Journal articles on the topic 'KIR region'
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1
Gemejiyeva, N. G., M. S. Ramazanova, A. Musrat, and A. V. Kerdyashkin. "Distribution and stocks of plant raw materials of promising alkaloid plants from South Balkhash." Проблемы ботаники Южной Сибири и Монголии 19, no. 1 (June 2, 2020): 93–97. http://dx.doi.org/10.14258/pbssm.2020019.
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In the article, the results of studies on the distribution and stocks of plant raw materials on promisingalkaloid-bearing plants from South Balkhash region are shown. Practical interests have the stocks of Haplophyllum perforatum Kar. et Kir. and Echinops albicaulis Kar. et Kir. The decrease in stocks of Echinops albicaulis was noted due toanthropogenic impact.
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Knyazev, M. S. "Astragalus habaheensis (sect. Erioceras, Fabaceae) in Mongolia and China." Novitates Systematicae Plantarum Vascularium, no. 51 (December 2020): 39–42. http://dx.doi.org/10.31111/novitates/2020.51.39.
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A new species to the flora of Mongolia, Astragalus habaheensis Y. X. Liou (A. arcuatus Kar. et Kir. s. l., Fabaceae), was revealed among herbarium material (LE!). It is assumed that all reports of A. arcuatus Kar. et Kir. and A. subarcuatus Popov for Xinjiang Uyghur Autonomous Region of China also belong to A. habaheensis. The difference between A. habaheensis and closely related species is illustrated by the original illustration and the identification key.
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Anderson, Stephen, Hongchuan Li, Andrew Huehn, Sarah Cooley, and Jeffrey Miller. "Characterization of a weakly expressed KIR2DL1 allele supports a positive role for the KIR distal promoter in proximal KIR promoter activation. (P1357)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 63.31. http://dx.doi.org/10.4049/jimmunol.190.supp.63.31.
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Abstract The variegated expression of the human KIR family of class I MHC receptors provides an interesting model system for the study of stochastic activation of gene transcription. Previous studies have linked distal KIR promoter transcription to the initiation of KIR expression from the proximal promoter. In order to identify novel genetic alterations associated with decreased KIR expression, a group of 182 donors was characterized for KIR gene content, KIR transcripts, and FACS analysis of KIR surface expression. An individual was discovered that possessed a single copy of the KIR2DL1 gene but had a low level of gene expression by either FACS or Q-PCR. Complete sequencing of the KIR2DL1 gene confirmed the presence of an intact coding region. Analysis of the three known promoter regions revealed a cluster of 3 single nucleotide polymorphisms (SNPs) in the distal promoter region approximately 1 kb upstream from the start of KIR2DL1 translation. These SNPs are also found in the distal promoter region of the non-transcribed KIR2DL5*002 allele as well as the KIR3DP1 pseudogene. One of these SNPs creates a binding site for the inhibitory ZEB1 transcription factor that overlaps a c-Myc binding site previously implicated in the activation of KIR genes by distal transcription. We therefore propose that the generation of this novel ZEB1-binding site antagonizes the Myc-associated activation of the KIR2DL1 gene by the distal promoter.
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Haack, Becky, Valarie McCullar, Todd Lenvik, Michelle Pitt, Stephen Anderson, and Jeffrey S. Miller. "C-MYC Induces KIR Expression Via a Novel Control Region Upstream of the Conventional Adult KIR Promoter." Blood 106, no. 11 (November 16, 2005): 764. http://dx.doi.org/10.1182/blood.v106.11.764.764.
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Abstract KIR determine whether NK cells will be alloreactive against targets. Although epigenetic control is thought to play a role in KIR expression, the mechanism of KIR repertoire formation is unknown. Recently, a probabilistic transcriptional mechanism has been shown to control the acquisition of mouse Ly49 receptors using a switch region upstream of each Ly49 promoter (S. Anderson). Based on this information, the DNA upstream of known KIR genes was scanned for similar motifs to test the hypothesis that similar control mechanisms are operant in human NK cells. A putative c-myc/AML binding site was found approximately 1Kb upstream of the traditional KIR promoters. Initiation of transcription in this region was observed by RNAse protection, and spliced KIR mRNAs originating in the upstream region were cloned. To look at the effects of c-myc on KIR expression, we transduced NK92 cells using retroviral murine stem cell virus vectors containing either c-myc/eGFP or eGFP alone. Cells expressing high levels of c-myc were 18% KIR positive as compared to 0.9% of control cells. To further look at the effect of c-myc on KIR from primary cells, we transduced CD34+ progenitors isolated from umbilical cord blood with c-myc/eGFP and eGFP vectors. eGFP+ cells were plated on the murine fetal liver line AFT024 and cultured with IL-15, IL-7, IL-3, Flt3 ligand, and c-kit ligand, all known to induce NK cell differentiation. Although c-myc is an oncogene, it did not promote autonomous growth of NK cells in the absence of exogenous cytokines. Proliferation was significantly increased in single cell progenitors over-expressing c-myc with 739.3x103 NK cell progeny compared to 0.56x103 from each control cell after 21 days (p<0.0001). At this early time point, 21.68 ± 3.25% of c-myc cells were KIR positive while 0.0% of control cells were KIR positive (p<0.0001) suggesting that c-myc targets KIR expression. Furthermore, bulk-transduced cells over expressing c-myc had 3.9 times the level of early non-coding transcripts originating from the upstream promoter as compared to eGFP transduced cells. A direct effect of c-myc on the upstream promoter was supported by ChIP assays demonstrating increased binding to the c-myc/AML site. The presence of these upstream transcripts directly correlates with increased conventional KIR transcripts as shown by Q-RT-PCR and an increase of KIR expression as shown by flow cytometry. These data show that c-myc play an important role in the differentiation of NK cells and in KIR acquisition. Experiments are currently in progress to look at the effects of the competing AML site on KIR expression and to investigate how non-coding RNA affects adult KIR expression. Understanding the mechanisms of KIR expression may lead to development of novel strategies to manipulate NK cells for therapeutic benefit.
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Nakimuli, Annettee, Olympe Chazara, Susan E. Hiby, Lydia Farrell, Stephen Tukwasibwe, Jyothi Jayaraman, James A. Traherne, et al. "A KIR B centromeric region present in Africans but not Europeans protects pregnant women from pre-eclampsia." Proceedings of the National Academy of Sciences 112, no. 3 (January 5, 2015): 845–50. http://dx.doi.org/10.1073/pnas.1413453112.
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In sub-Saharan Africans, maternal mortality is unacceptably high, with >400 deaths per 100,000 births compared with <10 deaths per 100,000 births in Europeans. One-third of the deaths are caused by pre-eclampsia, a syndrome arising from defective placentation. Controlling placentation are maternal natural killer (NK) cells that use killer-cell immunoglobulin-like receptor (KIR) to recognize the fetal HLA-C molecules on invading trophoblast. We analyzed genetic polymorphisms of maternal KIR and fetal HLA-C in 484 normal and 254 pre-eclamptic pregnancies at Mulago Hospital, Kampala, Uganda. The combination of maternal KIR AA genotypes and fetal HLA-C alleles encoding the C2 epitope associates with pre-eclampsia [P = 0.0318, odds ratio (OR) = 1.49]. The KIR genes associated with protection are located in centromeric KIR B regions that are unique to sub-Saharan African populations and contain the KIR2DS5 and KIR2DL1 genes (P = 0.0095, OR = 0.59). By contrast, telomeric KIR B genes protect Europeans against pre-eclampsia. Thus, different KIR B regions protect sub-Saharan Africans and Europeans from pre-eclampsia, whereas in both populations, the KIR AA genotype is a risk factor for the syndrome. These results emphasize the importance of undertaking genetic studies of pregnancy disorders in African populations with the potential to provide biological insights not available from studies restricted to European populations.
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Cichocki, Frank, Todd Lenvik, Stephen K. Anderson, and Jeffrey S. Miller. "Antisense transcripts negatively regulate transcription of multiple variegated killer immunoglobulin-like receptor (KIR) genes (136.38)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 136.38. http://dx.doi.org/10.4049/jimmunol.182.supp.136.38.
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Abstract The objective of this study is to understand the epigenetic mechanisms that regulate Killer Immunoglobulin-Like Receptor (KIR) gene regulation in human natural killer (NK) cells. We have previously identified both bidirectional transcription within the previously characterized KIR promoter and a novel promoter element upstream of the previously characterized promoter. Based on these findings, we propose that antisense transcripts homologous to the KIR promoter region participate in the establishment of the epigenetic modifications that silence individual KIR genes during human NK cell development. To test this prediction, we overexpressed KIR3DL1 antisense transcripts in developing NK cells and found that mature cells from these cultures exhibited a four-fold decrease in KIR expression relative to GFP-expressing controls. We have also identified 324 base pair and 28 base pair double-stranded RNA molecules homologous to the KIR3DL1 promoter region, suggesting that a siRNA mechanism may be responsible for establishment of the promoter methylation patterns within the KIR locus. Understanding the mechanisms of KIR expression, a requisite for NK cell education/licensing, may allow us to understand the acquisition of effector function and manipulate it for therapeutic benefit. R01 HL 55417
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Cichocki, Frank, Todd Lenvik, Stephen K. Anderson, and Jeffrey S. Miller. "Antisense Transcripts Negatively Regulate Transcription of Multiple Variegated Killer Immunoglobulin-Like Receptor (KIR) Genes." Blood 112, no. 11 (November 16, 2008): 105. http://dx.doi.org/10.1182/blood.v112.11.105.105.
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Abstract Natural killer cells are CD3 negative large granular lymphocytes that lyse virally infected and malignantly transformed targets. NK cell functions are regulated by an array of inhibitory and activating receptors, including members of the killer immunoglobulin-like receptor (KIR) family. Human KIR genes are expressed in a variegated and clonally restricted manner on the surface of mature NK cells. While it is well established that individual KIR gene expression is strongly correlated with the DNA methylation status of CpG dinucleotides within the promoter region proximal to the transcriptional start site, the mechanisms that regulate variegated KIR expression are largely unknown. Our goal is to uncover the genetic mechanisms governing KIR transcriptional regulation. We have recently identified an active distal promoter element approximately 1 Kb upstream of the transcriptional start site. This region contains c-MYC binding sites, and KIR expression is increased when MYC is overexpressed in developing NK cells or when c-MYC is physiologically increased by IL-15 activation. Bi-directional promoter activity is found within the previously characterized proximal promoter of all KIR genes. Therefore, double-stranded RNA with homology to the KIR promoter can be generated within this non-coding region. The generation of double-stranded RNA has recently been shown to contribute to promoter DNA methylation of the p15 gene in mammalian cells through a Dicer-independent mechanism. Using quantitative real-time PCR, we found that purified peripheral blood CD56+/KIR3DL1− NK cells express 5-fold more KIR3DL1 antisense transcript than purified CD56+/KIR3DL1+ cells. Therefore, the transcriptional activation of the KIR3DL1 gene correlates with a significant decrease in KIR3DL1 antisense expression. To explore the possibility that KIR antisense transcripts can silence KIR expression, we over-expressed the KIR3DL1 antisense transcript in CD34+ hematopoietic precursor cells and differentiated these cells into NK cells in vitro. After 21 days in culture, we assayed KIR3DL1 mRNA levels using quantitative real-time PCR. KIR3DL1 expression was reduced 4-fold compared to eGFP control cultures, further supporting the hypothesis that antisense transcripts negatively regulate KIR expression. Importantly, expression of the KIR2DL4 gene, which does not contain a promoter with significant homology to KIR3DL1 promoter, was not affected by KIR3DL1 antisense overexpression. This provides the first evidence for gene silencing through double-stranded RNA in the immune system and may be the key mechanism for the establishment of DNA promoter methylation within the KIR locus. Understanding the mechanisms of KIR expression, a requisite for NK cell education/licensing, may allow us to understand the acquisition of effector function and manipulate it for therapeutic benefit.
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Cichocki, Frank, Rebecca J. Hanson, Todd Lenvik, Michelle Pitt, Valarie McCullar, Hongchuan Li, Stephen K. Anderson, and Jeffrey S. Miller. "The transcription factor c-Myc enhances KIR gene transcription through direct binding to an upstream distal promoter element." Blood 113, no. 14 (April 2, 2009): 3245–53. http://dx.doi.org/10.1182/blood-2008-07-166389.
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Abstract The killer cell immunoglobulin-like receptor (KIR) repertoire of natural killer (NK) cells determines their ability to detect infected or transformed target cells. Although epigenetic mechanisms play a role in KIR gene expression, work in the mouse suggests that other regulatory elements may be involved at specific stages of NK-cell development. Here we report the effects of the transcription factor c-Myc on KIR expression. c-Myc directly binds to, and promotes transcription from, a distal element identified upstream of most KIR genes. Binding of endogenous c-Myc to the distal promoter element is significantly enhanced upon interleukin-15 (IL-15) stimulation in peripheral blood NK cells and correlates with an increase in KIR transcription. In addition, the overexpression of c-Myc during NK-cell development promotes transcription from the distal promoter element and contributes to the overall transcription of multiple KIR genes. Our data demonstrate the significance of the 5′ promoter element upstream of the conventional KIR promoter region and support a model whereby IL-15 stimulates c-Myc binding at the distal KIR promoter during NK-cell development to promote KIR transcription. This finding provides a direct link between NK-cell activation signals and KIR expression required for acquisition of effector function during NK-cell education.
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Li, Hongchuan, Andrew R. Huehn, Postbaccalaureate Fellow, Paul W. Wright, Research Biologist, Sarah Cooley, Jeffrey S. Miller, and Stephen K. Anderson. "Characterization Of a Weakly Expressed KIR2DL1 Allele." Blood 122, no. 21 (November 15, 2013): 4847. http://dx.doi.org/10.1182/blood.v122.21.4847.4847.
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Abstract The variegated expression of the human KIR family of class I MHC receptors provides an interesting model system for the study of stochastic activation of gene transcription. Previous studies have linked distal KIR promoter transcription to the initiation of KIR expression from the proximal promoter. In order to identify novel genetic alterations associated with decreased KIR expression, a group of 182 donors was characterized for KIR gene content, KIR transcripts, and FACS analysis of KIR surface expression. An individual was discovered that possessed a single copy of the KIR2DL1 gene but had a low level of gene expression by either FACS or Q-PCR. Complete sequencing of the KIR2DL1 gene confirmed the presence of an intact coding region. Analysis of promoter elements revealed a cluster of three single nucleotide polymorphisms (SNPs) in the distal promoter approximately 1 kb upstream from the start of KIR2DL1 translation. These SNPs are also found in the distal promoter region of the non-transcribed KIR2DL5*002 allele as well as the KIR3DP1 pseudogene. One of these SNPs creates a functional binding site for the ZEB1 transcription factor. Individuals possessing the ZEB1 site in their KIR2DL1 promoter produce high levels of a non-translatable distal KIR2DL1transcript that inhibits transcription from the proximal promoter, resulting in weak expression of this allele. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. Funded by NCI Contract HHSN261200800001E. Disclosures: Miller: Coronado Biosciences: Scientific Advisory Board Other.
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Ritari, Jarmo, Kati Hyvärinen, Jukka Partanen, and Satu Koskela. "KIR gene content imputation from single-nucleotide polymorphisms in the Finnish population." PeerJ 10 (January 7, 2022): e12692. http://dx.doi.org/10.7717/peerj.12692.
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The killer cell immunoglobulin-like receptor (KIR) gene cluster on chromosome 19 encodes cell surface glycoproteins that bind class I human leukocyte antigen (HLA) molecules as well as some other ligands. Through regulation of natural killer (NK) cell activity KIRs participate in tumour surveillance and clearing viral infections. KIR gene gene copy number variation associates with the outcome of transplantations and susceptibility to immune-mediated diseases. Inferring KIR gene content from genetic variant data is therefore desirable for immunogenetic analysis, particularly in the context of growing biobank genome data collections that rely on genotyping by microarray. Here we describe a stand-alone and freely available gene content imputation for 12 KIR genes. The models were trained using 807 Finnish biobank samples genotyped for 5900 KIR-region SNPs and analysed for KIR gene content with targeted sequencing. Cross-validation results demonstrate a high mean overall accuracy of 98.5% (95% CI [97.0–99.2]%) which compares favourably with previous methods including short-read sequencing based approaches.
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Saadati, Nasim, Maryam Khoshsokhan Mozaffar, Mahboubeh Sherafati, and Shahrokh Kazempour Osaloo. "Pseudoheterocaryum, a new genus segregated from Heterocaryum (Boraginaceae) on the basis of molecular data." Australian Systematic Botany 30, no. 1 (2017): 105. http://dx.doi.org/10.1071/sb16022.
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The phylogeny of Heterocaryum and Suchtelenia was examined using sequence data from the internal transcribed spacer region of the nuclear rDNA (ITS) and plastid trnL intron and trnL–trnF intergenic spacer (trnL–F) regions. Results indicated that Heterocaryum is non-monophyletic because of the inclusion of Suchtelenia calycina (C.A.Mey.) A.DC. Heterocaryum laevigatum (Kar. & Kir.) A.DC. formed a distinct branch sister to S. calycina and remaining Heterocaryum species. Hence, all species of Heterocaryum except H. laevigatum (type species of the genus) are transferred to a new genus, Pseudoheterocaryum. Taxonomic descriptions are presented for Pseudoheterocaryum and Heterocaryum, as well as a diagnostic key to the three genera included in the present study.
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Shapoo, Gowhar A., Zahoor A. Kaloo, Aijaz Hassan Ganie, Anzar A. Khuroo, and Seema Singh. "Dactylorhiza umbrosa (Kar. & Kir.) Nevski (Orchidaceae): an addition to flora of India from Kashmir Himalaya." Check List 12, no. 3 (June 17, 2016): 1904. http://dx.doi.org/10.15560/12.3.1904.
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Dactylorhiza umbrosa(Kar. &Kir.) Nevski is reported for the first time from Kashmir Himalaya, India. A brief description, illustration, photographs of diagnostic features, and a distribution map is provided. Also provided are comparative characters to distinguish D. umbrosa from other species already known from Kashmir Himalaya: D. hatagirea, D. kafiriana and D. viridis. The species shows rare distribution in the alpine habitats of this Himalayan region and overexploitation for local use poses threat to the existence of this rare medicinal orchid species. Therefore, the documentation of this species assumes significance for devising conservation strategies and sustainable use in this Himalayan region.
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Doti, Nunzianna, Pasqualina L. Scognamiglio, Stefania Madonna, Claudia Scarponi, Menotti Ruvo, Giuseppe Perretta, Cristina Albanesi, and Daniela Marasco. "New mimetic peptides of the kinase-inhibitory region (KIR) of SOCS1 through focused peptide libraries." Biochemical Journal 443, no. 1 (March 14, 2012): 231–40. http://dx.doi.org/10.1042/bj20111647.
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SOCS (suppressor of cytokine signalling) proteins are negative-feedback regulators of the JAK (Janus kinase)/STAT (signal transducer and activator of transcription) pathway. Their expression levels are low under physiological conditions, but they are up-regulated in response to cytokine stimulation in many immune and inflammatory processes. Overexpression of SOCS1 in keratinocyte clones abrogates the IFNγ (interferon γ)-induced expression of many pro-inflammatory genes and the release of related chemokines by blocking the JAK/STAT pathway. SOCS1 inhibits JAK2 kinase activity by binding the catalytic site of JAK2, with its KIR (kinase-inhibitory region) acting as a pseudo-substrate of the enzyme. In the present study, we screened a focused combinatorial peptide library of KIR to identify new peptides able to mimic its function with an improved affinity towards the JAK2 catalytic site. Using an alanine-scanning method, KIR residues that are crucial for the interaction with JAK2 were unveiled. In this way, the KIR sequence was restricted to a shorter segment and ‘non-essential’ residues were replaced by different amino acids following a simplified combinatorial approach. We selected a new unnatural sequence able to bind to JAK2 with Kd values in the nanomolar range. This peptide was tested in human keratinocyte cultures and reduced the phosphorylation of STAT1 and the expression levels of IRF-1 (interferon regulatory factor-1).
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Marin, Wesley M., Ravi Dandekar, Danillo G. Augusto, Tasneem Yusufali, Bianca Heyn, Jan Hofmann, Vinzenz Lange, Jürgen Sauter, Paul J. Norman, and Jill A. Hollenbach. "High-throughput Interpretation of Killer-cell Immunoglobulin-like Receptor Short-read Sequencing Data with PING." PLOS Computational Biology 17, no. 8 (August 2, 2021): e1008904. http://dx.doi.org/10.1371/journal.pcbi.1008904.
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The killer-cell immunoglobulin-like receptor (KIR) complex on chromosome 19 encodes receptors that modulate the activity of natural killer cells, and variation in these genes has been linked to infectious and autoimmune disease, as well as having bearing on pregnancy and transplant outcomes. The medical relevance and high variability of KIR genes makes short-read sequencing an attractive technology for interrogating the region, providing a high-throughput, high-fidelity sequencing method that is cost-effective. However, because this gene complex is characterized by extensive nucleotide polymorphism, structural variation including gene fusions and deletions, and a high level of homology between genes, its interrogation at high resolution has been thwarted by bioinformatic challenges, with most studies limited to examining presence or absence of specific genes. Here, we present the PING (Pushing Immunogenetics to the Next Generation) pipeline, which incorporates empirical data, novel alignment strategies and a custom alignment processing workflow to enable high-throughput KIR sequence analysis from short-read data. PING provides KIR gene copy number classification functionality for all KIR genes through use of a comprehensive alignment reference. The gene copy number determined per individual enables an innovative genotype determination workflow using genotype-matched references. Together, these methods address the challenges imposed by the structural complexity and overall homology of the KIR complex. To determine copy number and genotype determination accuracy, we applied PING to European and African validation cohorts and a synthetic dataset. PING demonstrated exceptional copy number determination performance across all datasets and robust genotype determination performance. Finally, an investigation into discordant genotypes for the synthetic dataset provides insight into misaligned reads, advancing our understanding in interpretation of short-read sequencing data in complex genomic regions. PING promises to support a new era of studies of KIR polymorphism, delivering high-resolution KIR genotypes that are highly accurate, enabling high-quality, high-throughput KIR genotyping for disease and population studies.
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Winter, C. C., and E. O. Long. "A single amino acid in the p58 killer cell inhibitory receptor controls the ability of natural killer cells to discriminate between the two groups of HLA-C allotypes." Journal of Immunology 158, no. 9 (May 1, 1997): 4026–28. http://dx.doi.org/10.4049/jimmunol.158.9.4026.
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Abstract To examine the structural basis for the specific recognition of the MHC class I allotypes HLA-Cw*0401 and HLA-Cw*0304 by the killer cell inhibitory receptors (KIR) cl42 and cl43, respectively, mutant KIR-Ig fusion proteins were tested by direct binding to cells transfected with single HLA-C alleles. The putative loop region at position 44-46 of KIR contained amino acids that were necessary for the discrimination between HLA-Cw*0401 and HLA-Cw*0304. Surprisingly, exchanging the methionine at position 44 in cl42 with the lysine at position 44 in cl43 was sufficient to switch the specificity of cl42 from HLA-Cw*0401 to HLA-Cw*0304, and vice versa. Thus, a single amino acid in the first Ig domain of these KIR determines their ability to discriminate between the two groups of HLA-C allotypes.
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Geltman, D. "Notes on some species of the genus Euphorbia L. (Euphorbiaceae) of Eastern Europe." Novitates Systematicae Plantarum Vascularium 42 (2011): 185–91. http://dx.doi.org/10.31111/novitates/2011.42.185.
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Several changes in taxonomy and status of Euphorbia L. species occurring in Eastern Europe are proposed. E. tyraica Klok. et Artemcz. is treated as a synonym of E. cyparissias L. A rare species endemic to Samarskaya Luka (Russia, Samara Region) — E. zhiguliensis (Prokh.) Prokh. is most probably a hybrid between E. caesia Kar. et Kir. and E. subtilis (Prokh.) Prokh. and should be designated as E. × zhiguliensis (Prokh.) Prokh. Localities of E. agraria Bieb. in the south-east of Eastern Europe which previously were regarded as alien can be in fact native.
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La Manna, Sara, Laura Lopez-Sanz, Susana Bernal, Luna Jimenez-Castilla, Ignacio Prieto, Giancarlo Morelli, Carmen Gomez-Guerrero, and Daniela Marasco. "Antioxidant Effects of PS5, a Peptidomimetic of Suppressor of Cytokine Signaling 1, in Experimental Atherosclerosis." Antioxidants 9, no. 8 (August 14, 2020): 754. http://dx.doi.org/10.3390/antiox9080754.
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The chronic activation of the Janus kinase/signal transducer and activator of the transcription (JAK/STAT) pathway is linked to oxidative stress, inflammation and cell proliferation. Suppressors of cytokine signaling (SOCS) proteins negatively regulate the JAK/STAT, and SOCS1 possesses a small kinase inhibitory region (KIR) involved in the inhibition of JAK kinases. Several studies showed that KIR-SOCS1 mimetics can be considered valuable therapeutics in several disorders (e.g., diabetes, neurological disorders and atherosclerosis). Herein, we investigated the antioxidant and atheroprotective effects of PS5, a peptidomimetic of KIR-SOCS1, both in vitro (vascular smooth muscle cells and macrophages) and in vivo (atherosclerosis mouse model) by analyzing gene expression, intracellular O2•− production and atheroma plaque progression and composition. PS5 was revealed to be able to attenuate NADPH oxidase (NOX1 and NOX4) and pro-inflammatory gene expression, to upregulate antioxidant genes and to reduce atheroma plaque size, lipid content and monocyte/macrophage accumulation. These findings confirm that KIR-SOCS1-based drugs could be excellent antioxidant agents to contrast atherosclerosis.
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Ademovic-Sazdanic, Dusica, Svetlana Vojvodic, Stevan Popovic, and Nada Konstantinidis. "Study of killer cell immunoglobulin-like receptor genes and HLA C ligands in hematopoietic stem cell transplantation pairs in Vojvodina." Genetika 48, no. 3 (2016): 933–43. http://dx.doi.org/10.2298/gensr1603933a.
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Objective: The aim of the study was to analyse KIR/HLA profiles and to create the predictive probabilities for the selection of the most suitable Hematopoietic Stem Cell Transplantation (HSCT) donor. Materials and Methods: The study was conducted on 92 patients with malignant hematological deseases and 181 their first degree relatives, from the region of Vojvodina. HLA and KIR genotyping was performed by polymerase chain reaction-sequence specific primers (PCR-SSP) assay. The analysis included the degree of HLA matching between transplant pairs, number of missing ligands for inhibitory KIR genes, existence of GvH / HvG ligand-ligand mismatches (specific for C1, C2 or Bw4 ligands) and distribution of C1/C1, C1/C2, C2/C2 HLA ligand groups in patients. Results: There was no significant differences in HLA frequencies between donors and recipients as analyzed by pairwise comparison, the probability of finding HLA identical donor is only 0.154, the probability of finding the donor with ? 1 KIR-ligand mismatch is 0.939, the probability of finding the donor with KIR-ligand mismatch for the KIR 2DL1 gene is 0.298, probability of having favorable C1/C1 and C2/C2 HLA ligand groups is 0.565. Conclusion: The results of our study could be used as a basis for the HSCT outcome prediction representing a powerful tool for choosing the most suitable donor.
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Cichocki, Frank M., Todd Lenvik, Stephen K. Anderson, and Jeffrey S. Miller. "STAT5A Overexpression Enhances Killer Immunoglobulin Receptor (KIR) Expression in Developing NK Cells and Is Associated with a Loss of Reverse Transcription from the Proximal KIR Promoter." Blood 110, no. 11 (November 16, 2007): 798. http://dx.doi.org/10.1182/blood.v110.11.798.798.
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Abstract Down-regulation of HLA-class I molecules is commonly observed in virally infected and malignantly transformed cells and can contribute to the ability of these cells to escape recognition by the adaptive immune system. NK cells are able to detect the loss of even single HLA alleles on potential target cells through their clonally distributed HLA-class I-specific inhibitory receptors (KIR). While it is well established that individual KIR gene expression is strongly correlated with the DNA methylation status of CpG dinucleotides in areas surrounding the transcription initiation region, the mechanisms that regulate variegated KIR expression are largely unknown. The manipulation of KIR expression is of considerable interest due to the widely reported correlation between KIR ligand status and patient survival in hematopoietic stem cell transplant settings. Because the transcription factor STAT5 is activated downstream of the BCR/ABL oncogene, which we have previously shown to substantially augment KIR expression levels in primary NK cells, we hypothesized that STAT5 could directly influence KIR expression. To test this hypothesis, we purified CD34+ hematopoietic progenitor cells from umbilical cord blood and retrovirally transduced these cells with either a control murine stem cell virus (MSCV) vector encoding eGFP alone or an MSCV vector encoding both eGFP and a constitutively active form of STAT5A, termed STAT5A 1*6. CD34/eGFP-positive cells were then purified and cultured on the EL08-D1 stroma line, known to support NK cell development. After a period of 28 days in culture, 6.25±2.73% of the NK cells in eGFP control cultures were KIR-positive compared with 29.3±4.27% of STAT5A 1*6 transductants. To more closely examine individual KIR expression at the transcriptional level, we carried out a quantitative RT-PCR analysis with probe sets previously validated for amplification of individual KIR (Cooley et al., Blood). We observed a general increase in the mRNA expression levels of both inhibitory and activating KIR in STAT5A 1*6-transduced cells. In order to investigate the mechanism underlying the increased KIR expression observed in the STAT5A 1*6-transductants, we performed an RT-PCR specific for the reverse transcript originating from the proximal promoter of the KIR3DL1 gene. In a model proposed by Anderson et al., reverse transcription from the bidirectional proximal promoter of variegated KIR genes may be responsible for the silencing of the KIR locus through the production of dsRNA, which then induces DNA methylation in a siRNA-dependent manner. Our RT-PCR results from multiple donors clearly show an absence of reverse proximal transcript in cells transduced with the STAT5A 1*6 construct in contrast to high levels of transcript in eGFP controls. These results provide evidence for a role of STAT5A in the induction of KIR expression and support a model of KIR regulation involving intergenic transcription and possibly siRNA-mediated gene silencing. A better understanding of how to manipulate these KIR expression patterns may be of benefit to exploit the potential of NK cell therapy to improve transplant outcomes.
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Yun, Gong, Jakub Tolar, Harriet Noreen, Bruce R. Blazar, and Jeffrey S. Miller. "A Novel Method for KIR-Ligand Typing by Pyrosequencing To Predict NK Cell Alloreactivity." Blood 106, no. 11 (November 16, 2005): 1407. http://dx.doi.org/10.1182/blood.v106.11.1407.1407.
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Abstract KIR-ligands are HLA molecules that can be grouped into 3 major categories based on the amino acid sequence determining the KIR-binding epitope in HLA-C and HLA-B alleles. Almost all HLA-C alleles are of the C1 or C2 group defined by single nucleotide polymorphisms (SNPs) found at amino acid positions 77 and 80. C1 is designated S77 and N80, while C2 is designated N77 and K80. Most HLA-B alleles can be classified as either Bw4 or Bw6, defined by SNPs located at amino acid position 77 and 80–83. Bw6 allele types which are invariant and consistently S77 and N80 are not KIR-ligands, in contrast to Bw4 which is a KIR-ligand and can have multiple amino acid sequences at these positions. Killer-immunoglobin receptors KIR2DL1, KIR2DL2 and KIR3DL1 bind KIR-ligands C1, C2 and Bw4 respectively, resulting in inhibition of NK cell mediated lysis. Recent transplant strategies based on KIR-ligand mismatch to predict NK cell alloreactivity have resulted in less relapse and better survival in patients with AML. Although allele level high-resolution HLA-typing is the gold standard for accurately determining KIR-ligand status, it is not performed at some centers and is cost prohibitive for retrospective cohorts. In these settings, KIR-ligand assignment is being extrapolated from serologic or low-resolution HLA data. This is only accurate in about 80% of donor/recipient pairs, because misclassifications based on the frequency of less common alleles can result in assignment to the opposite KIR-ligand group (Bw4 versus Bw6 or C1 versus C2). Our aim was to develop a high-throughput assay for determining KIR-ligand status which is accurate, inexpensive and rapid. Pyrosequencing is a relatively new method for sequencing DNA and is especially useful in detecting SNPs when most of the sequence is already known. Sequencing is based on a single strand of biotinylated DNA which is used as a template for a sequencing primer specific to the region of interest. As nucleotides are added base by base from the sequencing primer, the pyrosequencing apparatus (PSQ MA 96) can detect which base is added and in what quantity. This information can be used to determine if the sample is homozygous or heterozygous. We hypothesized that pyrosequencing would be a viable alternative to high resolution HLA-typing for KIR-ligand status determination. It directly sequences the ligand epitopes, thus avoiding misclassifications encountered with low resolution HLA-typing alone. This high throughput system would be of particular interest in analysis of banked RNA and DNA tissue samples for retrospective cohorts when high resolution typing is not available. KIR-ligand status was assigned for 34 samples by testing with both pyrosequencing and high-resolution HLA-typing. Initially we found a discrepancy rate of 9% between the two methods. To investigate discrepant samples, PCR products from these reactions were sequenced. We concluded that the initial PCR primer set was designed over a polymorphic region which did not amplify all known HLA-B or HLA-C alleles. The PCR primers were redesigned and the samples retested by pyrosequencing, resulting in full concordance with high resolution HLA data. Pyrosequencing is a sensitive, specific, high-throughput and inexpensive screening technique to rapidly determine KIR-ligand status for evaluating potential alloreactive NK cell or transplant donors.
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Moshkforoush, Arash, Baarbod Ashenagar, Osama F. Harraz, Fabrice Dabertrand, Thomas A. Longden, Mark T. Nelson, and Nikolaos M. Tsoukias. "The capillary Kir channel as sensor and amplifier of neuronal signals: Modeling insights on K+-mediated neurovascular communication." Proceedings of the National Academy of Sciences 117, no. 28 (June 29, 2020): 16626–37. http://dx.doi.org/10.1073/pnas.2000151117.
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Neuronal activity leads to an increase in local cerebral blood flow (CBF) to allow adequate supply of oxygen and nutrients to active neurons, a process termed neurovascular coupling (NVC). We have previously shown that capillary endothelial cell (cEC) inwardly rectifying K+(Kir) channels can sense neuronally evoked increases in interstitial K+and induce rapid and robust dilations of upstream parenchymal arterioles, suggesting a key role of cECs in NVC. The requirements of this signal conduction remain elusive. Here, we utilize mathematical modeling to investigate how small outward currents in stimulated cECs can elicit physiologically relevant spread of vasodilatory signals within the highly interconnected brain microvascular network to increase local CBF. Our model shows that the Kir channel can act as an “on–off” switch in cECs to hyperpolarize the cell membrane as extracellular K+increases. A local hyperpolarization can be amplified by the voltage-dependent activation of Kir in neighboring cECs. Sufficient Kir density enables robust amplification of the hyperpolarizing stimulus and produces responses that resemble action potentials in excitable cells. This Kir-mediated excitability can remain localized in the stimulated region or regeneratively propagate over significant distances in the microvascular network, thus dramatically increasing the efficacy of K+for eliciting local hyperemia. Modeling results show how changes in cEC transmembrane current densities and gap junctional resistances can affect K+-mediated NVC and suggest a key role for Kir as a sensor of neuronal activity and an amplifier of retrograde electrical signaling in the cerebral vasculature.
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Fry, A. M., L. L. Lanier, and A. Weiss. "Phosphotyrosines in the killer cell inhibitory receptor motif of NKB1 are required for negative signaling and for association with protein tyrosine phosphatase 1C." Journal of Experimental Medicine 184, no. 1 (July 1, 1996): 295–300. http://dx.doi.org/10.1084/jem.184.1.295.
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NKB1 is one member of a growing family of killer cell inhibitory receptors (KIR). It is expressed on natural killer (NK) cells and T cells, and has been shown to inhibit cytolytic functions of these cells upon interacting with its ligand, HLA-B (Bw4). We demonstrate here that the cytoplasmic region of NKB1 is capable of inhibiting T cell activation in Jurkat cells. The tyrosine phosphorylation of the NKB1 KIR consensus motif, YxxL(x)26 YxxL, induces an association with the protein tyrosine phosphatase 1C (PTP1C). Importantly, mutation of both tyrosines in the motif abolished the inhibitory functions of NKB1 and abrogated PTP1C association. Mutational analysis of the individual tyrosines suggest that the membrane proximal tyrosine may play a crucial role in mediating the inhibitory signal. These results demonstrate that KIR can not only inhibit cytolytic activity, but can also negatively regulate T cell receptor activation events that lead to downstream gene activation, and further supports a model that implicates PTP1C as a mediator in the KIR inhibitory signal.
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Fell, Elena. "Izhorians: A disappearing ethnic group indigenous to the Leningrad region." Acta Baltico-Slavica 43 (December 31, 2019): 206–28. http://dx.doi.org/10.11649/abs.2019.010.
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Izhorians: A disappearing ethnic group indigenous to the Leningrad regionThere is no body of research focusing specifically on Izhorians, a Finno-Ugrian minority group indigenous to the Leningrad region. Information about them is usually embedded in wider studies investigating Finnic minorities living at the intersection of Russia, Estonia and Finland. Consequently, it is fragmented, disjointed and marginalised, and available almost only in Russian, Estonian or Finnish. However, the most recent report on the state of the Izhorian language (which is part of a general study of Finnic minority languages in Russia) is available in English. Even though information about Izhorians lacks unity and cohesion, all researchers share the same concern, namely that Izhorians are disappearing as a distinct ethnic group. This concern manifests itself as a tendency to follow the dynamics of the Izhorian population, paying special attention to statistical data. Accordingly, this paper begins with a presentation of those data as a feature that connects all available research and proceeds to a commentary clarifying the reasons for the decline of this ethnic group. It also evaluates the current state of the Izhorian language. This review article presents a concise overview of selected research findings related to various issues concerning the study of Izhorians, including works by A. I. Kir′ianen, A. V. Labudin and A. A. Samodurov (2017); A. I. Kir′ianen (2016); N. Kuznetsova, E. Markus and M. Muslimov (2015); M. Muslimov (2005); A. P. Chush′′ialova (2010); F. I. Rozhanskiĭ and E. B. Markus (2013); and V. I. Mirenkov (2000). Iżorowie – zanikająca rdzenna grupa etniczna w regionie leningradzkimJak dotąd, nie ma literatury badawczej skupiającej się na Iżorach, rdzennej ugrofińskiej grupie etnicznej żyjącej w regionie leningradzkim. Informacje na ich temat zwykle stanowią część szerszych prac dotyczących mniejszości bałtofińskich na pograniczu Rosji, Estonii i Finlandii, są zatem fragmentaryczne, rozproszone, zmarginalizowane i dostępne niemal wyłącznie w językach rosyjskim, estońskim lub fińskim. Najnowsze studium dotyczące stanu języka iżorskiego (stanowiące część ogólnego opracowania na temat bałtofińskich mniejszości językowych w Rosji) jest dostępne w języku angielskim. Pomimo tego, że badania dotyczące Iżorów cechuje brak spójności, wszyscy badacze podzielają obawę o ich przetrwanie jako odrębnej grupy etnicznej, co przejawia się w tendencji do śledzenia dynamiki populacji, ze szczególnym uwzględnieniem danych statystycznych. Autorka wychodzi od przedstawienia tych danych jako elementu łączącego wszystkie dostępne badania i omawia przyczyny zanikania Iżorów jako odrębnej grupy etnicznej. Artykuł przedstawia również ocenę obecnego stanu języka iżorskiego. Zawiera też zwięzły przegląd wyników wybranych badań dotyczących Iżorów i omawia prace takich autorów jak: A. I. Kir′ianen, A. V. Labudin i A. A. Samodurov (2017); A. I. Kir′ianen (2016); N. Kuznetsova, E. Markus i M. Muslimov (2015); M. Muslimov (2005); A. P. Chush′′ialova (2010); F. I. Rozhanskiĭ i E. B. Markus (2013); V. I. Mirenkov (2000).
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Vojvodic, Svetlana, and D. Ademovic-Sazdanic. "Killer-cell immunoglobulin-like receptor genes linkage disequilibrium analysis in population of Vojvodina." Genetika 47, no. 2 (2015): 439–50. http://dx.doi.org/10.2298/gensr1502439v.
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Killer Immunoglobulin-like Receptors (KIRs) form a group of regulatory molecules that modulate cytolytic activity of natural killer cells and T cells through interaction with specific human leukocyte antigen (HLA) molecules on target cells. KIRs are encoded by the family of 16 homologous genes that vary substantially between haplotypes and display sequence polymorphism with allelic variation that also contributes to diversity within the complex. The aim of the study is to estimate two locus linkage disequilibrium for 16 KIR loci. In this study, we report the evaluation of KIR gene content, allele, haplotype and genotype frequencies in 175 unrelated healthy individuals from Vojvodina who were KIR typed by polymerase chain reaction-sequence specific primers genotyping assay. The linkage disequilibrium (LD) was studied at the structural level (presence or absence of 16 KIR genes). Our results revealed that linkage disequilibrium is present between telomeric gene pairs KIR2DL1~KIR2DL4, KIR2DP1~KIR2DL4, KIR2DP1~KIR3DL1, KIR2DL1~KIR3DL2, KIR2DP1~KIR3DL2, KIR2DL4~KIR3DL1, KIR2DL4~KIR2DS4, KIR2DL4~KIR3DL2 where (r2=1), but positive association between KIR genes, with higher observed than expected haplotype frequencies were observed for KIR3DS1~KIR2DS1 and KIR2DL5~KIR2DS1 pair of genes (r2=0.646) and (r2=0.371), respectively. Thirty-eight different genotypes were identified, where 12% of the individuals have unique genotype, present in only one person. Our results will help to understand the genetic background of the Vojvodina population, in illustrating the population migration events in the northern part of Serbia, in explaining the extensive genetic admixture amongst the different ethnic groups of the region and also in KIR-related disease studies.
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Stienstra, D., T. L. Anderson, and L. J. Ringer. "Statistical Inferences on Cleavage Fracture Toughness Data." Journal of Engineering Materials and Technology 112, no. 1 (January 1, 1990): 31–37. http://dx.doi.org/10.1115/1.2903183.
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A method to predict lower bound cleavage fracture toughness values from small data sets is presented. The method is derived from a Weibull statistic based micromechanical analysis and can be applied in the ductile-brittle transition region. Lower bound predictions can compare well with the ASME KIR and KIC design curves. Difficulties in comparing Weibull shape parameters calculated by different methods are also discussed and several calculation methods are compared with a Monte Carlo simulation. The preferred methods are the maximum likelihood estimators (MLEs), least squares with the (i−.5)/n centralizing approach, or a simple estimation scheme which gives a “Good Linear Unbiased Estimator.”
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Maenaka, Katsumi, Takeo Juji, Kenji Tadokoro, Karl Harlos, David I. Stuart, and E. Yvonne Jones. "Crystallization and preliminary diffraction studies of the extracellular region of human p58 killer cell inhibitory receptor (KIR2)." Acta Crystallographica Section D Biological Crystallography 54, no. 3 (May 1, 1998): 433–35. http://dx.doi.org/10.1107/s0907444997012201.
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Molecules of the human killer cell inhibitory receptor (KIR) family, which belong to the immunoglobulin superfamily (IgSF), are expressed on the surface of natural killer (NK) cells and some subsets of T cells. These receptors function to mediate the inhibition or activation of cytotoxic activity by recognizing HLA class I molecules on the target cell. The extracellular region of a p58 KIR specific for HLA-Cw1,3,7 (KIR2) has been overproduced in Escherichia coli and purified. The recombinant KIR2 has been crystallized in 9–10% poly(ethylene glycol) methyl ether (average Mr = 8000), 50mM HEPES, 8% ethylene glycol, 0.5% octyl-β-glucoside, pH 7.5, at 294 K using the sitting-drop vapour-diffusion method. Preliminary X-ray diffraction studies reveal the space group to be hexagonal (P6122 or P6522) with lattice constants a = b = 95.3, c = 130.8 Å. A native data set (3 Å resolution) has been collected at the Photon Factory (λ = 1.0 Å).
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Bedoya, Simone, Ashley Young, Tenisha Wilson, Howard Johnson, and Joseph Larkin III. "Evaluation of SOCS1 mimetic and antagonist peptides as therapeutic agents (P5152)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 195.5. http://dx.doi.org/10.4049/jimmunol.190.supp.195.5.
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Abstract The intracellular protein Suppressors of Cytokine Signaling1 (SOCS1) plays a critical role in moderating inflammatory cytokine signaling, thereby limiting immune responsiveness. We have shown that a peptide with the kinase inhibitory region of SOCS1 (SOCS1-KIR) inhibits Experimental Autoimmune Encephalomyelitis and rescues SOCS1-deficient mice from perinatal lethality. In contrast, a SOCS1antagonist pJAK2 enhances antiviral immunity to poxviruses. Therefore it is likely that peptides that modulate SOCS1 signaling possess the potential to modulate immune responses, and restore immune homeostasis. To evaluate the translational potential of SOCS1 mimetic peptides, we have assessed their pharmacodynamics by fluorescently labeling the peptides followed by injection into C57BL/6 mice. After 2 hours mice receiving Alexa 647 fluorochrome-conjugated SOCS1-KIR or pJAK2 were sacrificed, and subsequently whole organs and tissue histology were examined for the presence of the labeled peptides. We observed that pJAK2 and SOCS1-KIR were present in the brain, liver, lymph nodes, spleen, kidneys, lungs, and peritoneal cells. Notably, pJAK2 was selectively present within the thymus and heart. On a cellular level, SOCS1-KIR and pJAK2 were differentially present within CD4+ T cells, CD8+ T cells, CD11b+ macrophages, and B cells. These results help to lay the groundwork for the translational use of peptides that modulate SOCS signaling to regulate and/or maintain immune system homeostasis.
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Rangarajan, Hemalatha G., Marcelo De Souza Pereira, Ruta Brazauskas, Michael R. Verneris, Andrew St. Martin, Stephen R. Spellman, and Dean Anthony Lee. "Outcomes of Pediatric Patients with JMML Following Unrelated Donor Transplant: The Impact of Donor KIR Gene Content and KIR Ligand Matching." Blood 136, Supplement 1 (November 5, 2020): 42–43. http://dx.doi.org/10.1182/blood-2020-139891.
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Introduction Allogeneic hematopoietic cell transplantation (HCT) remains the sole curative therapy for patients with juvenile myelomonocytic leukemia (JMML) leading to a 5-year disease-free survival of ~50%. Whether donor NK cell determinants (e.g., KIR mismatch, KIR A/B genotype) correlate with relapse and survival are unknown. We previously demonstrated that JMML stem cells, defined as Lin-CD34+CD38-, express ligands for NKG2D, NKp30, and NKp44 at levels equal or greater than AML stem cells and that colony-forming units were significantly reduced following incubation of JMML cells with NK cells. Based on these observations we hypothesized that NK cell-dependent mechanisms are a major component of protection from JMML relapse after HCT, and specifically that determinants of greater donor NK cell function (e.g. KIR Bx donors or KIR ligand mismatch) are associated with reduced relapse. We therefore investigated NK cell-related donor and recipient immunogenetics as determinants for outcomes in children transplanted for JMML. Methods: Patients (0 to < 19 years) who received a first allogenic HCT from an alternative donor between 2000 to 2017 and had available donor samples from the Center for International Blood and Marrow Transplant Research (CIBMTR) repository were included in the study. Donor KIR typing was performed on pre-HCT samples and results were correlated with clinical data extracted from the CIBMTR database. The primary endpoint was disease free survival (DFS); secondary endpoints included relapse rate (REL), acute graft versus host disease (aGVHD), chronic graft versus host disease (cGVHD), GVHD relapse free survival (GRFS) and overall survival (OS). Patient and transplant related variables included age (< 2 years vs ≥ 2 years), sex, race, performance score (< 90 vs >90), disease status, graft type (bone marrow, peripheral blood, and cord blood), HLA matching (8/8 vs others), conditioning intensity (myeloablative vs others), use of serotherapy, GVHD prophylaxis (calcineurin inhibitor (CNI)+ methotrexate (Mtx) ± others vs others) and year of HCT (2000-2007 vs 2008-2017). KIR models tested included KIR genotype (AA vs Bx), Donor KIR B content (0-1 vs ≥ 2), centromeric and telomeric region score (AA vs AB vs BB), donor KIR B content score (best, better, neutral), KIR composite score (2 vs 3 vs 4), activating KIR content, presence of activating KIR DS4, ligand-ligand (L-L) mismatch, KIR ligand (KIR-L) mismatch, and missing ligand. Proportional hazards were checked for all covariates in every model. Univariate analysis was performed for primary and secondary outcomes of interest. Covariates with overall p-value < 0.05 and pairwise comparisons with p-value < 0.05 were considered significant. L-L and KIR-L mismatch effects were studied for all outcomes in a subgroup of HLA-mismatched donors (high resolution match <8/8). Results: 165 patients (113 males) with a median follow up of 85 (6-216) months met the study criteria. Of these, 111 received an unrelated donor transplant and 54 received cord blood transplants. This included 77 HLA-mismatched donor transplants. Almost all (161, 98%) received myeloablative conditioning. Half of the study cohort received ATG (91, 55%) and CNI + Mtx based GVHD prophylaxis (81, 49%). Based on donor KIR genotype, 43 patients received grafts from AA donors and 122 from Bx donors. On univariate analysis, there was no difference between AA vs Bx for the primary and secondary outcomes (Table 1). Considering the various KIR models, OS was significantly better for patients without L-L mismatch in the GVHD direction (HR 0.43 (95% CI: 0.20-0.91), p=0.027). Risk of grade II-IV aGVHD was lower in patients with Bx donors (HR 0.59 (CI: 0.35-0.99), p=0.047) and donors with B content score of ≥ 2 (HR 0.51 (0.29-0.89), p=0.017) (Table 2). Conclusion: To our knowledge this is the first study analyzing NK determinants in pediatric JMML HCT recipients. OS and aGVHD were the only outcomes associated with NK cell immunogenetics, but not in expected directions. These unexpected findings may be due to our limited sample size or heterogeneity in graft sources or treatment regimens. Our study identifies a potential benefit of donor of KIR-B genotypes and absence of L-L mismatch in the GVH direction for pediatric JMML patients. These observations require further investigation for confirmation and understanding of mechanism. Disclosures Verneris: Novartis: Membership on an entity's Board of Directors or advisory committees; Fate Therapeutics: Consultancy, Current equity holder in publicly-traded company; Bmogen: Consultancy, Current equity holder in publicly-traded company; Uptodate: Consultancy. Lee:Kiadis Pharma Netherlands B.V: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.
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Zambello, Renato, Elisa Scquizzato, Antonella Teramo, Monica Facco, Laura Pavan, Marta Miorin, Livio Trentin, Carlo Agostini, and Gianpietro Semenzato. "Analysis of KIR Framework Loci in Patients with NK-Type Lymphoproliferative Disease of Granular Lymphocytes (LDGL)." Blood 106, no. 11 (November 16, 2005): 2813. http://dx.doi.org/10.1182/blood.v106.11.2813.2813.
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Abstract To investigate whether a bias toward the presence of genes coding for activating KIRs were present in patients with NK-type lymphoproliferative disease of granular lymphocytes (NK-LDGL), by multiplex PCR analysis in this study we evaluated the KIR genotype in 35 patients with NK-LDGL and in 50 normal subjects. According to the published data in the Caucasian population, all individuals were positively scored for the framework loci (KIR2DL4+, KIR3DL2+ and KIR3DL3+). All genotypes were characterized by a gene encoding a group 1 HLA-C-specific inhibitory KIR, which was either KIR2DL1, KIR2DL2 or KIR2DL3 and at least contained one activating KIR gene. The KIR genotype analysis revealed that patients genotypes were largely represented by type B haplotype (34/35) that is characterized by the presence of multiple activating KIRs. The same KIR genotype was often shared between NK-LDGL patients. These genotypic profiles were not present in the group of controls and are infrequent (1,2%) or not still found in the Caucasian population. In contrast with literature data reporting that the frequency of haplotype A in homozigous state represents the most common condition in the Caucasian population (accounting for 1/3 of normal individuals), we surprisingly found that also almost all the controls studied (49/50) were equipped with the type B haplotype. When the genotypic frequency was considered, the most frequently gene content found was 9 in controls and 11 or 14 in patients, indicating that patients genotypes contained a higher number of genes than controls. This picture was almost entirely due to the high variability of the activating genes number. As far as the activating genes are concerned, although the number of control individuals analyzed was still low, the frequency of KIR2DS1, KIR2DS2, KIR2DS4, KIR1D and KIR3DS1 was found to be higher in patients than in controls. This indicates that genotypic profiles of NK-LDGL patients are characterized by an increased presence of activating KIRs. Consistent with these findings, the analysis of the KIR genes repertoire in NK-LDGL patients clearly indicates that the susceptibility to this disease is influenced by the KIR genotype and in particular by the presence of a considerable number of activating KIR genes. Moreover, we observed that healthy individuals scored as controls (all coming from the north-east of Italy) showed genotypes with a higher number of activating genes as compared to other Caucasian populations. This observation suggests that a genetic predisposition to development of NK-type LDGL might occur among the population of north-east of Italy and in turn this could explain the high frequency of NK-type LDGL in this Italian region.
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Nutalai, Rungtiwa, Silvana Gaudieri, Amonrat Jumnainsong, and Chanvit Leelayuwat. "Regulation of KIR3DL3 Expression via miRNA." Genes 10, no. 8 (August 9, 2019): 603. http://dx.doi.org/10.3390/genes10080603.
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Killer-cell immunoglobulin-like receptor (KIR) 3DL3 is a framework gene present in all human KIR haplotypes. Although the structure of KIR3DL3 is suggestive of an inhibitory receptor, the function of KIR3DL3 has not been demonstrated and cognate ligands have not been identified. KIR3DL3 has been shown to be constitutively expressed at a low RNA level in peripheral blood mononuclear cell (PBMC) and decidual natural kill (NK) cells, but cell surface expression of KIR3DL3 cannot be detected. Accordingly, post-transcriptional regulation of KIR3DL3 should exist. Using bioinformatics analysis, we identified three candidate micro ribonucleic acids (miRNAs; miR-26a-5p, -26b-5p and -185-5p) that potentially regulate KIR3DL3 expression. Luciferase reporter assays utilizing constructs with mutated miRNA-binding sites of miR-26a-5p, -26b-5p and -185-5p in the 3’-untranslated region (3’ UTR) of KIR3DL3 resulted in up-regulation of luciferase activity demonstrating a potential mechanism of gene regulation. Furthermore, knockdown of the same endogenous miRNAs using silencing ribonucleic acid (siRNA) led to induced surface expression of KIR3DL3. In conclusion, we provide a novel mechanism of functional regulation of KIR3DL3 via miRNAs. These findings are relevant in understanding the generation of KIR repertoire and NK cell clonality.
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Klopfenstein, Nathan, Stephanie Brandt, and C. Henrique Serezani. "Phagocyte-derived SOCS1 disrupts Staphylococcus aureus skin host defense." Journal of Immunology 204, no. 1_Supplement (May 1, 2020): 227.4. http://dx.doi.org/10.4049/jimmunol.204.supp.227.4.
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Abstract Methicillin-resistant Staphylococcus aureus (MRSA) skin infection is controlled by the actions of skin resident macrophages and the formation of a neutrophilic abscess that prevents bacterial spread and tissue damage. We and others have shown that myeloid differentiation factor 88 (MyD88) is required for the clearance of MRSA skin infection in mice. MyD88 expression is controlled by the balance between STAT1 and the suppressor of cytokine signaling 1 (SOCS1). Here, we hypothesized that SOCS1 inhibits antimicrobial effector functions and the inflammatory response, leading to poor abscess formation and tissue injury during MRSA skin infection. Our data show that MRSA skin infection enhances SOCS1 expression. Infection in myeloid-specific SOCS1 deficient mice displays decreased lesion size, lower bacterial loads, and increased abscess thickness when compared to WT mice. When we treated infected mice with a peptide that specifically inhibits the kinase inhibitory region (KIR) of SOCS1, it also improved infection outcome. Examining the mechanisms by which SOCS1 enhanced skin host defense, we observed increased phagocytosis and bacterial killing in SOCS1 deficient macrophages and KIR peptide-treated cells. Increased antimicrobial effector function correlated with enhanced STAT1 activation and increased production of IFNγ in vivo and in vitro. Next we tested whether IFNγ is crucial to improved host defense in KIR-treated mice. Our data show that the beneficial effect of SOCS1 KIR peptide in skin host defense was abrogated in mice treated with an IFNR blocking antibody and in the IFNR deficient mice. Overall, these data show that preventing SOCS1 actions enhances microbial clearance and host defense during MRSA skin infection.
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Hsu, Katharine C., Shohei Chida, Daniel E. Geraghty, and Bo Dupont. "The killer cell immunoglobulin-like receptor (KIR) genomic region: gene-order, haplotypes and allelic polymorphism." Immunological Reviews 190, no. 1 (December 2002): 40–52. http://dx.doi.org/10.1034/j.1600-065x.2002.19004.x.
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Ahmed, Chulbul M., Rea Dabelic, Lilian W. Waiboci, Lindsey D. Jager, Linda L. Heron, and Howard M. Johnson. "SOCS-1 Mimetics Protect Mice against Lethal Poxvirus Infection: Identification of a Novel Endogenous Antiviral System." Journal of Virology 83, no. 3 (November 19, 2008): 1402–15. http://dx.doi.org/10.1128/jvi.01138-08.
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ABSTRACT The suppressor of cytokine signaling 1 (SOCS-1) protein modulates cytokine signaling by binding to and inhibiting the function of Janus kinases (JAKs), ErbB, and other tyrosine kinases. We have developed a small tyrosine kinase inhibitor peptide (Tkip) that binds to the autophosphorylation site of tyrosine kinases and inhibits activation of STAT transcription factors. We have also shown that a peptide corresponding to the kinase-inhibitory region of SOCS-1, SOCS1-KIR, similarly interacts with the activation loop of JAK2 and blocks STAT activation. Poxviruses activate cellular tyrosine kinases, such as ErbB-1 and JAK2, in the infection of cells. We used the pathogenesis of vaccinia virus in C57BL/6 mice to determine the ability of the SOCS-1 mimetics to protect mice against lethal vaccinia virus infection. Injection of mice intraperitoneally with Tkip or SOCS1-KIR containing a palmitate for cell penetration, before and at the time of intranasal challenge with 2 × 106 PFU of vaccinia virus, resulted in complete protection at 100 μg. Initiation of treatment 1 day postinfection resulted in 80% survival. Administration of SOCS-1 mimetics by the oral route also protected mice against lethal effects of the virus. Both SOCS1-KIR and Tkip inhibited vaccinia virus transcription and replication at early and possibly later stages of infection. Vaccinia virus-induced phosphorylation of ErbB-1 and JAK2 was inhibited by the mimetics. Protected mice mounted a strong humoral and cellular response to vaccinia virus. The use of SOCS-1 mimetics in the treatment of poxvirus infections reveals an endogenous regulatory system that previously was not known to have an antiviral function.
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Dahlmann, Anke, Min Li, ZhongHua Gao, Deirdre McGarrigle, Henry Sackin, and Lawrence G. Palmer. "Regulation of Kir Channels by Intracellular pH and Extracellular K+." Journal of General Physiology 123, no. 4 (March 29, 2004): 441–54. http://dx.doi.org/10.1085/jgp.200308989.
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ROMK channels are regulated by internal pH (pHi) and extracellular K+ (K+o). The mechanisms underlying this regulation were studied in these channels after expression in Xenopus oocytes. Replacement of the COOH-terminal portion of ROMK2 (Kir1.1b) with the corresponding region of the pH-insensitive channel IRK1 (Kir 2.1) produced a chimeric channel (termed C13) with enhanced sensitivity to inhibition by intracellular H+, increasing the apparent pKa for inhibition by ∼0.9 pH units. Three amino acid substitutions at the COOH-terminal end of the second transmembrane helix (I159V, L160M, and I163M) accounted for these effects. These substitutions also made the channels more sensitive to reduction in K+o, consistent with coupling between the responses to pHi and K+o. The ion selectivity sequence of the activation of the channel by cations was K+ ≅ Rb+ > NH4+ >> Na+, similar to that for ion permeability, suggesting an interaction with the selectivity filter. We tested a model of coupling in which a pH-sensitive gate can close the pore from the inside, preventing access of K+ from the cytoplasm and increasing sensitivity of the selectivity filter to removal of K+o. We mimicked closure of this gate using positive membrane potentials to elicit block by intracellular cations. With K+o between 10 and 110 mM, this resulted in a slow, reversible decrease in conductance. However, additional channel constructs, in which inward rectification was maintained but the pH sensor was abolished, failed to respond to voltage under the same conditions. This indicates that blocking access of intracellular K+ to the selectivity filter cannot account for coupling. The C13 chimera was 10 times more sensitive to extracellular Ba2+ block than was ROMK2, indicating that changes in the COOH terminus affect ion binding to the outer part of the pore. This effect correlated with the sensitivity to inactivation by H+. We conclude that decreasing pHI increases the sensitivity of ROMK2 channels to K+o by altering the properties of the selectivity filter.
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Anderson, Stephen K., Veronique Pascal, Maureen P. Martin, Mary Carrington, and Hongchuan Li. "Genetic control of variegated KIR gene expression: polymorphisms of the bi-directional KIR3DL1 promoter are associated with distinct frequencies of gene expression (35.37)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S8—S9. http://dx.doi.org/10.4049/jimmunol.178.supp.35.37.
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Abstract The recent discovery of the bi-directional nature of the KIR gene promoters suggests that the relative strength of competing sense and antisense promoter elements might affect the probability of gene expression. Analysis of a panel of donors has revealed the presence of several functionally relevant promoter polymorphisms, clustered mainly in the inhibitory KIR family members, especially the KIR3DL1 alleles. The percentage of peripheral blood NK cells expressing either KIR3DL1 or KIR3DS1 was evaluated in individuals heterozygous at this locus. The KIR3DL1*001 and KIR3DS1 alleles were found to be expressed on a significantly higher percentage of NK cells than all other KIR3DL1 alleles. High frequency of expression was associated with a specific promoter polymorphism at a Sp1 transcription factor-binding site, and this change increased the relative promoter activity in the sense orientation. The KIR2DS4 promoter region is nearly identical to the KIR3DL1 promoter, and several polymorphisms are present, however none of the KIR2DS4 polymorphisms affect promoter activity in vitro and no association was observed between promoter polymorphisms and frequency of expression. This research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. Funded by NCI Contract N01-CO-12400
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Lee, Young Mee, Gareth A. Thompson, Ian Ashmole, Mark Leyland, Insuk So, and Peter R. Stanfield. "Multiple Residues in the P-Region and M2 of Murine Kir 2.1 Regulate Blockage by External Ba2+." Korean Journal of Physiology and Pharmacology 13, no. 1 (2009): 61. http://dx.doi.org/10.4196/kjpp.2009.13.1.61.
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Lara-Armi, Fernanda Formaggi, Jeane Eliete Laguila Visentainer, Ana Maria Sell, Hugo Vicentin Alves, Sonia Kaori Miyamoto, Hellen Capellari Menezes, and Dennis Armando Bertolini. "Influence of KIR in the HIV-1/AIDS disease in the North/Northwest region of Paraná State, Brazil." International Journal of Health Science 2, no. 63 (October 20, 2022): 2–22. http://dx.doi.org/10.22533/at.ed.15926322171010.
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Xie, Lai-Hua, Scott A. John, Bernard Ribalet, and James N. Weiss. "Long Polyamines Act as Cofactors in PIP2 Activation of Inward Rectifier Potassium (Kir2.1) Channels." Journal of General Physiology 126, no. 6 (November 28, 2005): 541–49. http://dx.doi.org/10.1085/jgp.200509380.
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Phosphatidylinosital-4,5-bisphosphate (PIP2) acts as an essential factor regulating the activity of all Kir channels. In most Kir members, the dependence on PIP2 is modulated by other factors, such as protein kinases (in Kir1), Gβγ (in Kir3), and the sulfonylurea receptor (in Kir6). So far, however, no regulator has been identified in Kir2 channels. Here we show that polyamines, which cause inward rectification by selectively blocking outward current, also regulate the interaction of PIP2 with Kir2.1 channels to maintain channel availability. Using spermine and diamines as polyamine analogs, we demonstrate that both spontaneous and PIP2 antibody–induced rundown of Kir2.1 channels in excised inside-out patches was markedly slowed by long polyamines; in contrast, polyamines with shorter chain length were ineffective. In K188Q mutant channels, which have a low PIP2 affinity, application PIP2 (10 μM) was unable to activate channel activity in the absence of polyamines, but markedly activated channels in the presence of long diamines. Using neomycin as a measure of PIP2 affinity, we found that long polyamines were capable of strengthening either the wild type or K188Q channels' interaction with PIP2. The negatively charged D172 residue inside the transmembrane pore region was critical for the shift of channel–PIP2 binding affinity by long polyamines. Sustained pore block by polyamines was neither sufficient nor necessary for this effect. We conclude that long polyamines serve a dual role as both blockers and coactivators (with PIP2) of Kir2.1 channels.
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Ahmed, Chulbul, Rea Dabelic, and Howard Johnson. "Enhancement of antiviral immunity by a peptide antagonist of SOCS (89.9)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 89.9. http://dx.doi.org/10.4049/jimmunol.184.supp.89.9.
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Abstract Suppressors of cytokine signaling (SOCS) are negative regulators of both innate and adaptive immunity via inhibition of signaling by cytokines such as interferons (IFNs). We have developed a small peptide antagonist of SOCS-1 that corresponds to the activation loop of the Janus kinase JAK2. SOCS-1 inhibits both type I and type II IFN activities by binding to the kinase activation loop via the kinase inhibitory region (KIR) of the SOCS. The antagonist, pJAK2(1001-1013), inhibited the replication of vaccinia virus and EMC virus in cell culture, suggesting that it possesses broad antiviral activity. In addition, pJAK2(1001-1013) protected mice against lethal vaccinia and EMC virus infection. pJAK2(1001-1013) increased the intracellular level of the constitutive IFNβ, which may play a role in the antagonist antiviral effect at the cellular level. pJAK2(1001-1013) also synergizes with IFNs as per IFN gamma mimetic to exert a multiplicative antiviral effect at the level of transcription, the cell, and protection of mice against lethal viral infection. pJAK2(1001-1013) binds to the KIR of both SOCS-1 and SOCS-3 and blocks their inhibitory effects on the GAS promoter. In addition to a direct antiviral effect and synergism with IFN, the SOCS antagonist also exhibits adjuvant effects on the humoral and cellular arms as well as an enhancement of polyI:C activation of TLR3. The SOCS antagonist thus presents a novel and effective approach to enhancement of host defense against viruses.
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Zhang, Xiaoli, Junda Su, Ningren Cui, Hongyu Gai, Zhongying Wu, and Chun Jiang. "The disruption of central CO2 chemosensitivity in a mouse model of Rett syndrome." American Journal of Physiology-Cell Physiology 301, no. 3 (September 2011): C729—C738. http://dx.doi.org/10.1152/ajpcell.00334.2010.
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People with Rett syndrome (RTT) have breathing instability in addition to other neuropathological manifestations. The breathing disturbances contribute to the high incidence of unexplained death and abnormal brain development. However, the cellular mechanisms underlying the breathing abnormalities remain unclear. To test the hypothesis that the central CO2 chemoreception in these people is disrupted, we studied the CO2 chemosensitivity in a mouse model of RTT. The Mecp2-null mice showed a selective loss of their respiratory response to 1–3% CO2 (mild hypercapnia), whereas they displayed more regular breathing in response to 6–9% CO2 (severe hypercapnia). The defect was alleviated with the NE uptake blocker desipramine (10 mg·kg−1·day−1 ip, for 5–7 days). Consistent with the in vivo observations, in vitro studies in brain slices indicated that CO2 chemosensitivity of locus coeruleus (LC) neurons was impaired in Mecp2-null mice. Two major neuronal pH-sensitive Kir currents that resembled homomeric Kir4.1 and heteromeric Ki4.1/Kir5.1 channels were identified in the LC neurons. The screening of Kir channels with real-time PCR indicated the overexpression of Kir4.1 in the LC region of Mecp2-null mice. In a heterologous expression system, an overexpression of Kir4.1 resulted in a reduction in the pH sensitivity of the heteromeric Kir4.1-Kir5.1 channels. Given that Kir4.1 and Kir5.1 subunits are also expressed in brain stem respiration-related areas, the Kir4.1 overexpression may not allow CO2 to be detected until hypercapnia becomes severe, leading to periodical hyper- and hypoventilation in Mecp2-null mice and, perhaps, in people with RTT as well.
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Sukka-Ganesh, BhagyaLaxmi, Yi Li, Westley H. Reeves, and Joseph Larkin. "Reduced Suppressor of Cytokine Signaling-1 levels in SLE patients correlates to enhanced STAT1 activation." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 124.23. http://dx.doi.org/10.4049/jimmunol.196.supp.124.23.
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Abstract Systemic Lupus erythematosus (SLE) is a chronic inflammatory autoimmune disorder with unknown etiology. Although the specific events dictating SLE pathology remain unclear, abundant evidence indicates a critical role for dysregulated cytokine signaling in disease progression. Notably, the suppressor of cytokine signaling (SOCS) family of intracellular proteins, in particular the kinase inhibitory region (KIR) bearing SOCS1 and SOCS3, play a critical role in regulating cytokine signaling. Here in this foundational study, we test the hypothesis that regulation of cytokine signaling in SLE patients may be perturbed by a lack of KIR bearing SOCS1 and SOCS3. We analyzed 34 SLE patients, segregated by disease activity (SLEDAI) and prednisone treatment, in comparison with 11 healthy controls. Real time RT-PCR and Western blot analysis showed significant reductions in SOCS1 and SOCS3 in PMBC’s of SLE patients by both mRNA and protein expression when compared to controls. Notably, decreased SOCS1, but not SOCS3 protein levels in the SLE patients were inversely correlated to activation of STAT1, but not Erk 1/2 or Akt. Notably, the inverted SOCS1/pSTAT1 ratio correlated to significantly enhanced MHC class II levels amongst SLE patients. These studies represent a critical first step in implicating a role of SOCS1 and SOCS3 deficiencies in the progression of human SLE, providing impetus for the performance for a larger multi-centered examination. Finally, these studies point to the possibility that peptides, previously shown to mimic SOCS signaling and inhibit rodent autoimmune disease, may have efficacy in the treatment of human SLE.
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Yarkın, Güllistan. "The Ideological Transformation of the PKK regarding the Political Economy of the Kurdish Region in Turkey." Kurdish Studies 3, no. 1 (May 1, 2015): 26–46. http://dx.doi.org/10.33182/ks.v3i1.390.
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When founded in 1978, the PKK defined itself as a socialist movement aiming to create a classless society through the formation of a new state-power. In the 1990s, the ideology of the PKK began to change and this transformation became apparent in the 2000s. The PKK has since completely abandoned its statist Marxist-Leninist national liberationist ideology, and has instead proposed to build “democratic modernity” through the creation of an anti-capitalist, anti-industrialist, women emancipatory and ecologist “democratic confederalism” framework. This project defines the ecologist-rural communes grounded on food sovereignty as its basic economic units. This article argues that the transformation of the PKK’s goals on the political economy of the Kurdish region is shaped by, on the one hand, the world systemic and internal restraints acting upon the PKK, and on the other hand, the ideological responses of the PKK to those restraints.Keywords: The PKK; Abdullah Öcalan; democratic modernity; democratic confederalism; anti-capitalist movements.Guherîna îdeolojîk di PKKyê de û aboriya siyasî ya herêma kurdî li TirkiyeyêGava di sala 1978an de hate damezrandin, PKKyê xwe wek hereketeke sosyalîst pênase kiribû û armanca xwe wisa danîbû ku civakeke bêçîn durist bike bi rêya avakirina desthilata dewleteke nû. Di salên 1990an de îdeolojiya PKKyê dest bi guherînê kir û di salên 2000an de ev guherîn pir aşkera bû. Ji hingê ve, PKKyê bi temamî dest ji îdeolojiya xwe ya Marksî-Lenînî ya azadiya neteweyî kêşaye, li batî wê, ragihandiye ku dixwaze “modernîteya demokratîk” ava bike bi rêya duristkirina çarçoveyeke “konfederaliya demokratîk” a dij-sermayedarî, dij-endûstrîgerî, jin-rizgarkerane û ekolojîk. Di vê projeyê de yekeyên aborî yên esasî ew komûnên ekolojîst-gundî ne ku li ser serbixweyiya xwe ya xurekî pêk hatine (anku ji bo bidestxistina xureka xwe ne muhtacê derve ne). Ev gotar diyar dike ku guherînên di armancên PKKyê yên li ser aboriya siyasî ya herêma kurdî, ji aliyekê ve, ji ber wan zext û berbest û mehdûdiyetên sîstemî yên global û navxweyî pêk hatine ku kar di PKKyê dikin, ji aliyê dî ve, ji ber bersivên îdeolojîk ên PKKyê ne bo wan berbest û mehdûdiyetan.
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Akyuz, Enes, Zuleyha Doganyigit, Yam Nath Paudel, Betul Koklu, Emin Kaymak, Chiara Villa, Alina Arulsamy, Mohd Farooq Shaikh, and Orrin Devinsky. "Immunoreactivity of Muscarinic Acetylcholine M2 and Serotonin 5-HT2B Receptors, Norepinephrine Transporter and Kir Channels in a Model of Epilepsy." Life 11, no. 4 (March 26, 2021): 276. http://dx.doi.org/10.3390/life11040276.
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Epilepsy is characterized by an imbalance in neurotransmitter activity; an increased excitatory to an inhibitory activity. Acetylcholine (ACh), serotonin, and norepinephrine (NE) may modulate neural activity via several mechanisms, mainly through its receptors/transporter activity and alterations in the extracellular potassium (K+) concentration via K+ ion channels. Seizures may disrupt the regulation of inwardly rectifying K+ (Kir) channels and alter the receptor/transporter activity. However, there are limited data present on the immunoreactivity pattern of these neurotransmitter receptors/transporters and K+ channels in chronic models of epilepsy, which therefore was the aim of this study. Changes in the immunoreactivity of epileptogenesis-related neurotransmitter receptors/transporters (M2, 5-HT2B, and NE transporter) as well as Kir channels (Kir3.1 and Kir6.2) were determined in the cortex, hippocampus and medulla of adult Wistar rats by utilizing a Pentylenetetrazol (PTZ)-kindling chronic epilepsy model. Increased immunoreactivity of the NE transporter, M2, and 5-HT2B receptors was witnessed in the cortex and medulla. While the immunoreactivity of the 5-HT2B receptor was found increased in the cortex and medulla, it was decreased in the hippocampus, with no changes observed in the M2 receptor in this region. Kir3.1 and Kir6.2 staining showed increase immunoreactivity in the cerebral cortex, but channel contrasting findings in the hippocampus and medulla. Our results suggest that seizure kindling may result in significant changes in the neurotransmitter system which may contribute or propagate to future epileptogenesis, brain damage and potentially towards sudden unexpected death in epilepsy (SUDEP). Further studies on the pathogenic role of these changes in neurotransmitter receptors/transporters and K+ channel immunoreactivity may identify newer possible targets to treat seizures or prevent epilepsy-related comorbidities.
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Hyde, T. H., and A. Yaghi. "An experimental investigation of dynamic crack propagation." Journal of Strain Analysis for Engineering Design 30, no. 3 (July 1, 1995): 175–83. http://dx.doi.org/10.1243/03093247v303175.
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Burst tests have been performed on closed-ended thin wall tubes with axially aligned, external, semicircular, crack-like flaws. The tubes were made of Araldite CT200 with HT907 hardener. Dynamic crack propagation rates between 0.14c1 and 0.30c1 were measured, c1 being the velocity of longitudinal waves in the walls of the tubes. The fracture surfaces exhibited a smooth mirror-like appearance near the crack initiation site. This was followed by a mist region and then a hackle region. The roughness in the hackle region becomes progressively greater with distance from the initiation site and crack branching can eventually occur. The KID/KIC (where KID is the applied dynamic stress intensity factor and KIC is the plane strain fracture toughness) value at which the hackle region begins is about 3.34 and the KID/KIC value at which branching begins is about 8.75. Previously reported work only contains results for KID/KIC up to about 5. The present work contains results for KID/KIC up to about 14, which correlate with previous work for KID/KIC values less than about 4. However, previous work has indicated that a unique relationship may exist between v/c1 and KID/KIC. The present work indicates that although this is a good approximation, a systematic variation with load (pressure in this case) has been detected.
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FINLIN, Brian S., Haipeng SHAO, Keiko KADONO-OKUDA, Nan GUO, and Douglas A. ANDRES. "Rem2, a new member of the Rem/Rad/Gem/Kir family of Ras-related GTPases." Biochemical Journal 347, no. 1 (March 27, 2000): 223–31. http://dx.doi.org/10.1042/bj3470223.
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Here we report the molecular cloning and biochemical characterization of Rem2 (for Rem, ad and G-related 2), a novel GTP-binding protein identified on the basis of its homology with the Rem, Rad, Gem and Kir (RGK) family of Ras-related small GTP-binding proteins. Rem2 mRNA was detected in rat brain and kidney, making it the first member of the RGK family to be expressed at relatively high levels in neuronal tissues. Recombinant Rem2 binds GTP saturably and exhibits a low intrinsic rate of GTP hydrolysis. Surprisingly, the guanine nucleotide dissociation constants for both Rem2 and Rem are significantly different than the majority of the Ras-related GTPases, displaying higher dissociation rates for GTP than GDP. Localization studies with green fluorescent protein (GFP)-tagged recombinant protein fusions indicate that Rem2 has a punctate, plasma membrane localization. Deletion of the C-terminal seven amino acid residues that are conserved in all RGK family members did not affect the cellular distribution of the GFP fusion protein, whereas a larger deletion, including much of the polybasic region of the Rem2 C-terminus, resulted in its redistribution to the cytosol. Thus Rem2 is a GTPase of the RGK family with distinctive biochemical properties and possessing a novel cellular localization signal, consistent with its having a unique role in cell physiology.
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Liddicoat, Anthony J., and Andy Kirkpatrick. "Dimensions of language education policy in Asia." Journal of Asian Pacific Communication 30, no. 1-2 (June 30, 2020): 7–33. http://dx.doi.org/10.1075/japc.00043.kir.
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Abstract This paper will identify the major trends that can be determined from an overall study of recent language policies across Asia. The trends can be seen across three interrelated themes, namely: the promotion and privileging of one language as the national language as part of an attempt to create a nation state, often in polities that are linguistically extremely diverse; a decrease in the promotion of indigenous languages other than the national language and the neglect of these in education in many countries; and the promotion of English as the first foreign language in education systems, often giving other ‘foreign’ languages a minimal role in education. Possible reasons and motivations for these trends will be discussed and countries where exceptions to these trends can be identified will be illustrated. The aim of the paper will be to discuss these trends and to critically evaluate selected language policies. The paper will conclude with predictions for the future linguistic ecology of the region and for the interrelationships of respective national languages, indigenous languages and English
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Fujiwara, Yuichiro, and Yoshihiro Kubo. "Functional Roles of Charged Amino Acid Residues on the Wall of the Cytoplasmic Pore of Kir2.1." Journal of General Physiology 127, no. 4 (March 13, 2006): 401–19. http://dx.doi.org/10.1085/jgp.200509434.
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It is known that rectification of currents through the inward rectifier K+ channel (Kir) is mainly due to blockade of the outward current by cytoplasmic Mg2+ and polyamines. Analyses of the crystal structure of the cytoplasmic region of Kir2.1 have revealed the presence of both negatively (E224, D255, D259, and E299) and positively (R228 and R260) charged residues on the wall of the cytoplasmic pore of Kir2.1, but the detail is not known about the contribution of these charged residues, the positive charges in particular, to the inward rectification. We therefore analyzed the functional significance of these charged amino acids using single/double point mutants in order to better understand the structure-based mechanism underlying inward rectification of Kir2.1 currents. As a first step, we used two-electrode voltage clamp to examine inward rectification in systematically prepared mutants in which one or two negatively or positively charged amino acids were neutralized by substitution. We found that the intensity of the inward rectification tended to be determined by the net negative charge within the cytoplasmic pore. We then used inside-out excised patch clamp recording to analyze the effect of the mutations on blockade by intracellular blockers and on K+ permeation. We observed that a decrease in the net negative charge within the cytoplasmic pore reduced both the susceptibility of the channel to blockade by Mg2+ or spermine and the voltage dependence of the blockade. It also reduced K+ permeation; i.e., it decreased single channel conductance, increased open-channel noise, and strengthened the intrinsic inward rectification in the total absence of cytoplasmic blockers. Taken together, these data suggest that the negatively charged cytoplasmic pore of Kir electrostatically gathers cations such as Mg2+, spermine, and K+ so that the transmembrane pore is sufficiently filled with K+ ions, which enables strong voltage-dependent blockade with adequate outward K+ conductance.
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Yamashita, Kenichiro, Yuka Takatori, and Yosuke Tashiro. "Development of Sequenc Characterized Amplified Region (SCAR) Markers Linked to the Fertility Restoring Gene for Cytoplasmic Male Sterile Allium fistulosum L. Possessing the Cytoplasm of A. galanthum Kar. et Kir." Engei Gakkai zasshi 71, no. 6 (2002): 777–79. http://dx.doi.org/10.2503/jjshs.71.777.
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Bagot, Martine, Alessandro Moretta, Simona Sivori, Roberto Biassoni, Claudia Cantoni, Cristina Bottino, Laurence Boumsell, and Armand Bensussan. "CD4+ cutaneous T-cell lymphoma cells express the p140–killer cell immunoglobulin-like receptor." Blood 97, no. 5 (March 1, 2001): 1388–91. http://dx.doi.org/10.1182/blood.v97.5.1388.
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Tumor cells of patients with cutaneous T-cell lymphoma (CTCL) have the cell surface phenotype of mature T-helper lymphocytes, and it may be impossible to differentiate them from nonmalignant lymphocytes in skin and blood. Until now, no specific cell membrane marker of CTCL has been reported. In the current study, it is reported for the first time that CTCL cells express the major histocompatibility complex class I binding p140–killer cell immunoglobulin-like receptor, which has been described on a minor subset of natural killer lymphocytes and on a marginal circulating CD8+ T lymphocyte subset. Interestingly, the molecular characterization of this KIR expressed by CTCL allowed us to isolate a novel allelic form of p140–KIR3DL, resulting in 4 amino acid substitutions, 3 in the extracellular immunoglobulin-like domain of the protein and one in the cytoplasmic region. This finding is likely to be important both for the pathophysiology and for the clinical treatment of patients with CTCL.
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Ota, Yuko, and Martin Flajnik. "Remarkable conservation of natural killer receptor, NKp30 (P6089)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 141.10. http://dx.doi.org/10.4049/jimmunol.190.supp.141.10.
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Abstract Comparative analysis of natural killer receptor (NKR) among vertebrates have revealed that they are remarkably plastic; some receptor families have expanded greatly, while others have been lost in a species-specific manner. Thus, NKR are extraordinarily rapidly evolving receptors that must adapt to rapidly changing pathogens. Therefore we were surprised to identify the activating NKR, NKp30 in the amphibian Xenopus and cartilaginous fish (shark, skate) databases. NKp30 is MHC-linked in humans and possesses a unique V-type immunoglobulin superfamily (IgSF) domain, the so-called “VJ”-type, which resembles the precursor of antigen receptors (AgR) and is assumed to have predated the emergence of AgR. Further database searches for NKR in jawless vertebrates and lower deuterostomes revealed no NKR orthologs, implying that NKp30 is the most conserved and oldest NKR in jawed vertebrates. While mammalian NKp30 is encoded by a single copy gene, with a cytoplasmic region that interacts with an ITAM-containing adaptor molecule, multiple NKp30 genes were found in Xenopus and sharks, some with ITIM-containing cytoplasmic regions, indicating inhibitory activity characteristic of other NKRs like KIR/CD94-NKG2. We are testing whether the MHC association of NKp30 is primordial, which would further suggest its coevolution with other MHC-linked proteins such as class I/II or B7 family members.