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1
Hirabayashi, Kei, Tomoko Iwanaga, Makoto Yamakawa, Naoyuki Tanaka, Keiichi Fukuyama, Yasuhiro Takahashi, and Kei Wada. "Structural analyses of the two cysteine desulfurases from Aquifex aeolicus." Acta Crystallographica Section A Foundations and Advances 70, a1 (August 5, 2014): C1648. http://dx.doi.org/10.1107/s205327331408351x.
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The cysteine desulfurase IscS is a highly conserved master enzyme initiating sulfur transfer to a wide range of acceptor proteins. IscS degrades L-cysteine into L-alanine and a sulfur atom in a pyridoxal 5'-phosphate (PLP) dependent manner. In this reaction, it is essential for a conserved Lys residue of IscS to form Schiff base (the covalent bonding interaction) with PLP. Recent accumulations of genomic information have revealed that some IscS homologues in archaea and thermophilic bacteria lack this invariant Lys. Here we report the crystal structures of two paralogous cysteine desulfurases, the canonical Aa IscS1 and the invariant Lys lacking Aa IscS2, from Aquifex aeolicus. Aa IscS1/Aa IscS2 were overproduced in E. coli, and purified by heat-treatment and several column chromatography, and crystallized. The structure of Aa IscS1 was determined at 2.00 Å (Rcryst= 19.4% and Rfree = 22.0%), and Aa IscS2 at 2.55 Å (Rcryst= 21.8% and Rfree = 27.0%). Overall structures as well as orientations of the residues in the active site were quite similar to each other. In Aa IscS1 the PLP adduct was anchored in the catalytic pocket of Aa IscS1 by the formation of the aldimine Schiff base with the invariant Lys. Whereas in Aa IscS2 the PLP was not seen in the active pocket, since the catalytic Lys was substituted by Leu. Alternatively, an electron density derived from unknown-small molecule was located in the catalytic site of Aa IscS2. The shape of this electron density was completely different from that of PLP. The Bijvoet difference map calculated from data collected at λ=1.7 Å overlapped with the electron density observed in the active site; the unknown-small molecule probably contains such metals as iron atoms. Furthermore, the ICP-MS analysis demonstrated that as-isolated Aa IscS2 harbored the iron atom in the solution state. More recently we obtained the experimental evidences that non-canonical Aa IscS2 was able to form the binary complex with Aa IscU, which is responsible for a scaffold for the assembly of a nascent Fe-S cluster. Base on the structural/biochemcal results, possible physiological functions of two cysteine desulfrurases will be discussed.
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DING, Huangen, and Robert J. CLARK. "Characterization of iron binding in IscA, an ancient iron-sulphur cluster assembly protein." Biochemical Journal 379, no. 2 (April 15, 2004): 433–40. http://dx.doi.org/10.1042/bj20031702.
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Iron–sulphur clusters are one of the most common types of redox centre in biology. At least six proteins (IscS, IscU, IscA, HscB, HscA and ferredoxin) have been identified as being essential for the biogenesis of iron–sulphur proteins in bacteria. It has been shown that IscS is a cysteine desulphurase that provides sulphur for iron–sulphur clusters, and that IscU is a scaffold for the IscS-mediated assembly of iron–sulphur clusters. The iron donor for iron–sulphur clusters, however, remains elusive. Here we show that IscA is an iron binding protein with an apparent iron association constant of 3.0×1019 M−1, and that iron-loaded IscA can provide iron for the assembly of transient iron–sulphur clusters in IscU in the presence of IscS and l-cysteine in vitro. The results suggest that IscA is capable of recruiting intracellular iron and delivering iron for iron–sulphur clusters in proteins.
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Liu, Jian She, Lin Qian, and Chun Li Zheng. "Biogenesis and Transfer of Iron-Sulfur Clusters from Acidithiobacillus ferrooxidans." Advanced Materials Research 825 (October 2013): 198–201. http://dx.doi.org/10.4028/www.scientific.net/amr.825.198.
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Iron-sulfur (Fe-S) proteins are ubiquitous and participate in multiple essential functions of life. However, little is currently known about the mechanisms of iron-sulfur biosynthesis and transfer in acidophilic microorganisms. In this study, the IscS, IscU and IscA proteins from Acidithiobacillus ferrooxidans were successfully expressed in Escherichia coli and purified by affinity chromatography. The IscS was a cysteine desulfurase which catalyzes desulfurization of L-cysteine and transfer sulfur for iron-sulfur cluster assembly. Purified IscU did not have an iron-sulfur cluster but could act as a scaffold protein to assemble the [2Fe-2S] cluster in vitro. The IscA was a [4Fe-4S] cluster binding protein, but it also acted as an iron binding protein. Further studies indicated that the iron sulfur clusters could be transferred from pre-assembled scaffold proteins to apo-form iron sulfur proteins, the reconstituted iron sulfur proteins could restore their physiological activities.
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Johnson, Deborah C., Mihaela-Carmen Unciuleac, and Dennis R. Dean. "Controlled Expression and Functional Analysis of Iron-Sulfur Cluster Biosynthetic Components within Azotobacter vinelandii." Journal of Bacteriology 188, no. 21 (August 25, 2006): 7551–61. http://dx.doi.org/10.1128/jb.00596-06.
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ABSTRACT A system for the controlled expression of genes in Azotobacter vinelandii by using genomic fusions to the sucrose catabolic regulon was developed. This system was used for the functional analysis of the A. vinelandii isc genes, whose products are involved in the maturation of [Fe-S] proteins. For this analysis, the scrX gene, contained within the sucrose catabolic regulon, was replaced by the contiguous A. vinelandii iscS, iscU, iscA, hscB, hscA, fdx, and iscX genes, resulting in duplicate genomic copies of these genes: one whose expression is directed by the normal isc regulatory elements (Pisc) and the other whose expression is directed by the scrX promoter (PscrX). Functional analysis of [Fe-S] protein maturation components was achieved by placing a mutation within a particular Pisc-controlled gene with subsequent repression of the corresponding PscrX-controlled component by growth on glucose as the carbon source. This experimental strategy was used to show that IscS, IscU, HscBA, and Fdx are essential in A. vinelandii and that their depletion results in a deficiency in the maturation of aconitase, an enzyme that requires a [4Fe-4S] cluster for its catalytic activity. Depletion of IscA results in a null growth phenotype only when cells are cultured under conditions of elevated oxygen, marking the first null phenotype associated with the loss of a bacterial IscA-type protein. Furthermore, the null growth phenotype of cells depleted of HscBA could be partially reversed by culturing cells under conditions of low oxygen. Conserved amino acid residues within IscS, IscU, and IscA that are essential for their respective functions and/or whose replacement results in a partial or complete dominant-negative growth phenotype were also identified using this system.
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Chen, Yun, Ya-Hui Tsai, Bor-Jiun Tseng, and Sheng-Hong Tseng. "Influence of Growth Hormone and Glutamine on Intestinal Stem Cells: A Narrative Review." Nutrients 11, no. 8 (August 17, 2019): 1941. http://dx.doi.org/10.3390/nu11081941.
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Growth hormone (GH) and glutamine (Gln) stimulate the growth of the intestinal mucosa. GH activates the proliferation of intestinal stem cells (ISCs), enhances the formation of crypt organoids, increases ISC stemness markers in the intestinal organoids, and drives the differentiation of ISCs into Paneth cells and enterocytes. Gln enhances the proliferation of ISCs and increases crypt organoid formation; however, it mainly acts on the post-proliferation activity of ISCs to maintain the stability of crypt organoids and the intestinal mucosa, as well as to stimulate the differentiation of ISCs into goblet cells and possibly Paneth cells and enteroendocrine cells. Since GH and Gln have differential effects on ISCs. Their use in combination may have synergistic effects on ISCs. In this review, we summarize the evidence of the actions of GH and/or Gln on crypt cells and ISCs in the literature. Overall, most studies demonstrated that GH and Gln in combination exerted synergistic effects to activate the proliferation of crypt cells and ISCs and enhance crypt organoid formation and mucosal growth. This treatment influenced the proliferation of ISCs to a similar degree as GH treatment alone and the differentiation of ISCs to a similar degree as Gln treatment alone.
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Ding, Baojin, Edward S. Smith, and Huangen Ding. "Mobilization of the iron centre in IscA for the iron–sulphur cluster assembly in IscU." Biochemical Journal 389, no. 3 (July 26, 2005): 797–802. http://dx.doi.org/10.1042/bj20050405.
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The biogenesis of iron–sulphur clusters requires the co-ordinated delivery of both iron and sulphur. It is now clear that sulphur in iron–sulphur clusters is derived from L-cysteine by cysteine desulphurases. However, the iron donor for the iron–sulphur cluster assembly still remains elusive. Our previous studies indicated that Escherichia coli IscA, a member of the iron–sulphur cluster assembly machinery, is an iron-binding protein that can provide iron for the iron–sulphur cluster assembly in a proposed scaffold IscU. To determine how the iron centre in IscA is transferred for the iron–sulphur cluster assembly in IscU, we explore the mobility of the iron centre in IscA. The UV–visible and EPR measurements show that L-cysteine, but not IscU, is able to mobilize the iron centre in IscA and make the iron available for the iron–sulphur cluster assembly in IscU. Other related biological thiols such as N-acetyl-L-cysteine or reduced glutathione have no effect on the iron centre of IscA, suggesting that L-cysteine is unique in mobilizing the iron centre of IscA. Nevertheless, L-cysteine alone is not sufficient to transfer the iron from IscA to IscU. Both L-cysteine and cysteine desulphurase (IscS) are required for the IscA-mediated assembly of iron–sulphur clusters in IscU. The results suggest that L-cysteine may have two distinct functions in the biogenesis of iron–sulphur clusters: to mobilize the iron centre in IscA and to provide sulphur via cysteine desulphurase (IscS) for the iron–sulphur cluster assembly in IscU.
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Leipuviene, Ramune, Qiang Qian, and Glenn R. Björk. "Formation of Thiolated Nucleosides Present in tRNA from Salmonella enterica serovar Typhimurium Occurs in Two Principally Distinct Pathways." Journal of Bacteriology 186, no. 3 (February 1, 2004): 758–66. http://dx.doi.org/10.1128/jb.186.3.758-766.2004.
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ABSTRACT tRNA from Salmonella enterica serovar Typhimurium contains five thiolated nucleosides, 2-thiocytidine (s2C), 4-thiouridine (s4U), 5-methylaminomethyl-2-thiouridine (mnm5s2U), 5-carboxymethylaminomethyl-2-thiouridine (cmnm5s2U), and N-6-(4-hydroxyisopentenyl)-2-methylthioadenosine (ms2io6A). The levels of all of them are significantly reduced in cells with a mutated iscS gene, which encodes the cysteine desulfurase IscS, a member of the ISC machinery that is responsible for [Fe-S] cluster formation in proteins. A mutant (iscU52) was isolated that carried an amino acid substitution (S107T) in the IscU protein, which functions as a major scaffold in the formation of [Fe-S] clusters. In contrast to the iscS mutant, the iscU52 mutant showed reduced levels of only two of the thiolated nucleosides, ms2io6A (10-fold) and s2C (more than 2-fold). Deletions of the iscU, hscA, or fdx genes from the isc operon lead to a similar tRNA thiolation pattern to that seen for the iscU52 mutant. Unexpectedly, deletion of the iscA gene, coding for an alternative scaffold protein for the [Fe-S] clusters, showed a novel tRNA thiolation pattern, where the synthesis of only one thiolated nucleoside, ms2io6A, was decreased twofold. Based on our results, we suggest two principal distinct routes for thiolation of tRNA: (i) a direct sulfur transfer from IscS to the tRNA modifying enzymes ThiI and MnmA, which form s4U and the s2U moiety of (c)mnm5s2U, respectively; and (ii) an involvement of [Fe-S] proteins (an unidentified enzyme in the synthesis of s2C and MiaB in the synthesis of ms2io6A) in the transfer of sulfur to the tRNA.
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Marinoni, Elodie N., Jaim S. de Oliveira, Yvain Nicolet, Estella C. Raulfs, Patricia Amara, Dennis R. Dean, and Juan C. Fontecilla-Camps. "(IscS-IscU)2Complex Structures Provide Insights into Fe2S2Biogenesis and Transfer." Angewandte Chemie 124, no. 22 (April 18, 2012): 5535–38. http://dx.doi.org/10.1002/ange.201201708.
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Marinoni, Elodie N., Jaim S. de Oliveira, Yvain Nicolet, Estella C. Raulfs, Patricia Amara, Dennis R. Dean, and Juan C. Fontecilla-Camps. "(IscS-IscU)2Complex Structures Provide Insights into Fe2S2Biogenesis and Transfer." Angewandte Chemie International Edition 51, no. 22 (April 18, 2012): 5439–42. http://dx.doi.org/10.1002/anie.201201708.
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Li, Feng-Fei, Bi-Jun Chen, Wei Li, Ling Li, Min Zha, S. Zhou, M. G. Bachem, and Zi-Lin Sun. "Islet Stellate Cells Isolated from Fibrotic Islet of Goto-Kakizaki Rats Affect Biological Behavior of Beta-Cell." Journal of Diabetes Research 2016 (2016): 1–9. http://dx.doi.org/10.1155/2016/6924593.
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We previously isolated islet stellate cells (ISCs) from healthy Wistar rat islets. In the present study, we isolated “already primed by diabetic environment” ISCs from islets of Goto-Kakizaki rats, determined the gene profile of these cells, and assessed the effects of these ISCs on beta-cell function and survival. We detected gene expression of ISCs by digital gene expression. INS-1 cell proliferation, apoptosis, and insulin production were measured after being treated with ISCs supernatant (SN). We observed the similar expression pattern of ISCs and PSCs, but 1067 differentially expressed genes. Insulin production in INS-1 cells cultured with ISC-SN was significantly reduced. The 5-ethynyl-2′-deoxyuridine-positive INS-1 cells treated with ISC-SN were decreased. Propidium iodide- (PI-) positive INS-1 cells were 2.6-fold higher than those in control groups. Caspase-3 activity was increased. In conclusion, ISCs presented in fibrotic islet of GK rats might be special PSCs, which impaired beta-cell function and proliferation and increased beta-cell apoptosis.
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Zhang, Mingzi, Mei Hua Jiang, Dae-Wook Kim, Woosung Ahn, Eunkyung Chung, Youngsook Son, and Guangfan Chi. "Comparative Analysis of the Cell Fates of Induced Schwann Cells from Subcutaneous Fat Tissue and Naïve Schwann Cells in the Sciatic Nerve Injury Model." BioMed Research International 2017 (2017): 1–12. http://dx.doi.org/10.1155/2017/1252851.
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Purpose. The fate and function of the induced Schwann cells (iSCs) like cells from adipose tissue have not been critically evaluated in vivo after transplantation. The objective of this study is to compare the fate of iSCs with naïve SCs (nSCs) after transplantation into the lesion sites of sciatic nerve, respectively. Methods. Adipose-derived stem cells from eGFP-expressing transgenic rat’s subcutaneous fat were induced to iSCs in vitro. iSCs were injected to the sciatic nerve lesion area after crush injury and the cells fate was comparatively analyzed with that of nSCs from the same rat. Results. At 12 weeks after transplantation, nSCs were detected only in the restricted area of cell transplantation site but iSCs were widely distributed all over the sciatic nerve. Based on double fluorescence observations, both iSCs and naïve ones were colocalized with P0-expressing myelin sheath, outbound by laminin-expressing basal membrane, and terminated at contactin-associated protein-expressing doublets. However, some of iSCs were also differentiated to the fibrocyte/fibroblast-like cells. In the histological analysis of repaired sciatic nerves, axon density was higher in iSC-received group than in the nSCs group and normal sciatic nerve. Conclusion. iSCs induced from subcutaneous fat tissues have higher engraftment and migration capacity than nSCs.
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Xu, Wei, Jun Liang, H. F. Geng, Jun Lu, Rui Li, X. L. Wang, Qian Lv, et al. "Wingless-Type MMTV Integration Site Family Member 5a Is a Key Secreted Islet Stellate Cell-Derived Product that Regulates Islet Function." International Journal of Endocrinology 2019 (April 11, 2019): 1–8. http://dx.doi.org/10.1155/2019/7870109.
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Background. Emerging evidence suggests that T2DM is attributable to the dysfunction of β-cells and the activation of islet stellate cells (ISCs). The wingless-type MMTV integration site family member 5a (Wnt5a)/frizzled 5 (Fzd5) signalling pathway might take part in this process. Our study is aimed at defining the status of ISCs during β-cell insulin secretion homeostasis by determining the role of the Wnt5a protein in the regulation of insulin production. We examined the effects of the status of ISCs on β-cell insulin secretion in normoglycemic db/m and hyperglycaemic db/db mice. Methods. iTRAQ protein screening and RNA interference were used to determine novel ISC-derived secretory products that may use other mechanisms to influence the function of islets. Results. We showed a significant reduction in insulin secretion by β-cells in vitro when they were cocultured with db/db ISCs compared to when they were cocultured with ISCs isolated from normoglycemic db/m mice; in addition, both Wnt5a and its receptor Fzd5 were more highly expressed by quiescent ISCs than by activated db/db ISCs. Treatment with exogenous Wnt5a increased the secretion of insulin in association with the deactivation of ISCs. Conclusion. Our observations revealed that the Wnt5a protein is a key effector of ISC-mediated improvement in islet function.
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Howe, Ann C., and Bessie Stanback. "ISCS in review." Science Education 69, no. 1 (January 1985): 25–37. http://dx.doi.org/10.1002/sce.3730690104.
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Tantaleán, Juan C., Manuel A. Araya, Claudia P. Saavedra, Derie E. Fuentes, José M. Pérez, Iván L. Calderón, Philip Youderian, and Claudio C. Vásquez. "The Geobacillus stearothermophilus V iscS Gene, Encoding Cysteine Desulfurase, Confers Resistance to Potassium Tellurite in Escherichia coli K-12." Journal of Bacteriology 185, no. 19 (October 1, 2003): 5831–37. http://dx.doi.org/10.1128/jb.185.19.5831-5837.2003.
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ABSTRACT Many eubacteria are resistant to the toxic oxidizing agent potassium tellurite, and tellurite resistance involves diverse biochemical mechanisms. Expression of the iscS gene from Geobacillus stearothermophilus V, which is naturally resistant to tellurite, confers tellurite resistance in Escherichia coli K-12, which is naturally sensitive to tellurite. The G. stearothermophilus iscS gene encodes a cysteine desulfurase. A site-directed mutation in iscS that prevents binding of its pyridoxal phosphate cofactor abolishes both enzyme activity and its ability to confer tellurite resistance in E. coli. Expression of the G. stearothermophilus iscS gene confers tellurite resistance in tellurite-hypersensitive E. coli iscS and sodA sodB mutants (deficient in superoxide dismutase) and complements the auxotrophic requirement of an E. coli iscS mutant for thiamine but not for nicotinic acid. These and other results support the hypothesis that the reduction of tellurite generates superoxide anions and that the primary targets of superoxide damage in E. coli are enzymes with iron-sulfur clusters.
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Lauhon, Charles T. "Requirement for IscS in Biosynthesis of All Thionucleosides in Escherichia coli." Journal of Bacteriology 184, no. 24 (December 15, 2002): 6820–29. http://dx.doi.org/10.1128/jb.184.24.6820-6829.2002.
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ABSTRACT Escherichia coli tRNA contains four naturally occurring nucleosides modified with sulfur. Cysteine is the intracellular sulfur source for each of these modified bases. We previously found that the iscS gene, a member of the nifS cysteine desulfurase gene family, is required for 4-thiouridine biosynthesis in E. coli. Since IscS does not bind tRNA, its role is the mobilization and distribution of sulfur to enzymes that catalyze the sulfur insertion steps. In addition to iscS, E. coli contains two other nifS homologs, csdA and csdB, each of which has cysteine desulfurase activity and could potentially donate sulfur for thionucleoside biosynthesis. Double csdA csdB and iscS csdA mutants were prepared or obtained, and all mutants were analyzed for thionucleoside content. It was found that unfractionated tRNA isolated from the iscS mutant strain contained <5% of the level of sulfur found in the parent strain. High-pressure liquid chromatography analysis of tRNA nuclease digests from the mutant strain grown in the presence of [35S]cysteine showed that only a small fraction of 2-thiocytidine was present, while the other thionucleosides were absent when cells were isolated during log phase. As expected, digests from the iscS mutant strain contained 6-N-dimethylallyl adenosine (i6A) in place of 6-N-dimethylallyl-2-methylthioadenosine and 5-methylaminomethyl uridine (mnm5U) instead of 5-methylaminomethyl-2-thiouridine. Prolonged growth of the iscS and iscS csdA mutant strains revealed a gradual increase in levels of 2-thiocytidine and 6-N-dimethylallyl-2-methylthioadenosine with extended incubation (>24 h), while the thiouridines remained absent. This may be due to a residual level of Fe-S cluster biosynthesis in iscS deletion strains. An overall scheme for thionucleoside biosynthesis in E. coli is discussed.
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Kurokawa, Ken, Yoku Hayakawa, and Kazuhiko Koike. "Plasticity of Intestinal Epithelium: Stem Cell Niches and Regulatory Signals." International Journal of Molecular Sciences 22, no. 1 (December 31, 2020): 357. http://dx.doi.org/10.3390/ijms22010357.
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The discovery of Lgr5+ intestinal stem cells (ISCs) triggered a breakthrough in the field of ISC research. Lgr5+ ISCs maintain the homeostasis of the intestinal epithelium in the steady state, while these cells are susceptible to epithelial damage induced by chemicals, pathogens, or irradiation. During the regeneration process of the intestinal epithelium, more quiescent +4 stem cells and short-lived transit-amplifying (TA) progenitor cells residing above Lgr5+ ISCs undergo dedifferentiation and act as stem-like cells. In addition, several recent reports have shown that a subset of terminally differentiated cells, including Paneth cells, tuft cells, or enteroendocrine cells, may also have some degree of plasticity in specific situations. The function of ISCs is maintained by the neighboring stem cell niches, which strictly regulate the key signal pathways in ISCs. In addition, various inflammatory cytokines play critical roles in intestinal regeneration and stem cell functions following epithelial injury. Here, we summarize the current understanding of ISCs and their niches, review recent findings regarding cellular plasticity and its regulatory mechanism, and discuss how inflammatory cytokines contribute to epithelial regeneration.
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Ellyard, Julia I., Danielle T. Avery, Tri Giang Phan, Nathan J. Hare, Philip D. Hodgkin, and Stuart G. Tangye. "Antigen-selected, immunoglobulin-secreting cells persist in human spleen and bone marrow." Blood 103, no. 10 (May 15, 2004): 3805–12. http://dx.doi.org/10.1182/blood-2003-09-3109.
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Abstract Plasma cells (PCs) represent the final stage of B-cell differentiation and are devoted to the production of immunoglobulin (Ig). Perturbations to their development can result in human disorders characterized by PC expansion and hypergammaglobulinemia. Ig-secreting cells (ISCs) have been identified in secondary lymphoid tissues and bone marrow (BM). Most ISCs in lymphoid tissue are short-lived; in contrast, ISCs that migrate to the BM become long-lived PCs and continue to secrete immunoglobulin for extended periods. However, a small population of long-lived PCs has been identified in rodent spleen, suggesting that PCs may persist in secondary lymphoid tissue and that the spleen, as well as the BM, plays an important role in maintaining long-term humoral immunity. For these reasons, we examined ISCs in human spleen and identified a population that appears analogous to long-lived rodent splenic PCs. Human splenic ISCs shared morphologic, cellular, molecular, and functional characteristics with long-lived PCs in BM, demonstrating their commitment to the PC lineage. Furthermore, the detection of highly mutated immunoglobulin V region genes in splenic ISCs suggested they are likely to be antigen-selected and to secrete high-affinity immunoglobulin. Thus, our results suggest that splenic ISCs have an important role in humoral immunity and may represent the affected cell type in some B-cell dyscrasias.
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Tabrizian, Tahmineh, Donghai Wang, Fangxia Guan, Zunju Hu, Amanda P. Beck, Fabien Delahaye, and Derek M. Huffman. "Apc inactivation, but not obesity, synergizes with Pten deficiency to drive intestinal stem cell-derived tumorigenesis." Endocrine-Related Cancer 24, no. 6 (June 2017): 253–65. http://dx.doi.org/10.1530/erc-16-0536.
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Obesity is a major risk factor for colorectal cancer and can accelerate Lgr5+ intestinal stem cell (ISC)-derived tumorigenesis after the inactivation of Apc. However, whether non-canonical pathways involving PI3K-Akt signaling in ISCs can lead to tumor formation, and if this can be further exacerbated by obesity is unknown. Despite the synergy between Pten and Apc inactivation in epithelial cells on intestinal tumor formation, their combined role in Lgr5+-ISCs, which are the most rapidly dividing ISC population in the intestine, is unknown. Lgr5+-GFP mice were provided low-fat diet (LFD) or high-fat diet (HFD) for 8 months, and the transcriptome was evaluated in Lgr5+-ISCs. For tumor studies, Lgr5+-GFP and Lgr5+-GFP–Pten flox/flox mice were tamoxifen treated to inactivate Pten in ISCs and provided LFD or HFD until 14–15 months of age. Finally, various combinations of Lgr5+-ISC-specific, Apc- and Pten-deleted mice were generated and evaluated for histopathology and survival. HFD did not overtly alter Akt signaling in ISCs, but did increase other metabolic pathways. Pten deficiency, but not HFD, increased BrdU-positive cells in the small intestine (P < 0.05). However, combining Pten and Apc deficiency synergistically increased proliferative markers, tumor pathology and mortality, in a dose-dependent fashion (P < 0.05). In summary, we show that HFD alone fails to drive Akt signaling in ISCs and that Pten deficiency is dispensable as a tumor suppressor in Lgr5+-ISCs. However, combining Pten and Apc deficiency in ISCs synergistically increases proliferation, tumor formation and mortality. Thus, aberrant Wnt/β-catenin, rather than PI3K-Akt signaling, is requisite for obesity to drive Lgr5+ ISC-derived tumorigenesis.
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Liang, Shao-jie, Xiang-guang Li, and Xiu-qi Wang. "Notch Signaling in Mammalian Intestinal Stem Cells: Determining Cell Fate and Maintaining Homeostasis." Current Stem Cell Research & Therapy 14, no. 7 (September 23, 2019): 583–90. http://dx.doi.org/10.2174/1574888x14666190429143734.
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: The intestine serves mainly as a place for digestion and absorption and functions as an immune and endocrine organ. Intestinal stem cells (ISCs) play critical roles in the maintenance of intestinal homeostasis and regeneration, and a complex of signaling pathways is involved in these processes. The Notch signaling pathway is induced via distinct cell-to-cell connections, which are activated through the binding of the Notch ligand on the surface of niche cells to the Notch receptor on ISCs. Numerous studies have shown the central importance of Notch signaling in the proliferation and differentiation of ISCs. Here, we summarize the latest research progress on the crucial functions of Notch signaling in maintaining homeostasis and determining the cell fate of ISCs. Furthermore, the challenges of Notch signaling in colon cancer therapy strategies are also discussed. Several important questions regarding Notch regulation of ISCs are proposed.
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Lundgren, Hans K., and Glenn R. Björk. "Structural Alterations of the Cysteine Desulfurase IscS of Salmonella enterica Serovar Typhimurium Reveal Substrate Specificity of IscS in tRNA Thiolation." Journal of Bacteriology 188, no. 8 (April 15, 2006): 3052–62. http://dx.doi.org/10.1128/jb.188.8.3052-3062.2006.
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ABSTRACT The cysteine desulfurase IscS in Salmonella enterica serovar Typhimurium is required for the formation of all four thiolated nucleosides in tRNA, which is thought to occur via two principally different biosynthetic pathways. The synthesis of 4-thiouridine (s4U) and 5-methylaminomethyl-2-thiouridine (mnm5s2U) occurs by a transfer of sulfur from IscS via various proteins to the target nucleoside in the tRNA, and no iron-sulfur cluster protein participates, whereas the synthesis of 2-thiocytidine (s2C) and N 6-(4-hydroxyisopentenyl)-2-methylthioadenosine (ms2io6A) is dependent on iron-sulfur cluster proteins, whose formation and maintenance depend on IscS. Accordingly, inactivation of IscS should result in decreased synthesis of all thiolated nucleosides. We selected mutants defective either in the synthesis of a thiolated nucleoside (mnm5s2U) specific for the iron-sulfur protein-independent pathway or in the synthesis of a thiolated nucleoside (ms2io6A) specific for the iron-sulfur protein-dependent pathway. Although we found altered forms of IscS that influenced the synthesis of all thiolated nucleosides, consistent with the model, we also found mutants defective in subsets of thiolated nucleosides. Alterations in the C-terminal region of IscS reduced the level of only ms2io6A, suggesting that the synthesis of this nucleoside is especially sensitive to minor aberrations in iron-sulfur cluster transfer activity. Our results suggest that IscS has an intrinsic substrate specificity in how it mediates sulfur mobilization and/or iron-sulfur cluster formation and maintenance required for thiolation of tRNA.
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Bossmann, Stefan H., and Raul Neri. "Isoselenocyanates: Synthesis and Their Use for Preparing Selenium-Based Heterocycles." Synthesis 53, no. 12 (January 22, 2021): 2015–28. http://dx.doi.org/10.1055/a-1370-2046.
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AbstractIsoselenocyanates (ISCs) are a class of organoselenium compounds that have been recognized as potential chemotherapeutic and chemopreventative agents against cancer(s) and infectious diseases. ISC compounds are chemically analogous to their isosteric relatives, isothiocyanates (ITCs); however, they possess increased biological activity, such as enhanced cytotoxicity against cancer cells. ISCs not only serve as significant products, but also as precursors and essential intermediates for a variety of organoselenium compounds, such as selenium-containing heterocycles, which are biologically active. While syntheses of ISCs have become less difficult to accomplish, the syntheses of selenium-containing heterocycles are often difficult due to the use of highly toxic selenium reagents. Because of this, ISCs can serve as versatile reagents for the preparation of these heterocycles. In this review, the classical and recent syntheses of ISCs will be discussed, along with notable and recent synthetic work employing ISCs to access novel selenium-containing heterocycles.1 Introduction1.1 Selenium and Health2 Isoselenocyanates2.1 Preparation of Isoselenocyanates3 Selenium-Containing Heterocycles3.1 Notable Synthetic Work3.2 Recent Synthetic Work3.2.1 Synthesis of N-(3-Methyl-4-phenyl-3H-selenazol-2-ylidene)benzamide Derivatives3.2.2 Synthesis and X-ray Studies of Diverse Selenourea Derivatives3.2.3 Synthesis of Heteroarene-Fused [1,2,4]Thiadiazoles/Selenadiazoles via Iodine-Promoted [3+2] Oxidative Cyclization3.2.4 2-Amino-1,3-selenazole Derivatives via Base-Promoted Multicomponent Reactions4 Conclusion
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Hiramatsu, Yukiko, Akihisa Fukuda, Satoshi Ogawa, Norihiro Goto, Kozo Ikuta, Motoyuki Tsuda, Yoshihide Matsumoto, et al. "Arid1a is essential for intestinal stem cells through Sox9 regulation." Proceedings of the National Academy of Sciences 116, no. 5 (January 11, 2019): 1704–13. http://dx.doi.org/10.1073/pnas.1804858116.
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Inactivating mutations of Arid1a, a subunit of the Switch/sucrose nonfermentable chromatin remodeling complex, have been reported in multiple human cancers. Intestinal deletion of Arid1a has been reported to induce colorectal cancer in mice; however, its functional role in intestinal homeostasis remains unclear. We investigated the functional role of Arid1a in intestinal homeostasis in mice. We found that intestinal deletion of Arid1a results in loss of intestinal stem cells (ISCs), decreased Paneth and goblet cells, disorganized crypt-villous structures, and increased apoptosis in adult mice. Spheroids did not develop from intestinal epithelial cells deficient for Arid1a. Lineage-tracing experiments revealed that Arid1a deletion in Lgr5+ ISCs leads to impaired self-renewal of Lgr5+ ISCs but does not perturb intestinal homeostasis. The Wnt signaling pathway, including Wnt agonists, receptors, and target genes, was strikingly down-regulated in Arid1a-deficient intestines. We found that Arid1a directly binds to the Sox9 promoter to support its expression. Remarkably, overexpression of Sox9 in intestinal epithelial cells abrogated the above phenotypes, although Sox9 overexpression in intestinal epithelial cells did not restore the expression levels of Wnt agonist and receptor genes. Furthermore, Sox9 overexpression permitted development of spheroids from Arid1a-deficient intestinal epithelial cells. In addition, deletion of Arid1a concomitant with Sox9 overexpression in Lgr5+ ISCs restores self-renewal in Arid1a-deleted Lgr5+ ISCs. These results indicate that Arid1a is indispensable for the maintenance of ISCs and intestinal homeostasis in mice. Mechanistically, this is mainly mediated by Sox9. Our data provide insights into the molecular mechanisms underlying maintenance of ISCs and intestinal homeostasis.
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Du, Jun Wei, Wei Qiang Chen, Zhong Zhu, Xin Liu, Si Jun Wan, and Chang Bin Liao. "A Redundancy Design Schema of Distributed Real-Time Database Applied in ISCS." Applied Mechanics and Materials 174-177 (May 2012): 2142–46. http://dx.doi.org/10.4028/www.scientific.net/amm.174-177.2142.
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Reliability is one of the most important properties of integrated supervisory and control system (ISCS) in metro. Redundancy technology, a fault tolerant mechanism, can significantly improve ISCS reliability. This paper introduces a redundancy design schema and its implementation in distributed real-time database, which is the kernel part of ISCS, Including upstream and downstream data redundancy processing technology, fault detection and redundancy switch technology. The result shows that this schema is feasible and reasonable.
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Spivey, Justin, Rebekah Wrenn, Beiyu Liu, Eileen K. Maziarz, Eileen K. Maziarz, and Bridgette Kram. "1303. Characterization of Isavuconazole Serum Concentrations with Various Administration Routes in a Hospitalized Cohort." Open Forum Infectious Diseases 7, Supplement_1 (October 1, 2020): S665—S666. http://dx.doi.org/10.1093/ofid/ofaa439.1486.
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Abstract Background Patients with invasive fungal infections are often critically ill and immunosuppressed with multiple comorbidities that may impact drug absorption and exposure. This study sought to characterize isavuconazole serum concentrations (ISCs) in a cohort of real-world hospitalized patients when administered by intravenous solution (IV), enteral as intact capsules, or tube as opened capsule contents. Methods This retrospective cohort analysis included all hospitalized patients who received isavuconazole as prophylaxis or treatment between September 2017 and September 2018 and had therapeutic drug monitoring performed. For patients receiving isavuconazole by tube, the capsules were opened and contents were diluted with 10-30 mL of sterile water. Administration was per package insert for intact capsules and IV solution. ISCs were obtained as part of routine care and were quantified by high-performance liquid chromatography. An appropriate trough was defined as within 4 hours of the next scheduled dose. Currently, there is a lack of correlation between isavuconazole exposure and efficacy or toxicity; thus, ISCs were compared between administration routes. Results 93 ISCs were obtained during 65 encounters from 55 unique patients. The majority of patients were post-transplant (69.1%) and death occurred during 12 (18.5%) encounters. ISCs based on different characteristics of the cohort are shown in Table 1. All ISC assessments were detectable, median 2.3 mg/dL (Q1: 1.5 mg/dL, Q3: 3.3 mg/dL). Administration via tube achieved similar ISCs compared with IV therapy (1.6 mg/dL vs. 1.9 mg/dL, respectively). However, administration of intact capsules resulted in higher median ISCs, 3 mg/dL (Q1: 1.9 mg/dL, Q3: 4.1 mg/dL). All 14 patients with administration via tube were post-transplant, which was not shown to have a significant impact on ISCs (median, transplant 2.2 mg/dL vs. non-transplant 2.7 mg/dL). Table 1. Characterization of Isavuconazole Concentrations Conclusion ISCs were detectable in all patients regardless of transplant status or location at the time of assessment. Administration of isavuconazole via an enteral feeding tube achieved comparable serum concentrations compared with FDA-approved routes of administration and may represent an important alternative for select patients. Disclosures All Authors: No reported disclosures
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Xingmeng, Jiang, Wu Li, Pan Liwu, Ge Mingtao, and Hu Daidi. "Rolling Bearing Fault Diagnosis Based on ELCD Permutation Entropy and RVM." Journal of Engineering 2016 (2016): 1–7. http://dx.doi.org/10.1155/2016/1308108.
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Aiming at the nonstationary characteristic of a gear fault vibration signal, a recognition method based on permutation entropy of ensemble local characteristic-scale decomposition (ELCD) and relevance vector machine (RVM) is proposed. First, the vibration signal was decomposed by ELCD; then a series of intrinsic scale components (ISCs) were obtained. Second, according to the kurtosis of ISCs, principal ISCs were selected and then the permutation entropy of principal ISCs was calculated and they were combined into a feature vector. Finally, the feature vectors were input in RVM classifier to train and test and identify the type of rolling bearing faults. Experimental results show that this method can effectively diagnose four kinds of working condition, and the effect is better than local characteristic-scale decomposition (LCD) method.
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Fischer, Jared M., Peter P. Calabrese, Ashleigh J. Miller, Nina M. Muñoz, William M. Grady, Darryl Shibata, and R. Michael Liskay. "Single cell lineage tracing reveals a role for TgfβR2 in intestinal stem cell dynamics and differentiation." Proceedings of the National Academy of Sciences 113, no. 43 (October 10, 2016): 12192–97. http://dx.doi.org/10.1073/pnas.1611980113.
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Intestinal stem cells (ISCs) are maintained by a niche mechanism, in which multiple ISCs undergo differential fates where a single ISC clone ultimately occupies the niche. Importantly, mutations continually accumulate within ISCs creating a potential competitive niche environment. Here we use single cell lineage tracing following stochastic transforming growth factor β receptor 2 (TgfβR2) mutation to show cell autonomous effects of TgfβR2 loss on ISC clonal dynamics and differentiation. Specifically, TgfβR2 mutation in ISCs increased clone survival while lengthening times to monoclonality, suggesting that Tgfβ signaling controls both ISC clone extinction and expansion, independent of proliferation. In addition, TgfβR2 loss in vivo reduced crypt fission, irradiation-induced crypt regeneration, and differentiation toward Paneth cells. Finally, altered Tgfβ signaling in cultured mouse and human enteroids supports further the in vivo data and reveals a critical role for Tgfβ signaling in generating precursor secretory cells. Overall, our data reveal a key role for Tgfβ signaling in regulating ISCs clonal dynamics and differentiation, with implications for cancer, tissue regeneration, and inflammation.
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Seok, Chua Bee, Harris Shah Abd Hamid, and Rosnah Ismail. "Psychometric Properties of the Intrapreneurial Self-Capital Scale in Malaysian University Students." Sustainability 11, no. 3 (February 8, 2019): 881. http://dx.doi.org/10.3390/su11030881.
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The Intrapreneurial Self-Capital Scale (ISCS) is a 28-item measure intended to measure individual resources used to manage career and life challenges. The Intrapreneurial Self-Capital (ISC) is a higher order construct composed of seven specific constructs: core self-evaluation, hardiness, resilience, creative self-efficacy, decisiveness, goal mastery, and vigilance. In the new research area of the psychology of sustainability and sustainable development, ISC constitutes a promising core of resources to face the challenges of the 21st century. The aim of the current study was to determine the factor structure and psychometric properties (i.e., reliability and concurrent validity) of a Malaysian version of ISCS among university students. The self-report questionnaire was administered to 1491 university students in Sabah, Malaysia. Confirmatory factor analyses were performed to assess the latent structure of the Malaysian ISCS. The final indices of Goodness of Fit showed satisfactory fit to the data. The Cronbach’s alpha of the Malaysian ISCS is 0.81. The Malaysian ISCS correlates with Career Adaptability r = 0.31 (p < 0.01) and with Life Project Reflexivity r = 0.44 (p < 0.01), thus showing an adequate concurrent validity evidence. The Malaysian ISCS provides a promising research area in psychology (both positive and sustainability). Malaysian parents, teachers and counselors can also use this tool for their development and intervention efforts.
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Dong, Ping, Ying Zhang, Dong-yong Yan, Yi Wang, Xiu Xu, Ying-chun Zhao, and Tian-tian Xiao. "Protective Effects of Human Milk-Derived Exosomes on Intestinal Stem Cells Damaged by Oxidative Stress." Cell Transplantation 29 (January 1, 2020): 096368972091269. http://dx.doi.org/10.1177/0963689720912690.
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Breastfeeding has been shown to have a protective effect on the occurrence of necrotizing enterocolitis (NEC), but the mechanism remains unclear. In the context of NEC pathogenesis, many of the protective properties of exosomes on the intestinal epithelial compartment make it an ideal therapeutic target. In the present study, our hypothesis was that intestinal stem cells (ISCs) would be protected from injury by human milk-derived exosomes (HMDEs). Human breast milk was collected, and exosomes were isolated using ExoQuick reagent. Magnetic-activated cell sorting isolation of prominin-1+ ISCs was performed from small intestines of neonatal rat. ISCs were treated with or without H2O2, and HMDEs, an equal volume of HMDE-free milk, or a control solution [phosphate-buffered solution (PBS)] was added, respectively. In the absence of HMDEs, exposure of ISCs to H2O2 led to decreased cell viability. However, addition of HMDEs to ISCs exposed to H2O2 led to significantly increased ISC viability. There was a significant upregulation of mRNA expression of Axin2, c-Myc, and Cyclin D1 genes of the Wnt/β-catenin axis in ISCs treated with HMDEs (6.99 ± 2.34, 4.21 ± 1.68, 6.17 ± 2.22, respectively, P < 0.05 for all), as compared to control. In the presence of carnosic acid (a specific Wnt/β-catenin signaling inhibitor), the cell viability was significantly decreased. Thus, HMDEs protect ISCs from oxidative stress injury in vitro, which were possibly mediated via the Wnt/β-catenin signaling pathway. Our findings indicate that oral administration of HMDEs might be a promising measure in treating NEC or in preventing the development of NEC in high-risk infants when breast milk is not available.
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Urbina, Hugo D., Jonathan J. Silberg, Kevin G. Hoff, and Larry E. Vickery. "Transfer of Sulfur from IscS to IscU during Fe/S Cluster Assembly." Journal of Biological Chemistry 276, no. 48 (September 27, 2001): 44521–26. http://dx.doi.org/10.1074/jbc.m106907200.
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Smith, Archer D., Jeverson Frazzon, Dennis R. Dean, and Michael K. Johnson. "Role of conserved cysteines in mediating sulfur transfer from IscS to IscU." FEBS Letters 579, no. 23 (September 6, 2005): 5236–40. http://dx.doi.org/10.1016/j.febslet.2005.08.046.
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Du, Jun Wei, and Ya Dong Fang. "Integrated Supervisory Control System Based on Distributed Component Management." Applied Mechanics and Materials 340 (July 2013): 744–48. http://dx.doi.org/10.4028/www.scientific.net/amm.340.744.
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The Distributed Component management technique is a key technology to achieve millions monitor-points and determine the performance of the integrated supervisory control system (ISCS) in rail transit. A feasible technique applied to ISCS is described, which includes the distributed component architecture, component index with positioning and redundant components management. The application results show that the performance of ISCS is unaffected significantly by the number of nodes increased based on this technique. Therefore, this technique meets the millions monitor-points level monitoring performance requirements.
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Hu, Deqing, Han Yan, Xi C. He, and Linheng Li. "Recent advances in understanding intestinal stem cell regulation." F1000Research 8 (January 18, 2019): 72. http://dx.doi.org/10.12688/f1000research.16793.1.
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Intestinal homeostasis and regeneration are driven by intestinal stem cells (ISCs) lying in the crypt. In addition to the actively cycling ISCs that maintain daily homeostasis, accumulating evidence supports the existence of other pools of stem/progenitor cells with the capacity to repair damaged tissue and facilitate rapid restoration of intestinal integrity after injuries. Appropriate control of ISCs and other populations of intestinal epithelial cells with stem cell activity is essential for intestinal homeostasis and regeneration while their deregulation is implicated in colorectal tumorigenesis. In this review, we will summarize the recent findings about ISC identity and cellular plasticity in intestine, discuss regulatory mechanisms that control ISCs for intestinal homeostasis and regeneration, and put a particular emphasis on extrinsic niche-derived signaling and intrinsic epigenetic regulation. Moreover, we highlight several fundamental questions about the precise mechanisms conferring robust capacity for intestine to maintain physiological homeostasis and repair injuries.
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Dahl, Jan-Ulrik, Alexander Urban, Andrea Bolte, Promjit Sriyabhaya, Janet L. Donahue, Manfred Nimtz, Timothy J. Larson, and Silke Leimkühler. "The Identification of a Novel Protein Involved in Molybdenum Cofactor Biosynthesis in Escherichia coli." Journal of Biological Chemistry 286, no. 41 (August 19, 2011): 35801–12. http://dx.doi.org/10.1074/jbc.m111.282368.
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In the second step of the molybdenum cofactor (Moco) biosynthesis in Escherichia coli, the l-cysteine desulfurase IscS was identified as the primary sulfur donor for the formation of the thiocarboxylate on the small subunit (MoaD) of MPT synthase, which catalyzes the conversion of cyclic pyranopterin monophosphate to molybdopterin (MPT). Although in Moco biosynthesis in humans, the thiocarboxylation of the corresponding MoaD homolog involves two sulfurtransferases, an l-cysteine desulfurase, and a rhodanese-like protein, the rhodanese-like protein in E. coli remained enigmatic so far. Using a reverse approach, we identified a so far unknown sulfurtransferase for the MoeB-MoaD complex by protein-protein interactions. We show that YnjE, a three-domain rhodanese-like protein from E. coli, interacts with MoeB possibly for sulfur transfer to MoaD. The E. coli IscS protein was shown to specifically interact with YnjE for the formation of the persulfide group on YnjE. In a defined in vitro system consisting of MPT synthase, MoeB, Mg-ATP, IscS, and l-cysteine, YnjE was shown to enhance the rate of the conversion of added cyclic pyranopterin monophosphate to MPT. However, YnjE was not an enhancer of the cysteine desulfurase activity of IscS. This is the first report identifying the rhodanese-like protein YnjE as being involved in Moco biosynthesis in E. coli. We believe that the role of YnjE is to make the sulfur transfer from IscS for Moco biosynthesis more specific because IscS is involved in a variety of different sulfur transfer reactions in the cell.
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Keller, Sarah, Volker König, and Ralph Mösges. "Thermal Water Applications in the Treatment of Upper Respiratory Tract Diseases: A Systematic Review and Meta-Analysis." Journal of Allergy 2014 (June 1, 2014): 1–17. http://dx.doi.org/10.1155/2014/943824.
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Background. Thermal water inhalations and irrigations have a long tradition in the treatment of airway diseases. Currently there exists no systematic review or meta-analysis on the effectiveness of thermal water treatment in upper respiratory tract diseases. Methods. A systematic search in the databases of MEDLINE, EMBASE, CENTRAL, ISI Web of Science, and MedPilot was accomplished. Results. Eight evaluable outcome parameters from 13 prospective clinical studies were identified for 840 patients. Mucociliary clearance time improves significantly (P<0.01) for the pooled thermal water subgroup and the sulphurous subgroup after 2 weeks (−6.69/minutes) and after 90 days (−8.33/minutes), not for isotonic sodium chloride solution (ISCS). Nasal resistance improved significantly after 2 weeks (Radon, ISCS, and placebo), after 30 days (sulphur and ISCS), and after 90 days (sulphur). Nasal flow improved significantly with the pooled thermal water, radon alone, and ISCS subgroups. For the IgE parameter only sulphurous thermal water (P<0.01) and ISCS (P>0.01) were analyzable. Adverse events of minor character were only reported for sulphurous treatment (19/370). Conclusion. Thermal water applications with radon or sulphur can be recommended as additional nonpharmacological treatment in upper airway diseases. Also in comparison to isotonic saline solution it shows significant improvements and should be investigated further.
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Resende, Luís Pedro, Augusta Monteiro, Rita Brás, Tatiana Lopes, and Claudio E. Sunkel. "Aneuploidy in intestinal stem cells promotes gut dysplasia in Drosophila." Journal of Cell Biology 217, no. 11 (October 3, 2018): 3930–46. http://dx.doi.org/10.1083/jcb.201804205.
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Aneuploidy is associated with different human diseases including cancer. However, different cell types appear to respond differently to aneuploidy, either by promoting tumorigenesis or causing cell death. We set out to study the behavior of adult Drosophila melanogaster intestinal stem cells (ISCs) after induction of chromosome missegregation either by abrogation of the spindle assembly checkpoint or through kinetochore disruption or centrosome amplification. These conditions induce moderate levels of aneuploidy in ISCs, and we find no evidence of apoptosis. Instead, we observe a significant accumulation of ISCs associated with increased stem cell proliferation and an excess of enteroendocrine cells. Moreover, aneuploidy causes up-regulation of the JNK pathway throughout the posterior midgut, and specific inhibition of JNK signaling in ISCs is sufficient to prevent dysplasia. Our findings highlight the importance of understanding the behavior of different stem cell populations to aneuploidy and how these can act as reservoirs for genomic alterations that can lead to tissue pathologies.
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Yu, Songwei, Haili Chang, and Hanjun Wang. "Design of Cloud Computing and Microservice-Based Urban Rail Transit Integrated Supervisory Control System Plus." Urban Rail Transit 6, no. 4 (November 9, 2020): 187–204. http://dx.doi.org/10.1007/s40864-020-00138-z.
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AbstractIn traditional metro weak current systems, subsystems built by different manufacturers are physically separated, and devices are redundant while data are isolated. This causes low resource use, high maintenance cost, long customization cycles, and high interface complexity. In this paper, based on an analysis of the problems in traditional metro weak current systems, a novel cloud and microservice-based urban rail transit integrated supervisory control system (ISCS) named ISCS Plus is proposed. The integration mode of each subsystem is determined by analyzing safety requirements, real-time performance, and business characteristics. An infrastructure platform is designed to share resources and isolate applications based on cloud computing technology, while traditional subsystems are decomposed as microservices and merged into different applications. Finally, the entire architecture of ISCS Plus is established and its features are discussed. ISCS Plus plays a key role in the systematic, intelligent, and automatic solution for metro weak current systems and supports the development of the world's leading metro weak current systems.
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Strilbytska, Olha. "Regulation of Drosophila Intestinal Stem Cell Maintenance and Proliferation." Journal of Vasyl Stefanyk Precarpathian National University 2, no. 1 (April 30, 2015): 77–84. http://dx.doi.org/10.15330/jpnu.2.1.77-84.
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To maintain gut homeostasis intestinal stem cells (ISCs) constantly replace damagedones. This process is conservative from Drosophila to human. Proliferation and differentiation ofISCs in adult Drosophila midgut are regulated by growth factors which are secreted in thesurrounding cells collectively forming ISCs niche. Here I discuss an interaction between ISCs withits niche through conservative signaling pathways. Several evidences on significance ofcooperation between multiple signaling pathways including Notch, Wingless, JAK/STAT, EGFR,Hippo, and insulin signaling for regulation of stem cell maintenance and activity are provided.Further investigation in this area will allow us to understand how proper regulation of ISCsmaintenance and differentiation can assist to ensure intestinal integrity
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Ahmed, Jawad H., Manal S. Al Diwan, and Abdullah M. Jawad. "Effect of methoxyverapamil, diltiazem, morphine and their combination on the formation of irreversibly sickled cells: an in vitro study." Eastern Mediterranean Health Journal 3, no. 2 (March 15, 1997): 301–9. http://dx.doi.org/10.26719/1997.3.2.301.
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The effect of methoxyverapamil and diltiazem [calcium antagonists] and morphine [calcium antagonist activity] on the formation of irreversibly sickled cells [ISCs] was investigated. Methoxyverapamil at therapeutic concentration and 10 times that level resulted in a 12% and 21% reduction in the formation of ISCs respectively, which was statistically significant. Diltiazem also produced a significant reduction in ISCs but morphine produced no significant reduction. Combination of these drugs produced a net effect similar to their individual effects. These drugs might be useful in decreasing the intensity of sickling crises and vaso-occlusive events. Thus in vivo trials in patients with sickle-cell disease are suggested
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LaGier, Michael J., Jan Tachezy, Frantisek Stejskal, Katerina Kutisova, and Janet S. Keithly. "Mitochondrial-type iron–sulfur cluster biosynthesis genes (IscS and IscU) in the apicomplexan Cryptosporidium parvum." Microbiology 149, no. 12 (December 1, 2003): 3519–30. http://dx.doi.org/10.1099/mic.0.26365-0.
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Several reports have indicated that the iron–sulfur cluster [Fe–S] assembly machinery in most eukaryotes is confined to the mitochondria and chloroplasts. The best-characterized and most highly conserved [Fe–S] assembly proteins are a pyridoxal-5′-phosphate-dependent cysteine desulfurase (IscS), and IscU, a protein functioning as a scaffold for the assembly of [Fe–S] prior to their incorporation into apoproteins. In this work, genes encoding IscS and IscU homologues have been isolated and characterized from the apicomplexan parasite Cryptosporidium parvum, an opportunistic pathogen in AIDS patients, for which no effective treatment is available. Primary sequence analysis (CpIscS and CpIscU) and phylogenetic studies (CpIscS) indicate that both genes are most closely related to mitochondrial homologues from other organisms. Moreover, the N-terminal signal sequences of CpIscS and CpIscU predicted in silico specifically target green fluorescent protein to the mitochondrial network of the yeast Saccharomyces cerevisiae. Overall, these findings suggest that the previously identified mitochondrial relict of C. parvum may have been retained by the parasite as an intracellular site for [Fe–S] assembly.
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Van Landeghem, Laurianne, M. Agostina Santoro, Adrienne E. Krebs, Amanda T. Mah, Jeffrey J. Dehmer, Adam D. Gracz, Brooks P. Scull, Kirk McNaughton, Scott T. Magness, and P. Kay Lund. "Activation of two distinct Sox9-EGFP-expressing intestinal stem cell populations during crypt regeneration after irradiation." American Journal of Physiology-Gastrointestinal and Liver Physiology 302, no. 10 (May 15, 2012): G1111—G1132. http://dx.doi.org/10.1152/ajpgi.00519.2011.
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Recent identification of intestinal epithelial stem cell (ISC) markers and development of ISC reporter mice permit visualization and isolation of regenerating ISCs after radiation to define their functional and molecular phenotypes. Previous studies in uninjured intestine of Sox9-EGFP reporter mice demonstrate that ISCs express low levels of Sox9-EGFP (Sox9-EGFP Low), whereas enteroendocrine cells (EEC) express high levels of Sox9-EGFP (Sox9-EGFP High). We hypothesized that Sox9-EGFP Low ISCs would expand after radiation, exhibit enhanced proliferative capacities, and adopt a distinct gene expression profile associated with rapid proliferation. Sox9-EGFP mice were given 14 Gy abdominal radiation and studied between days 3 and 9 postradiation. Radiation-induced changes in number, growth, and transcriptome of the different Sox9-EGFP cell populations were determined by histology, flow cytometry, in vitro culture assays, and microarray. Microarray confirmed that nonirradiated Sox9-EGFP Low cells are enriched for Lgr5 mRNA and mRNAs enriched in Lgr5-ISCs and identified additional putative ISC markers. Sox9-EGFP High cells were enriched for EEC markers, as well as Bmi1 and Hopx, which are putative markers of quiescent ISCs. Irradiation caused complete crypt loss, followed by expansion and hyperproliferation of Sox9-EGFP Low cells. From nonirradiated intestine, only Sox9-EGFP Low cells exhibited ISC characteristics of forming organoids in culture, whereas during regeneration both Sox9-EGFP Low and High cells formed organoids. Microarray demonstrated that regenerating Sox9-EGFP High cells exhibited transcriptomic changes linked to p53-signaling and ISC-like functions including DNA repair and reduced oxidative metabolism. These findings support a model in which Sox9-EGFP Low cells represent active ISCs, Sox9-EGFP High cells contain radiation-activatable cells with ISC characteristics, and both participate in crypt regeneration.
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Takashima, Shuichiro, Masanori Kadowaki, Kazutoshi Aoyama, Motoko Koyama, Takeshi Oshima, Kazuma Tomizuka, Koichi Akashi, and Takanori Teshima. "The Wnt agonist R-spondin1 regulates systemic graft-versus-host disease by protecting intestinal stem cells." Journal of Experimental Medicine 208, no. 2 (January 31, 2011): 285–94. http://dx.doi.org/10.1084/jem.20101559.
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Graft-versus-host disease (GVHD) is a major complication of allogeneic bone marrow transplantation (BMT), and damage to the gastrointestinal (GI) tract plays a critical role in amplifying systemic disease. Intestinal stem cells (ISCs) play a pivotal role not only in physiological tissue renewal but also in regeneration of the intestinal epithelium after injury. In this study, we have discovered that pretransplant conditioning regimen damaged ISCs; however, the ISCs rapidly recovered and restored the normal architecture of the intestine. ISCs are targets of GVHD, and this process of ISC recovery was markedly inhibited with the development of GVHD. Injection of Wnt agonist R-spondin1 (R-Spo1) protected against ISC damage, enhanced restoration of injured intestinal epithelium, and inhibited subsequent inflammatory cytokine cascades. R-Spo1 ameliorated systemic GVHD after allogeneic BMT by a mechanism dependent on repair of conditioning-induced GI tract injury. Our results demonstrate for the first time that ISC damage plays a central role in amplifying systemic GVHD; therefore, we propose ISC protection by R-Spo1 as a novel strategy to improve the outcome of allogeneic BMT.
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Amcheslavsky, Alla, Naoto Ito, Jin Jiang, and Y. Tony Ip. "Tuberous sclerosis complex and Myc coordinate the growth and division of Drosophila intestinal stem cells." Journal of Cell Biology 193, no. 4 (May 9, 2011): 695–710. http://dx.doi.org/10.1083/jcb.201103018.
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Intestinal stem cells (ISCs) in the adult Drosophila melanogaster midgut can respond to damage and support repair. We demonstrate in this paper that the tuberous sclerosis complex (TSC) plays a critical role in balancing ISC growth and division. Previous studies have shown that imaginal disc cells that are mutant for TSC have increased rates of growth and division. However, we report in this paper that loss of TSC in the adult Drosophila midgut results in the formation of much larger ISCs that have halted cell division. These mutant ISCs expressed proper stem cell markers, did not differentiate, and had defects in multiple steps of the cell cycle. Slowing the growth by feeding rapamycin or reducing Myc was sufficient to rescue the division defect. The TSC mutant guts had a thinner epithelial structure than wild-type tissues, and the mutant flies were more susceptible to tissue damage. Therefore, we have uncovered a context-dependent phenotype of TSC mutants in adult ISCs, such that the excessive growth leads to inhibition of division.
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Wasicko, M. J., J. E. Melton, J. A. Neubauer, N. Krawciw, and N. H. Edelman. "Cervical sympathetic and phrenic nerve responses to progressive brain hypoxia." Journal of Applied Physiology 68, no. 1 (January 1, 1990): 53–58. http://dx.doi.org/10.1152/jappl.1990.68.1.53.
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To determine if depression of central respiratory output during progressive brain hypoxia (PBH) can be generalized to other brain stem outputs, we examined the effect of PBH on the tonic (tSCS) and inspiratory-synchronous (iSCS) components of preganglionic superior cervical sympathetic (SCS) nerve activity. Peak phrenic and SCS activity were measured in nine anesthetized, paralyzed, peripherally chemodenervated, vagotomized cats. PBH was produced by inhalation of 0.5% CO in 40% O2 while blood pressure and end-tidal CO2 were maintained constant. A progressive reduction in arterial O2 content from 14.3 +/- 0.6 to 4.5 +/- 0.3 vol% caused a 79 +/- 7% depression of peak phrenic activity and an 84 +/- 10% reduction of iSCS activity, but tSCS activity increased 42 +/- 21%. During CO2 rebreathing, iSCS activity increased in parallel with peak phrenic activity while tSCS activity was unchanged. The slopes of the CO2 responses of both phrenic (6.3 +/- 1.2%max/mmHg) and iSCS (4.6 +/- 0.8%max/mmHg) activity were unaffected by PBH. In four of nine hypocapnic and three of nine hypoxic studies, inspiratory activity in the SCS nerve was observed even after completely silencing the phrenic neurogram.(ABSTRACT TRUNCATED AT 250 WORDS)
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Wolff, A. C., U. Kutscha, T. Wetter, P. Knaup, and S. Garde. "CSI-ISC." Methods of Information in Medicine 45, no. 01 (2006): 10–18. http://dx.doi.org/10.1055/s-0038-1634031.
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Summary Objectives: The introduction of information system components (ISCs) usually leads to a change in existing processes, e.g. processes of patient care. These processes might become even more complex and variable than before. An early participation of end users and a better understanding of human factors during design and introduction of ISCs are key factors for a successful introduction of ISCs in health care. Nonetheless no specialized methods have been developed until now to systematically support the integration of ISCs in existing processes of patient care while taking into account these requirements. In this paper, therefore, we introduce a procedure model to implement Concepts for Smooth Integration of ISCs (CSI-ISC). Methods: Established theories from economics and social sciences have been applied in our model, among them the stress-strain-concept, the contrastive task analysis (KABA), and the phase model for the management of information systems. Results: CSI-ISC is based on the fact that while introducing new information system components, users experience additional workload. One essential aim during the introduction process therefore should be to systematically identify, prioritize and ameliorate workloads that are being imposed on human beings by information technology in health care. To support this, CSI-ISC consists of a static part (workload framework) and a dynamic part (guideline for the introduction of information system components into existing processes of patient care). Conclusions: The application of CSI-ISC offers the potential to minimize additional workload caused by information system components systematically. CSI-ISC rationalizes decisions and supports the integration of the information system component into existing processes of patient care.
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Takashima, S., M. L. Martin, S. A. Jansen, Y. Fu, J. Bos, D. Chandra, M. H. O’Connor, et al. "T cell–derived interferon-γ programs stem cell death in immune-mediated intestinal damage." Science Immunology 4, no. 42 (December 6, 2019): eaay8556. http://dx.doi.org/10.1126/sciimmunol.aay8556.
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Despite the importance of intestinal stem cells (ISCs) for epithelial maintenance, there is limited understanding of how immune-mediated damage affects ISCs and their niche. We found that stem cell compartment injury is a shared feature of both alloreactive and autoreactive intestinal immunopathology, reducing ISCs and impairing their recovery in T cell–mediated injury models. Although imaging revealed few T cells near the stem cell compartment in healthy mice, donor T cells infiltrating the intestinal mucosa after allogeneic bone marrow transplantation (BMT) primarily localized to the crypt region lamina propria. Further modeling with ex vivo epithelial cultures indicated ISC depletion and impaired human as well as murine organoid survival upon coculture with activated T cells, and screening of effector pathways identified interferon-γ (IFNγ) as a principal mediator of ISC compartment damage. IFNγ induced JAK1- and STAT1-dependent toxicity, initiating a proapoptotic gene expression program and stem cell death. BMT with IFNγ–deficient donor T cells, with recipients lacking the IFNγ receptor (IFNγR) specifically in the intestinal epithelium, and with pharmacologic inhibition of JAK signaling all resulted in protection of the stem cell compartment. In addition, epithelial cultures with Paneth cell–deficient organoids, IFNγR-deficient Paneth cells, IFNγR–deficient ISCs, and purified stem cell colonies all indicated direct targeting of the ISCs that was not dependent on injury to the Paneth cell niche. Dysregulated T cell activation and IFNγ production are thus potent mediators of ISC injury, and blockade of JAK/STAT signaling within target tissue stem cells can prevent this T cell–mediated pathology.
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Horiuchi, K., SK Ballas, and T. Asakura. "The effect of deoxygenation rate on the formation of irreversibly sickled cells." Blood 71, no. 1 (January 1, 1988): 46–51. http://dx.doi.org/10.1182/blood.v71.1.46.46.
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Abstract The effects of the deoxygenation rate on the formation of irreversibly sickled cells (ISCs) were investigated by using metabolically replete sickle cells (SS cells). We found that the formation of ISCs required Ca2+ and that the amount formed depended on the rate of deoxygenation. When less dense SS discocytes were deoxygenated slowly by flushing with 95% N2 and 5% CO2 at a rate of 3 mL/min, the percentage of ISCs increased from 5% to 26.5% after 24 hours. In contrast, upon rapid deoxygenation (10, 35 mL/min) ISC formation was reduced significantly. The difference may be related to fact that more sickle-shaped cells were formed upon slow deoxygenation than upon the rapid deoxygenation that resulted in the formation of star-shaped and granulated cells. So- called ISCs were formed more easily from sickle-shaped cells. To express the shape of sickled cells numerically, we calculated the mean maximum cell length (MCL) after cells were incubated under various deoxygenation conditions. The MCL of slowly deoxygenated SS cells after 24 hours of incubation was about twice (20.0 +/- 7.0 micron) that of quickly deoxygenated (35 mL/min) SS cells (12.5 +/- 5.0 microns) (initial MCL, 8.0 +/- 1.0 micron). The decrease in potassium content was greater with slow deoxygenation than with rapid deoxygenation. Because the increase in sodium influx was less than that of potassium efflux under slow deoxygenation, SS cells became more dense than those rapidly deoxygenated. In the absence of Ca2+, morphological changes were the same as in the presence of Ca2+; however, under this condition there was no change in density, and no ISCs were formed regardless of the rate of deoxygenation. These results demonstrate that the number of ISCs formed correlates with the MCL. The length of fibers of sickle hemoglobin may be a determinant of the length of sickled cells. This suggests that membrane stretching plays an important role in cell density and irreversible membrane deformation.
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Horiuchi, K., SK Ballas, and T. Asakura. "The effect of deoxygenation rate on the formation of irreversibly sickled cells." Blood 71, no. 1 (January 1, 1988): 46–51. http://dx.doi.org/10.1182/blood.v71.1.46.bloodjournal71146.
Full textAbstract:
The effects of the deoxygenation rate on the formation of irreversibly sickled cells (ISCs) were investigated by using metabolically replete sickle cells (SS cells). We found that the formation of ISCs required Ca2+ and that the amount formed depended on the rate of deoxygenation. When less dense SS discocytes were deoxygenated slowly by flushing with 95% N2 and 5% CO2 at a rate of 3 mL/min, the percentage of ISCs increased from 5% to 26.5% after 24 hours. In contrast, upon rapid deoxygenation (10, 35 mL/min) ISC formation was reduced significantly. The difference may be related to fact that more sickle-shaped cells were formed upon slow deoxygenation than upon the rapid deoxygenation that resulted in the formation of star-shaped and granulated cells. So- called ISCs were formed more easily from sickle-shaped cells. To express the shape of sickled cells numerically, we calculated the mean maximum cell length (MCL) after cells were incubated under various deoxygenation conditions. The MCL of slowly deoxygenated SS cells after 24 hours of incubation was about twice (20.0 +/- 7.0 micron) that of quickly deoxygenated (35 mL/min) SS cells (12.5 +/- 5.0 microns) (initial MCL, 8.0 +/- 1.0 micron). The decrease in potassium content was greater with slow deoxygenation than with rapid deoxygenation. Because the increase in sodium influx was less than that of potassium efflux under slow deoxygenation, SS cells became more dense than those rapidly deoxygenated. In the absence of Ca2+, morphological changes were the same as in the presence of Ca2+; however, under this condition there was no change in density, and no ISCs were formed regardless of the rate of deoxygenation. These results demonstrate that the number of ISCs formed correlates with the MCL. The length of fibers of sickle hemoglobin may be a determinant of the length of sickled cells. This suggests that membrane stretching plays an important role in cell density and irreversible membrane deformation.
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Xu, Wei, Peter M. Jones, Houfa Geng, Rui Li, Xuekui Liu, Yinxia Li, Qian Lv, et al. "Islet Stellate Cells Regulate Insulin Secretion via Wnt5a in Min6 Cells." International Journal of Endocrinology 2020 (February 24, 2020): 1–12. http://dx.doi.org/10.1155/2020/4708132.
Full textAbstract:
Background. Type 2 diabetes mellitus is a serious public health problem worldwide. Accumulating evidence has shown that β-cell dysfunction is an important mechanism underlying diabetes mellitus. The changes in the physiological state of islet stellate cells (ISCs) and the effects of these cells on β cell function play an important role in the development of diabetes. This study aimed at elucidating the mechanism by which ISCs regulate insulin secretion from Min6 cells via the Wnt5a protein. Methods. Glucose-stimulated insulin secretion (GSIS) from Min6 cells was examined by estimating the insulin levels in response to high glucose challenge after culture with ISC supernatant or exogenous Wnt5a. Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR) analyses were used to observe changes in the β-catenin, receptor tyrosine kinase-like orphan receptor 2 (Ror2), Ca (2+)/calmodulin (CaM)-dependent protein kinase II (CamKII), forkhead box O1 (FoxO1), pancreatic and duodenal homeobox 1 (PDX1), glucose transporter 2 (Glut2), insulin, and Cask mRNA and protein levels in the Wnt and insulin secretory pathways. Flow cytometry was used to confirm the intracellular Ca2+ concentration in Min6 cells. Results. We observed a significant increase in insulin secretion from Min6 cells cocultured in vitro with supernatant from db/m mouse ISCs compared to that from Min6 cells cocultured with supernatant from db/db mouse ISCs; The intracellular Ca2+ concentration in Min6 cells increased in cultured in vitro with supernatant from db/m mouse ISCs and exogenous Wnt5a compared to that from control Min6 cells. Culture of Min6 cells with exogenous Wnt5a caused a significant increase in pCamKII, pFoxO1, PDX-1, and Glut2 levels compared to those in Min6 cells cultured alone; this treatment further decreased Ror2 and Cask expression but did not affect β-catenin expression. Conclusion. ISCs regulate insulin secretion from Min6 cells through the Wnt5a protein-induced Wnt-calcium and FoxO1-PDX1-GLUT2-insulin signalling cascades.
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Nakamura, M., K. Saeki, and Y. Takahashi. "Hyperproduction of Recombinant Ferredoxins in Escherichia coli by Coexpression of the ORF1-ORF2-iscS-iscU-iscA-hscB-hscA-fdx-ORF3 Gene Cluster." Journal of Biochemistry 126, no. 1 (July 1, 1999): 10–18. http://dx.doi.org/10.1093/oxfordjournals.jbchem.a022409.
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Smith, Archer D., Jeffrey N. Agar, Keith A. Johnson, Jeverson Frazzon, I. Jonathan Amster, Dennis R. Dean, and Michael K. Johnson. "Sulfur Transfer from IscS to IscU: The First Step in Iron−Sulfur Cluster Biosynthesis." Journal of the American Chemical Society 123, no. 44 (November 2001): 11103–4. http://dx.doi.org/10.1021/ja016757n.
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