ; Soil Pollutants/analysis ; Soil Pollutants/chemistry ; Waste Disposal, Fluid/methods ; Water Pollutants, Chemical/analysis
    Chemical Substances Metals, Heavy ; Soil ; Soil Pollutants ; Water Pollutants, Chemical ; Phosphorus (27YLU75U4W)
    Language English
    Publishing date 2013-11
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 120089-6
    ISSN 1879-1298 ; 0045-6535 ; 0366-7111
    ISSN (online) 1879-1298
    ISSN 0045-6535 ; 0366-7111
    DOI 10.1016/j.chemosphere.2013.07.080
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article: The effect of irrigation with anaerobic baffled reactor effluent on nutrient availability, soil properties and maize growth

    Bame, I.B / J.C. Hughes / L.W. Titshall / C.A. Buckley

    Agricultural water management. 2014 Mar. 01, v. 134

    2014  

    Abstract: ... a clayey soil (Sepane (Se), Aquic Haplustalf). Fertilizer (N, P and K) was applied at the recommended rate ... dry matter yield (4.90g pot−1) and accumulated more N, P, K, Ca and Mg than all other treatments. After ... accumulated more N, P and K than those water-irrigated with no lime as well as the equivalent limed treatments ...

    Abstract A glasshouse study was carried out to assess the availability to maize of nutrients from anaerobic baffled reactor (ABR) effluent. Maize was grown for 6 weeks in pots with three contrasting soils namely a sandy soil (Cartref (Cf), Typic Haplaquept), an organic, acidic soil (Inanda (Ia), Rhodic Hapludox) and a clayey soil (Sepane (Se), Aquic Haplustalf). Fertilizer (N, P and K) was applied at the recommended rate, half the recommended rate and zero fertilizer for each of the soils used. Lime was applied to the Ia following recommendations. Plants were irrigated with either effluent or tap water. Dry matter yields and nutrient concentrations for effluent-irrigated maize were significantly higher (p<0.05) than for all water-irrigated plants. For each soil, the unfertilized, effluent-irrigated plants were not significantly different in most of the above-ground nutrient concentrations from the water-irrigated plants at half fertilization. Phosphorus deficiency was observed in the Ia and Se but not in the Cf, irrespective of fertilizer treatment. Plants grown on the Cf irrigated with effluent and fully fertilized had the highest above-ground dry matter yield (4.90g pot−1) and accumulated more N, P, K, Ca and Mg than all other treatments. After harvest, P in the Cf soil was significantly higher (p<0.05) in the effluent-irrigated than the water-irrigated soils reflecting P input from the effluent. Concurrently, the effect of the effluent was further investigated by planting maize on the Ia with neither lime application nor fertilization. Plants that received effluent irrigation and no lime had significantly higher (p<0.05) dry matter yields (2.67g pot−1) and accumulated more N, P and K than those water-irrigated with no lime as well as the equivalent limed treatments. This suggests an interaction effect between the lime and effluent properties.
    Keywords Hapludox ; Haplustalfs ; NPK fertilizers ; Zea mays ; acid soils ; calcium ; clay soils ; corn ; dry matter accumulation ; fertilizer rates ; greenhouse experimentation ; magnesium ; nitrogen ; nutrient availability ; nutrients ; phosphorus ; planting ; potassium ; sandy soils ; selenium ; soil properties ; tap water ; wastewater irrigation
    Language English
    Dates of publication 2014-0301
    Size p. 50-59.
    Publishing place Elsevier B.V.
    Document type Article
    ZDB-ID 751144-9
    ISSN 1873-2283 ; 0378-3774
    ISSN (online) 1873-2283
    ISSN 0378-3774
    DOI 10.1016/j.agwat.2013.11.011
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  8. Article: Leachate characteristics as influenced by application of anaerobic baffled reactor effluent to three soils: a soil column study

    Bame, I.B / Hughes, J.C / Titshall, L.W / Buckley, C.A

    Chemosphere. 2013 Nov., v. 93, no. 9

    2013  

    Abstract: ... contained plant nutrients such as P, S, Ca, Mg, and K. Results indicated that after application of 16 pore ...

    Abstract A soil column study was undertaken in the laboratory with three contrasting soil types namely a sandy soil (Longlands (Typic Plinthaquult), E horizon), an organic soil (Inanda (Rhodic Hapludox), A horizon) and a clayey soil (Sepane (Aquic Haplustalf), A horizon). Anaerobic baffled reactor (ABR) effluent was leached through the soil and distilled water was concurrently used as a control. The effluent was slightly basic (pH 7.4–7.6), had heavy metal concentrations below permissible limits for irrigation purposes and contained plant nutrients such as P, S, Ca, Mg, and K. Results indicated that after application of 16 pore volumes, the concentrations of Ca²⁺ and Mg²⁺ were lower in the leachates than in the original effluent indicating adsorption by the soils and Mg²⁺ was preferentially adsorbed to Ca²⁺. Phosphorus was strongly adsorbed in all soils. While its adsorption in the Inanda could be attributed to organic matter and the presence of iron oxides and oxyhydroxides, the clay type and amount in the Sepane was likely responsible for P adsorption. The NO₃ ⁻–N, which was initially low in the effluent, increased as leaching progressed while the NH₄–N decreased. A chemical balance to ascertain loss or gain of major elements from the effluent application indicated P to be strongly immobilised from the effluent representing 41, 6 and 10 fold the fertilizer needs for maize in the Inanda, Longlands and Sepane, respectively. Results obtained indicated that the chemical composition of ABR effluent is significantly altered when leached through soils with distinct properties.
    Keywords E horizons ; Hapludox ; Haplustalfs ; Plinthaquults ; adsorption ; calcium ; clay ; clay soils ; corn ; fertilizers ; heavy metals ; iron oxides ; irrigation ; leachates ; leaching ; magnesium ; nutrients ; organic matter ; organic soils ; pH ; phosphorus ; sandy soils
    Language English
    Dates of publication 2013-11
    Size p. 2171-2179.
    Publishing place Elsevier Ltd
    Document type Article
    ZDB-ID 120089-6
    ISSN 1879-1298 ; 0045-6535 ; 0366-7111
    ISSN (online) 1879-1298
    ISSN 0045-6535 ; 0366-7111
    DOI 10.1016/j.chemosphere.2013.07.080
    Database NAL-Catalogue (AGRICOLA)

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  9. Article ; Online: Transcripts involved in calcium signaling and telencephalic neuronal fate are altered in induced pluripotent stem cells from bipolar disorder patients.

    Chen, H M / DeLong, C J / Bame, M / Rajapakse, I / Herron, T J / McInnis, M G / O'Shea, K S

    Translational psychiatry

    2014  Volume 4, Page(s) e375

    Abstract: Bipolar disorder (BP) is a chronic psychiatric condition characterized by dynamic, pathological mood fluctuations from mania to depression. To date, a major challenge in studying human neuropsychiatric conditions such as BP has been limited access to ... ...

    Abstract Bipolar disorder (BP) is a chronic psychiatric condition characterized by dynamic, pathological mood fluctuations from mania to depression. To date, a major challenge in studying human neuropsychiatric conditions such as BP has been limited access to viable central nervous system tissue to examine disease progression. Patient-derived induced pluripotent stem cells (iPSCs) now offer an opportunity to analyze the full compliment of neural tissues and the prospect of identifying novel disease mechanisms. We have examined changes in gene expression as iPSC derived from well-characterized patients differentiate into neurons; there was little difference in the transcriptome of iPSC, but BP neurons were significantly different than controls in their transcriptional profile. Expression of transcripts for membrane bound receptors and ion channels was significantly increased in BP-derived neurons compared with controls, and we found that lithium pretreatment of BP neurons significantly altered their calcium transient and wave amplitude. The expression of transcription factors involved in the specification of telencephalic neuronal identity was also altered. Control neurons expressed transcripts that confer dorsal telencephalic fate, whereas BP neurons expressed genes involved in the differentiation of ventral (medial ganglionic eminence) regions. Cells were responsive to dorsal/ventral patterning cues, as addition of the Hedgehog (ventral) pathway activator purmorphamine or a dorsalizing agent (lithium) stimulated expression of NKX2-1 (ventral identity) or EMX2 (dorsal) in both groups. Cell-based models should have a significant impact on our understanding of the genesis and therefore treatment of BP; the iPSC cell lines themselves provide an important resource for comparison with other neurodevelopmental disorders.
    MeSH term(s) Adult ; Bipolar Disorder/drug therapy ; Bipolar Disorder/genetics ; Bipolar Disorder/pathology ; Body Patterning/genetics ; Calcium Signaling/drug effects ; Calcium Signaling/genetics ; Cell Differentiation/drug effects ; Cell Differentiation/genetics ; Disease Progression ; Female ; Gene Expression/drug effects ; Gene Expression/genetics ; Homeodomain Proteins/genetics ; Humans ; Lithium Carbonate/therapeutic use ; Longitudinal Studies ; Male ; Middle Aged ; Neurons/drug effects ; Neurons/metabolism ; Neurons/pathology ; Nuclear Proteins/genetics ; Oligonucleotide Array Sequence Analysis ; Pluripotent Stem Cells/drug effects ; Pluripotent Stem Cells/pathology ; Reference Values ; Telencephalon/drug effects ; Telencephalon/metabolism ; Telencephalon/pathology ; Thyroid Nuclear Factor 1 ; Transcription Factors/genetics ; Transcription, Genetic/drug effects ; Transcription, Genetic/genetics
    Chemical Substances Homeodomain Proteins ; Nuclear Proteins ; Thyroid Nuclear Factor 1 ; Transcription Factors ; empty spiracles homeobox proteins ; Lithium Carbonate (2BMD2GNA4V)
    Language English
    Publishing date 2014-03-25
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2609311-X
    ISSN 2158-3188 ; 2158-3188
    ISSN (online) 2158-3188
    ISSN 2158-3188
    DOI 10.1038/tp.2014.12
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  10. Article ; Online: Utilizing structure based drug design and metabolic soft spot identification to optimize the in vitro potency and in vivo pharmacokinetic properties leading to the discovery of novel reversible Bruton's tyrosine kinase inhibitors.

    Hopkins, Brian T / Bame, Eris / Bell, Noah / Bohnert, Tonika / Bowden-Verhoek, Jon K / Bui, Minna / Cancilla, Mark T / Conlon, Patrick / Cullen, Patrick / Erlanson, Daniel A / Fan, Junfa / Fuchs-Knotts, Tarra / Hansen, Stig / Heumann, Stacey / Jenkins, Tracy J / Gua, Chuck / Liu, Ying / Liu, YuTing / Lulla, Mukush /
    Marcotte, Douglas / Marx, Isaac / McDowell, Bob / Mertsching, Elisabeth / Negrou, Ella / Romanowski, Michael J / Scott, Daniel / Silvian, Laura / Yang, Wenjin / Zhong, Min

    Bioorganic & medicinal chemistry

    2021  Volume 44, Page(s) 116275

    Abstract: Bruton's tyrosine kinase (BTK) is an essential node on the BCR signaling in B cells, which are clinically validated to play a critical role in B-cell lymphomas and various auto-immune diseases such as Multiple Sclerosis (MS), Pemphigus, and rheumatoid ... ...

    Abstract Bruton's tyrosine kinase (BTK) is an essential node on the BCR signaling in B cells, which are clinically validated to play a critical role in B-cell lymphomas and various auto-immune diseases such as Multiple Sclerosis (MS), Pemphigus, and rheumatoid arthritis (RA). Although non-selective irreversible BTK inhibitors have been approved for oncology, due to the emergence of drug resistance in B-cell lymphoma associated with covalent inhibitor, there an unmet medical need to identify reversible, selective, potent BTK inhibitor as viable therapeutics for patients. Herein, we describe the identification of Hits and subsequence optimization to improve the physicochemical properties, potency and kinome selectivity leading to the discovery of a novel class of BTK inhibitors. Utilizing Met ID and structure base design inhibitors were synthesized with increased in vivo metabolic stability and oral exposure in rodents suitable for advancing to lead optimization.
    MeSH term(s) Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors ; Agammaglobulinaemia Tyrosine Kinase/metabolism ; Dose-Response Relationship, Drug ; Drug Discovery ; Humans ; Molecular Structure ; Protein Kinase Inhibitors/chemistry ; Protein Kinase Inhibitors/metabolism ; Protein Kinase Inhibitors/pharmacokinetics ; Structure-Activity Relationship
    Chemical Substances Protein Kinase Inhibitors ; Agammaglobulinaemia Tyrosine Kinase (EC 2.7.10.2)
    Language English
    Publishing date 2021-06-15
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1161284-8
    ISSN 1464-3391 ; 0968-0896
    ISSN (online) 1464-3391
    ISSN 0968-0896
    DOI 10.1016/j.bmc.2021.116275
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