Journal articles: 'NCR3'

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Yau, Anthony C. Y., Jonatan Tuncel, Sabrina Haag, Ulrika Norin, Miranda Houtman, Leonid Padyukov, and Rikard Holmdahl. "Conserved 33-kb haplotype in the MHC class III region regulates chronic arthritis." Proceedings of the National Academy of Sciences 113, no. 26 (June 14, 2016): E3716—E3724. http://dx.doi.org/10.1073/pnas.1600567113.

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Genome-wide association studies have revealed many genetic loci associated with complex autoimmune diseases. In rheumatoid arthritis (RA), the MHC gene HLA-DRB1 is the strongest candidate predicting disease development. It has been suggested that other immune-regulating genes in the MHC contribute to the disease risk, but this contribution has been difficult to show because of the strong linkage disequilibrium within the MHC. We isolated genomic regions in the form of congenic fragments in rats to test whether there are additional susceptibility loci in the MHC. By both congenic mapping in inbred strains and SNP typing in wild rats, we identified a conserved, 33-kb large haplotype Ltab-Ncr3 in the MHC-III region, which regulates the onset, severity, and chronicity of arthritis. The Ltab-Ncr3 haplotype consists of five polymorphic immunoregulatory genes: Lta (lymphotoxin-α), Tnf, Ltb (lymphotoxin-β), Lst1 (leukocyte-specific transcript 1), and Ncr3 (natural cytotoxicity-triggering receptor 3). Significant correlation in the expression of the Ltab-Ncr3 genes suggests that interaction of these genes may be important in keeping these genes clustered together as a conserved haplotype. We studied the arthritis association and the spliceo-transcriptome of four different Ltab-Ncr3 haplotypes and showed that higher Ltb and Ncr3 expression, lower Lst1 expression, and the expression of a shorter splice variant of Lst1 correlate with reduced arthritis severity in rats. Interestingly, patients with mild RA also showed higher NCR3 expression and lower LST1 expression than patients with severe RA. These data demonstrate the importance of a conserved haplotype in the regulation of complex diseases such as arthritis.

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Thiam, Alassane, Sabrina Baaklini, Babacar Mbengue, Samia Nisar, Maryam Diarra, Sandrine Marquet, Mouhamadou Mansour Fall, et al. "NCR3 polymorphism, haematological parameters, and severe malaria in Senegalese patients." PeerJ 6 (December 3, 2018): e6048. http://dx.doi.org/10.7717/peerj.6048.

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Background Host factors, including host genetic variation, have been shown to influence the outcome of Plasmodium falciparum infection. Genome-wide linkage studies have mapped mild malaria resistance genes on chromosome 6p21, whereas NCR3-412 polymorphism (rs2736191) lying within this region was found to be associated with mild malaria. Methods Blood samples were taken from 188 Plasmodium falciparum malaria patients (76 mild malaria patients, 85 cerebral malaria patients, and 27 severe non-cerebral malaria patients). NCR3-412 (rs2736191) was analysed by sequencing, and haematological parameters were measured. Finally, their association with clinical phenotypes was assessed. Results We evidenced an association of thrombocytopenia with both cerebral malaria and severe non-cerebral malaria, and of an association of high leukocyte count with cerebral malaria. Additionally, we found no association of NCR3-412 with either cerebral malaria, severe non-cerebral malaria, or severe malaria after grouping cerebral malaria and severe non-cerebral malaria patients. Conclusions Our results suggest that NCR3 genetic variation has no effect, or only a small effect on the occurrence of severe malaria, although it has been strongly associated with mild malaria. We discuss the biological meaning of these results. Besides, we confirmed the association of thrombocytopenia and high leukocyte count with severe malaria phenotypes.

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Tian, Jian, Ningfeng Wu, Jiang Li, Yajie Liu, Jun Guo, Bin Yao, and Yunliu Fan. "Nickel-Resistant Determinant from Leptospirillum ferriphilum." Applied and Environmental Microbiology 73, no. 7 (February 9, 2007): 2364–68. http://dx.doi.org/10.1128/aem.00207-07.

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ABSTRACT Leptospirillum ferriphilum strain UBK03 isolated from a mine in Jiangxi, China, is resistant to Ni2+ (30 to 40 mM). A four-gene nickel resistance cluster was identified and, when transformed into Escherichia coli, enabled growth in 6 mM nickel. Mutation experiments revealed that the genes ncrA, ncrB, and ncrC could confer nickel resistance in Escherichia coli, whereas the gene ncrY could have a negative effect on nickel resistance.

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Rusakiewicz, S., G. Nocturne, T. Lazure, M. Semeraro, C. Flament, S. Caillat-Zucman, D. Sene, et al. "NCR3/NKp30 Contributes to Pathogenesis in Primary Sjogren's Syndrome." Science Translational Medicine 5, no. 195 (July 24, 2013): 195ra96. http://dx.doi.org/10.1126/scitranslmed.3005727.

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Marrero, Jeannette, Georg Auling, Orquidea Coto, and Dietrich Nies. "High-Level Resistance to Cobalt and Nickel in Cuban Serratia marcescens Strains Isolated from Serpentine Deposits." Advanced Materials Research 20-21 (July 2007): 521–25. http://dx.doi.org/10.4028/www.scientific.net/amr.20-21.521.

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A collection of highly nickel and cobalt-resistant enterobacteria were isolated from the Punta Gorda serpentine deposit (Moa, Cuba). The most nickel and cobalt resistant strain (termed C- 1) was assigned to Serratia marcescens by 16S rRNA analysis and DNA/DNA hybridization and the molecular mechanisms underlying its inducible cobalt and nickel resistance was investigated. Genes involved in metal resistance were identified by transposon mutagenesis followed by selection for Co- and Ni-sensitive derivatives. The transposon insertion causing the highest decrease in metal resistance was located in the ncrABC determinant. The three ORFs (ncrA, ncrB and ncrC) were cloned in E. coli. The predicted NcrA product was an NreB ortholog of the major facilitator protein superfamily and was central for Co/Ni resistance in S. marcescens strain C-1. NcrA also mediated metal resistance in E. coli and caused decreased accumulation of Co and Ni in this heterologous host. NcrB may be a regulatory protein. NcrC was a protein of the Ni–Co transport (NiCoT) protein family and necessary for full metal resistance in E. coli, but only when NcrA was also present. Without NcrA, NcrC caused a slight decrease in metal resistance and mediated increased accumulation of Ni and Co. As the cytoplasmic metal concentration can be assumed to be the result of a flow equilibrium of uptake and efflux processes, this interplay between metal uptake system NcrC and metal efflux system NcrA may contribute to nickel and cobalt resistance in this bacterium.

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Delahaye, Nicolas F., Mathieu Barbier, Francis Fumoux, and Pascal Rihet. "Association analyses of NCR3 polymorphisms with P. falciparum mild malaria." Microbes and Infection 9, no. 2 (February 2007): 160–66. http://dx.doi.org/10.1016/j.micinf.2006.11.002.

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Skrzypski, Marcin Tomasz, Amelia Szymanowska-Narloch, Ewa Jassem, Michał Marczyk, Joanna Polanska, Wojciech Biernat, Witold Rzyman, Agnieszka Maciejewska, Ryszard Pawlowski, and Jacek Jassem. "Prognostic value of NK and T-lymphocytes markers in operable non-small cell lung cancer (NSCLC)." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 11556. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.11556.

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11556 Background: Therapies aimed at activation of T and NK cells are developed to expand NSCLC treatments options. It is conceivable that markers of ‘immune ignorant’, ‘immune excluding’ or ‘inflamed’ tumor phenotypes could be prognostic or predictive of benefit from specific immune-targeting therapies. Aim: To assess the prognostic value of expression of T and NK cells mRNA markers and immune-related genes in early stage NSCLC. Methods: qRT-PCR was used to assess 48 mRNAs levels in frozen cancer tissue sections and matched normal lung parenchyma from 56 surgically treated stage I-IIIA NSCLC patients. The mRNA expression (normalized vs. 4 reference genes) was compared between the groups that did (44%) or did not relapse, as well as clinicopathological features (33% never-smokers, 75% lung adenocarcinoma). Results: Low expression of FAS-L (p.adj. = 0.048) , TIGIT and LAG3 was correlated with shorter distant metastasis free survival (DMFS) (p < 0.04). Expression of PD-1 (p = 0.024) and CTLA4 (p = 0.04) was significantly lower in relapsed vs. non-relapsed NSCLCs, whereas there was no difference for PDL-1 and PDL-2. Expression of NK activation markers: NCR3 and NCR1, but not NCR3-ligand 1 was significantly lower in relapsed vs. not relapsed NSCLCs. Other NK cell markers: CD96 and NKG2D were expressed at lower levels (p = 0.02) in relapsed vs. not relapsed NSCLCs, whereas there was no difference for NKG2C and NKG2A. Expression of CXCR3 was lower in relapsed NSCLCs (p = 0.03), however, the expression of its ligands (chemoattractants for lymphocytes) - CXCL9, CXCL10 or CXCL11 or endothelin receptor type B was not different according to metastatic status. GITR and FOXP3 expression was significantly higher in cancers vs. normal lung parenchyma (p.adj. < 0.003). There were no differences in expression according to gender, smoking or NSCLC histological types. Conclusions: Non-inflamed NSCLC phenotype is associated with higher risk of dissemination after primary resection. Neoplastic tissue is characterized by higher level of immune tolerance in comparison to normal lung tissue.

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Kinlein, Allison, Morgan E. Janes, Jacob Kincer, Tereza Almeida, Hanover Matz, Jianxin Sui, Michael F. Criscitiello, Martin F. Flajnik, and Yuko Ohta. "Analysis of shark NCR3 family genes reveals primordial features of vertebrate NKp30." Immunogenetics 73, no. 4 (March 19, 2021): 333–48. http://dx.doi.org/10.1007/s00251-021-01209-6.

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Fend, Laetitia, Sylvie Rusakiewicz, Julien Adam, Bérangère Bastien, Anne Caignard, Meriem Messaoudene, Christina Iribarren, et al. "Prognostic impact of the expression of NCR1 and NCR3 NK cell receptors and PD-L1 on advanced non-small cell lung cancer." OncoImmunology 6, no. 1 (May 13, 2016): e1163456. http://dx.doi.org/10.1080/2162402x.2016.1163456.

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Kang, Emily, Cigall Kadoch, James L. Rubenstein, Lewis L. Lanier, and James A. Wells. "A functional mammalian display screen identifies rare antibodies that stimulate NK cell–mediated cytotoxicity." Proceedings of the National Academy of Sciences 118, no. 31 (July 30, 2021): e2104099118. http://dx.doi.org/10.1073/pnas.2104099118.

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Therapies that boost the antitumor immune response have shown a great deal of success. Although most of these therapies have focused on enhancing T cell functions, there is a growing interest in developing therapies that can target other immune cell subsets. Like T cells, natural killer (NK) cells are cytotoxic effector cells that play a key role in the antitumor response. To advance the development of NK-based therapies, we developed a functional screen to rapidly identify antibodies that can activate NK cells. We displayed antibodies on a mammalian target cell line and probed their ability to stimulate NK cell–mediated cytotoxicity. From this screen, we identified five antibodies that bound with high affinity to NK cells and stimulated NK cell–mediated cytotoxicity and interferon-γ (IFN-γ) secretion. We demonstrate that these antibodies can be further developed into bispecific antibodies to redirect NK cell–mediated cytotoxicity toward CD20+ B cell lymphoma cells and HER2+ breast cancer cells. While antibodies to two of the receptors, CD16 and NCR1, have previously been targeted as bispecific antibodies to redirect NK cell–mediated cytotoxicity, we demonstrate that bispecific antibodies targeting NCR3 can also potently activate NK cells. These results show that this screen can be used to directly identify antibodies that can enhance antitumor immune responses.

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Mantovani, Stefania, Barbara Oliviero, Andrea Lombardi, Stefania Varchetta, Dalila Mele, Angelo Sangiovanni, Giorgio Rossi, et al. "Deficient Natural Killer Cell NKp30-Mediated Function and Altered NCR3 Splice Variants in Hepatocellular Carcinoma." Hepatology 69, no. 3 (February 14, 2019): 1165–79. http://dx.doi.org/10.1002/hep.30235.

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Prada, Nicole, Guillemette Antoni, Frédéric Commo, Sylvie Rusakiewicz, Michaela Semeraro, Faroudy Boufassa, Olivier Lambotte, Laurence Meyer, Marie-Lise Gougeon, and Laurence Zitvogel. "Analysis of NKp30/NCR3 isoforms in untreated HIV-1-infected patients from the ANRS SEROCO cohort." OncoImmunology 2, no. 3 (March 2013): e23472. http://dx.doi.org/10.4161/onci.23472.

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Liu, Guiyou, Yang Hu, Shuilin Jin, Fang Zhang, Qinghua Jiang, and Junwei Hao. "Cis-eQTLs regulate reduced LST1 gene and NCR3 gene expression and contribute to increased autoimmune disease risk." Proceedings of the National Academy of Sciences 113, no. 42 (October 11, 2016): E6321—E6322. http://dx.doi.org/10.1073/pnas.1614369113.

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Yau, Anthony C. Y., Jonatan Tuncel, and Rikard Holmdahl. "The Major Histocompatibility Complex Class III Haplotype Ltab-Ncr3 Regulates Adjuvant-Induced but Not Antigen-Induced Autoimmunity." American Journal of Pathology 187, no. 5 (May 2017): 987–98. http://dx.doi.org/10.1016/j.ajpath.2016.12.022.

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Mulcahy, H., K. P. O'Rourke, C. Adams, M. G. Molloy, and F. O'Gara. "LST1 and NCR3 expression in autoimmune inflammation and in response to IFN-γ, LPS and microbial infection." Immunogenetics 57, no. 12 (December 17, 2005): 893–903. http://dx.doi.org/10.1007/s00251-005-0057-2.

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Hollyoake, M. "NKp30 (NCR3) is a Pseudogene in 12 Inbred and Wild Mouse Strains, but an Expressed Gene in Mus caroli." Molecular Biology and Evolution 22, no. 8 (April 27, 2005): 1661–72. http://dx.doi.org/10.1093/molbev/msi162.

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Day, Nancy, Evan Shereck, Janet Ayello, Catherine McGuinn, Prakash Satwani, Duane Lewis, Carmella van de Ven, Ronald J. Wapner, Megan S. Lim, and Mitchell S. Cairo. "NK Receptor (NKR)-Mediated Signaling Pathways in Cord Blood (CB) CD56dim Versus Peripheral Blood (PB) CD56dim NK Cells: Implication for Immaturity in Cord Blood NK CD56dim Innate Immunity." Blood 112, no. 11 (November 16, 2008): 4897. http://dx.doi.org/10.1182/blood.v112.11.4897.4897.

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Abstract Background: NK cells are characterized by absent CD3 but expression of CD56dim (90%, cytotoxic) and CD56bright (10%, mediator). NK cells may contribute to the immaturity in cord blood innate and adaptive immunity, and play an important role in the GVL effect post CBT. However, little is known regarding the NKR signaling pathways in CB vs PB CD56dim NK cells and its relationship to the cytotoxic activity. We previously demonstrated the ability to ex-vivo expand CB into NK subsets with profound NK in-vitro and in-vivo cytotoxic activity (Ayello/Cairo BBMT 2006). We further observed that there were 33 and 37 proteins over and under expressed by proteomic expression profiling studies of CB vs PB CD56dim (Shereck/Cairo, ASH 2007; ASPHO 2007; AACR 2007). The differential protein expressions included NKG2A, IP3R type 3, NCR3, MAPKAPK5, Notch 2, PLEK, and NF-X1 using both immunophenotype and proteomic profiling studies. Objectives: To understand the importance of NKR signaling pathways in mediating the differential protein expression and thus in regulating the NK cytotoxic activities in CB vs PB CD56dim, we compared the genomic expression pattern in CB vs PB CD56dim. Methods: For CD56dim isolation, first, NK cells were isolated indirectly by magnetic separation from non-NK cells. Second, the pre-enriched NK cells (CD56+/CD3−) from CB and PB were directly labeled with CD16 (FCGR3) MicroBeads, and the CD56+ CD16+ NK cells (CD56dim) were eluted after removing the column from the magnetic field (Miltenyi). Purity of CD56dim NK cells were then examined by flow cytometry (BD FACScan). For genomic studies, total RNA was isolated and reverse transcribed to cDNA using T7-Oligo (dT) primer. cRNA was Biotin-labeled by in vitro transcription. Fragmented biotin-labeled cRNA was hybridized to GeneChip U133A_2 in GCOS-operated Fluidics Station 450, and then scanned by GeneChip Scanner 3000 (Affymetrix). Data were analyzed using Agilent GeneSpring. Signal intensities were compared using one way ANOVA and Welch Test for statistical analysis. Results: There were 193 and 222 genes over and under expressed at the genomic level between CB vs PB CD56dim NK cells, respectively. CB vs PB CD56dim significantly overexpressed NKG2A (2.14F), CD16b (2.46F), KIR2D (2.13F), NKp44 (NCR2; 2.62F), PBX1 (4.29F), ENPEP (3.93F). There was no significant difference in NKR gene expression of CD16a, CD161, NKG2C, and NKp46 in CB vs PB CD56dim. CB vs PB CD56dim underexpressed the following NK genes: IP3R (1.32F), MAPKAPK5 (1.77F), NCR3 (1.24F), ACACB (3.23F), BBS1 (2.00F). Conclusion: CB vs PB CD56dim overexpressed NKG2A, CD16b, KIR2D, and NKp44 genes compared to only NKG2A was overexpressed at the protein level. These results suggest that NKR protein product levels in CB CD56dim may be directly regulated at the translation level, but not the transcription level. The discrepancy of IP3R, ENPEP, PBX1, and MAPKAPK5 gene expression suggest the involvements of IP3 and calcium ions in NKR signaling pathways. Since the Notch2, PLEK, and NF-X1 gene expression patterns were not increased, the augmented protein levels may result from the regulation of protein translation. The potential regulators of this process may include PBX1, ENPEP, ACACB, and BBS1 though the roles of these regulators need to be defined. We conclude that genomic differences between CB vs PB CD56dim may play an important role in regulating NKR signaling pathway, and thus contribute to disparate cytotoxic activity between CB vs PB and suggest a possible explanation for immaturity of cord blood innate and adaptive immunity.

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Susman, Ellen B. "Cooperative Learning: A Review of Factors That Increase the Effectiveness of Cooperative Computer-Based Instruction." Journal of Educational Computing Research 18, no. 4 (June 1998): 303–22. http://dx.doi.org/10.2190/2mmx-r2r9-kmct-ncr3.

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Despite great expectations in the educational community, Cooperative Computer-Based Instruction (C-CBI) has not been shown to increase students's learning over individual CBI (I-CBI). These lack of findings may be due to the varied implementation of C-CBI. This meta-analysis concentrates on the presence of two factors, cooperative learning training and problem-solving CBI, in studies which compare C-CBI and I-CBI. The results of twenty-three studies were coded and effect sizes were calculated. Effect sizes were analyzed to determine if a greater difference exists between the cooperative and individual conditions when students were trained and used a problem-solving CBI. Results show that studies that included these elements have greater mean effect sizes ( es = .413) than the mean of all studies ( es = .251). This study provides more evidence that cooperative learning and problem-solving CBIs are important factors in increasing achievement, group interaction, and elaboration in C-CBI.

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Benkaroun, Jessica, Gregory Robertson, Hugh Whitney, and Andrew Lang. "Analysis of the Variability in the Non-Coding Regions of Influenza A Viruses." Veterinary Sciences 5, no. 3 (August 25, 2018): 76. http://dx.doi.org/10.3390/vetsci5030076.

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The genomes of influenza A viruses (IAVs) comprise eight negative-sense single-stranded RNA segments. In addition to the protein-coding region, each segment possesses 5′ and 3′ non-coding regions (NCR) that are important for transcription, replication and packaging. The NCRs contain both conserved and segment-specific sequences, and the impacts of variability in the NCRs are not completely understood. Full NCRs have been determined from some viruses, but a detailed analysis of potential variability in these regions among viruses from different host groups and locations has not been performed. To evaluate the degree of conservation in NCRs among different viruses, we sequenced the NCRs of IAVs isolated from different wild bird host groups (ducks, gulls and seabirds). We then extended our study to include NCRs available from the National Center for Biotechnology Information (NCBI) Influenza Virus Database, which allowed us to analyze a wider variety of host species and more HA and NA subtypes. We found that the amount of variability within the NCRs varies among segments, with the greatest variation found in the HA and NA and the least in the M and NS segments. Overall, variability in NCR sequences was correlated with the coding region phylogeny, suggesting vertical coevolution of the (coding sequence) CDS and NCR regions.

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Baaklini, Sabrina, Sarwat Afridi, Thy Ngoc Nguyen, Felix Koukouikila-Koussounda, Mathieu Ndounga, Jean Imbert, Magali Torres, Lydie Pradel, Francine Ntoumi, and Pascal Rihet. "Beyond genome-wide scan: Association of a cis-regulatory NCR3 variant with mild malaria in a population living in the Republic of Congo." PLOS ONE 12, no. 11 (November 9, 2017): e0187818. http://dx.doi.org/10.1371/journal.pone.0187818.

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Marrero, Jeannette, A. Diaz, Antonio Valle, Domingo Cantero, José Manuel Gómez, and Orquidea Coto. "Nickel and Cobalt Removal Capacities of Native Metal-Resistant Bacteria." Advanced Materials Research 71-73 (May 2009): 617–20. http://dx.doi.org/10.4028/www.scientific.net/amr.71-73.617.

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Genetic determinants for heavy metal resistance could be exploited in the design of bioprocesses for environmental cleanup. The removal of Ni(II), Co(II), Cr(VI) and Mn(II) was investigated using Serratia marcescens strains C-1, C4, 16 and Kluyvera sp. Nic3 isolated from nickel deposits in Moa, Holguín (Cuba). The high nickel and cobalt resistance of S. marcescens C-1 is based on the NreB- genetic determinant ncrABC, which encodes histidine-rich proteins, NcrA, NcrB and NcrC. NcrC is a Ni(II)/Co(II) uptake protein. In this work the presence of ncrAB fragment in S. marcescens C4, 16 and Kluyvera sp. Nic3 was determined by PCR. ncrAB fragment was efficiently amplified from genomic DNA of the strains C4 and 16 but not from strain Nic3. Strains C4, 16 and C-1 showed the highest resistance to Ni(II) and Co(II). The Ni(II)/Co(II) removal capacities of C4, 16 and C-1 strains were two times higher than that by Nic3 (12.88 mg of Ni(II)/g of biomass and 9.77 mg of Co(II)/g of biomass). Uptake of Cr(VI) and Mn(II) was not observed for any of these strains. pH value has an important influence on the Ni(II) and Co(II) removal capacity of S. marcescens C-1. Additional studies are currently in progress aimed to check the metal removal efficiency of strain C1 in batch reactors.

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Roy, Proyash, Mingkee Achom, Helen Wilkinson, Beatriz Lagunas, and Miriam L. Gifford. "Symbiotic Outcome Modified by the Diversification from 7 to over 700 Nodule-Specific Cysteine-Rich Peptides." Genes 11, no. 4 (March 25, 2020): 348. http://dx.doi.org/10.3390/genes11040348.

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Legume-rhizobium symbiosis represents one of the most successfully co-evolved mutualisms. Within nodules, the bacterial cells undergo distinct metabolic and morphological changes and differentiate into nitrogen-fixing bacteroids. Legumes in the inverted repeat lacking clade (IRLC) employ an array of defensin-like small secreted peptides (SSPs), known as nodule-specific cysteine-rich (NCR) peptides, to regulate bacteroid differentiation and activity. While most NCRs exhibit bactericidal effects in vitro, studies confirm that inside nodules they target the bacterial cell cycle and other cellular pathways to control and extend rhizobial differentiation into an irreversible (or terminal) state where the host gains control over bacteroids. While NCRs are well established as positive regulators of effective symbiosis, more recent findings also suggest that NCRs affect partner compatibility. The extent of bacterial differentiation has been linked to species-specific size and complexity of the NCR gene family that varies even among closely related species, suggesting a more recent origin of NCRs followed by rapid expansion in certain species. NCRs have diversified functionally, as well as in their expression patterns and responsiveness, likely driving further functional specialisation. In this review, we evaluate the functions of NCR peptides and their role as a driving force underlying the outcome of rhizobial symbiosis, where the plant is able to determine the outcome of rhizobial interaction in a temporal and spatial manner.

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Montiel, Jesús, J. Allan Downie, Attila Farkas, Péter Bihari, Róbert Herczeg, Balázs Bálint, Peter Mergaert, Attila Kereszt, and Éva Kondorosi. "Morphotype of bacteroids in different legumes correlates with the number and type of symbiotic NCR peptides." Proceedings of the National Academy of Sciences 114, no. 19 (April 24, 2017): 5041–46. http://dx.doi.org/10.1073/pnas.1704217114.

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In legume nodules, rhizobia differentiate into nitrogen-fixing forms called bacteroids, which are enclosed by a plant membrane in an organelle-like structure called the symbiosome. In the Inverted Repeat-Lacking Clade (IRLC) of legumes, this differentiation is terminal due to irreversible loss of cell division ability and is associated with genome amplification and different morphologies of the bacteroids that can be swollen, elongated, spherical, and elongated–branched, depending on the host plant. In Medicago truncatula, this process is orchestrated by nodule-specific cysteine-rich peptides (NCRs) delivered into developing bacteroids. Here, we identified the predicted NCR proteins in 10 legumes representing different subclades of the IRLC with distinct bacteroid morphotypes. Analysis of their expression and predicted sequences establishes correlations between the composition of the NCR family and the morphotypes of bacteroids. Although NCRs have a single origin, their evolution has followed different routes in individual lineages, and enrichment and diversification of cationic peptides has resulted in the ability to impose major morphological changes on the endosymbionts. The wide range of effects provoked by NCRs such as cell enlargement, membrane alterations and permeabilization, and biofilm and vesicle formation is dependent on the amino acid composition and charge of the peptides. These effects are strongly influenced by the rhizobial surface polysaccharides that affect NCR-induced differentiation and survival of rhizobia in nodule cells.

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Haag, Andrew M., Jeremy Cheng, and Robi Wirove. "Describing the not criminally responsible population in Alberta’s history: Sociodemographic, mental health, and criminological profiles." Journal of Community Safety and Well-Being 1, no. 3 (November 18, 2016): 68. http://dx.doi.org/10.35502/jcswb.24.

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This is the first paper to look at the entire population of those found Not Criminally Responsible on Account of Mental Disorder (NCR) in Alberta, Canada. The Alberta NCR Project examined longitudinal data from the NCR population to describe sociodemographic, mental health, and criminological profiles. Data were collected for the period of 1941 (i.e., the first known case in Alberta) to October 15, 2015, using archived patient chart information. The majority of Alberta NCRs have not completed high school, are diagnosed with some form of psychosis, and were found by the court to be NCR due to a violent crime. The Alberta NCR population has grown by an average of seven NCR accused per year and, of those who have reached absolute discharge, each person spent an average of 5.7 years under the Alberta Review Board (the provincial body that oversees those found NCR). Those who committed a homicide had significantly longer hospitalizations than those under every other crime category, except attempted homicide.

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Hudspeth, Kelly, Manuela Fogli, Daniel V. Correia, Joanna Mikulak, Alessandra Roberto, Silvia Della Bella, Bruno Silva-Santos, and Domenico Mavilio. "Engagement of NKp30 on Vδ1 T cells induces the production of CCL3, CCL4, and CCL5 and suppresses HIV-1 replication." Blood 119, no. 17 (April 26, 2012): 4013–16. http://dx.doi.org/10.1182/blood-2011-11-390153.

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AbstractNatural cytotoxicity receptors (NCRs) were originally identified as specific natural killer cell activating receptors that, on binding to their endogenous ligands, trigger the killing of tumor cell targets. We recently described the differentiation of a novel subset of NCR+ Vδ1 T cells characterized by a remarkably high cytolytic potential against cancer cells. Here we demonstrate that the engagement of NKp30, one of the NCRs expressed de novo on Vδ1 T cells after stimulation, triggers the production of high levels of CCL3/MIP-1α, CCL4/ MIP-1β, and CCL5/RANTES but not of CXCL12/SDF-1. In turn, this NKp30-induced secretion of cc-chemokines is able to significantly suppress the replication of a CCR5 tropic strain of HIV-1 in CD4+/CCR5+ infected PM1 cell lines. This experimental evidence disclosing an unanticipated antiviral function of NCR+ Vδ1 T cells opens new avenues for understanding the pathogenic role and for manipulating the function of γδ T cells in HIV-1 infection.

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Nowbakht, Pegah, Mihai-Constantin S. Ionescu, Andreas Rohner, Christian P. Kalberer, Emmanuel Rossy, Lucia Mori, David Cosman, Gennaro De Libero, and Aleksandra Wodnar-Filipowicz. "Ligands for natural killer cell–activating receptors are expressed upon the maturation of normal myelomonocytic cells but at low levels in acute myeloid leukemias." Blood 105, no. 9 (May 1, 2005): 3615–22. http://dx.doi.org/10.1182/blood-2004-07-2585.

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AbstractNatural killer (NK) cell–mediated cytolytic activity against tumors requires the engagement of activating NK receptors by the tumor-associated ligands. Here, we have studied the role of NKG2D and natural cytotoxicity receptors (NCRs) in the recognition of human leukemia. To detect as-yet-unknown cell-surface molecules recognized by NCRs, we developed soluble forms of NKp30, NKp44, and NKp46 as staining reagents binding the putative cognate ligands. Analysis of UL16-binding protein-1 (ULBP1), ULBP2, and ULBP3 ligands for NKG2D and of potential ligands for NKp30, NKp44, and NKp46 in healthy hematopoietic cells demonstrated the ligand-negative phenotype of bone marrow–derived CD34+ progenitor cells and the acquisition of cell-surface ligands during the course of myeloid differentiation. In acute myeloid leukemia (AML), leukemic blasts from approximately 80% of patients expressed very low levels of ULBPs and NCR-specific ligands. Treatment with differentiation-promoting myeloid growth factors, together with interferon-γ, upregulated cell-surface levels of ULBP1 and putative NCR ligands on AML blasts, conferring an increased sensitivity to NK cell–mediated lysis. We conclude that the ligand-negative/low phenotype in AML is a consequence of cell maturation arrest on malignant transformation and that defective expression of ligands for the activating NKG2D and NCR receptors may compromise leukemia recognition by NK cells.

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Ponnampalam, A. P., G. C. Weston, A. C. Trajstman, B. Susil, and P. A. W. Rogers. "266.Human endometrial cycle stages can be determined by global gene expression profiling." Reproduction, Fertility and Development 16, no. 9 (2004): 266. http://dx.doi.org/10.1071/srb04abs266.

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Endometrium is a dynamic tissue which undergoes cyclic changes each month, under the overall control of oestrogen and progesterone. The aims of this study were to investigate the changing global gene expression profile of human endometrium during the menstrual cycle using microarray technology and to determine the correlation between histopathological evaluation and molecular profile of the samples. Curettings of endometrium were collected from 43 cycling women and immediately snap frozen. The menstrual cycle was divided into seven stages by histological evaluation. Standard two-color cDNA microarrays were performed on the 43 samples against a common reference, using a 10.5 K cDNA glass slide microarray. Expressed genes were identified using a Scanarray 5000 UV laser scanner. Quantarray software was used to quantify the relative gene expression values. Normalisation and visualisation of the gene expression changes were performed using the GeneSpring software package. Hierarchical clustering of all 43 samples was performed, based on the expression profile of 571 genes, which were identified as differentially expressed by parametric ANOVA with Benjamini-Hochberg correction. The 43 samples were sorted into nine groups which all agreed with histopathology by either being in the same group or an adjacent group apart from four samples. For further analysis, the four outliers were removed, one group was excluded due to lack of replicates and two groups were merged to get the final molecular classification of the cycle. The statistical analysis was repeated and 1452 genes were identified as differentially expressed at P d 0.05. The data were also independently analysed by a CSIRO algorithm called GeneRave and the results from both methods were comparable. mRNA expression profiles of the genes TGF a (Hs.170009), NCR3 (Hs.509513) and FUT4 (Hs.390420) were verified using real-time PCR. We have shown for the first time that endometrial cycle stage prediction is possible based on global gene expression profile.

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Sáiz, M., S. Gómez, E. Martínez-Salas, and F. Sobrino. "Deletion or substitution of the aphthovirus 3′ NCR abrogates infectivity and virus replication." Journal of General Virology 82, no. 1 (January 1, 2001): 93–101. http://dx.doi.org/10.1099/0022-1317-82-1-93.

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The 3′ noncoding region (NCR) of the genomic picornaviral RNA is believed to contain major cis-acting signals required for negative-strand RNA synthesis. The 3′ NCR of foot-and-mouth disease virus (FMDV) was studied in the context of a full-length infectious clone in which the genetic element was deleted or exchanged for the equivalent region of a distantly related swine picornavirus, swine vesicular disease virus (SVDV). Deletion of the 3′ NCR, while maintaining the intact poly(A) tail as well as its replacement for the SVDV counterpart, abrogated virus replication in susceptible cells as determined by infectivity and Northern blot assays. Nevertheless, the presence of the SVDV sequence allowed the synthesis of low amounts of chimeric viral RNA at extended times post-transfection as compared to RNAs harbouring the 3′ NCR deletion. The failure to recover viable viruses or revertants after several passages on susceptible cells suggests that the presence of specific sequences contained within the FMDV 3′ NCR is essential to complete a full replication cycle and that FMDV and SVDV 3′ NCRs are not functionally interchangeable.

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Tang, Qin, Bartosz Grzywacz, Hongbo Wang, Nandini Kataria, John E. Wagner, Bruce R. Blazar, Jeffrey S. Miller, and Michael R. Verneris. "Umbilical Cord Blood T Cells Express the Natural Cytotoxicity Receptors, NKp30, NKp44 and NKp46 after IL-15 Stimulation, but Only NKp30 Is Functional." Blood 110, no. 11 (November 16, 2007): 61. http://dx.doi.org/10.1182/blood.v110.11.61.61.

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Abstract The natural cytotoxicity receptors (NCRs), NKp30, NKp44 and NKp46, are a recently identified group of receptors that play a central role in NK cell killing of malignant cells. Previous studies show that the NCRs are restricted to the NK cell lineage. However, we noted that a small fraction of freshly isolated umbilical cord blood (UCB) T cells expressed NKp30 (1.7±0.9%, n=8), but not NKp44 (0.4±0.4%, n=8) or NKp46 (0.5±0.4%, n=8). Thus, we investigated whether NCRs could be induced on either UCB or adult peripheral blood (PB) T cells after culture in IL-15 for 14 days. This cytokine was chosen since previous studies show that IL-15 induces other NK cell receptors on both UCB and PB T cells. Surprisingly, UCB, but not PB T cells, acquired NKp30 (37±10% vs 4±2%, p=0.01), NKp44 (41±20% vs. 1±0.6%, p=0.01) and NKp46 (13±7% vs 0.6±0.5%, p=0.01). NCRs were found mainly on CD8+ or CD3+CD56+ UCB T cells. Further studies addressed whether other cytokines could induce NCR expression on UCB T cells. Both IL-2 and IL-15 showed a dose dependent induction of NCRs. In contrast, IL-7 induced only NKp30 on UCB T cells, but in a non-dose dependent manner. IL-4 abrogated NCR expression, even in the presence of IL-15. Considering that the ligands for the NCRs are not yet elucidated, we performed functional studies using agonist mAbs and NK cells served as controls. Surprisingly, while all three NCRs were expressed on IL-15 expanded UCB T cells, only NKp30 was functional as demonstrated by degranulation (CD107a), IFN-γ release, and redirected killing assays (reverse ADCC). Previous studies show that the NKp30, −44 and −46 cooperate to induce NK killing. However, the simultaneous triggering of all 3 NCRs did not increase UCB T cell cytotoxicity. Some NK cell receptors modulate TCR triggering, but this was not the case with NCRs. We did find that another NK cell receptor, NKG2D, enhanced the cytoxic triggering of NKp30, but not other NCRs. To address the lack of function of NKp44 and −46 on UCB T cells, the expression of adapter proteins required for signaling through these receptors were determined. The proximal receptor for NKp44 signaling, DAP12, was absent in UCB T cells. Thus, the lack of DAP12 likely explains the absence of NKp44 signaling. Both of the adapters used by NKp30 and −46 (FcεR1γ and CD3ζ) were detected. As stated above, NKp46 was expressed on significantly fewer cells than NKp30 (13±7% vs 37±10%) and this likely accounts for the lack of NKp46 function. Considering that UCB contains mostly naive T cells, we hypothesized that PB naive T cells may also acquire NCRs. To test this, PB T cell subsets (naive, central memory and effector memory) were FACS sorted and cultured for 14 days in IL-15. NKp30 was induced on a small number of naive, but not memory PB T cells. Unlike UCB T cells, NKp30 on naive PB T cells was non-functional. PB T cells lacked FcεR1γ, while UCB T cells expressed it, suggesting that this adapter protein is critical for NKp30 signaling. Collectively, these results show that UCB T cells are unique in their ability to acquire NCRs. Moreover, only NKp30 is functional. The lack of function of NKp44 and -46 is due to the absence of DAP12 and the low level of NKp46 expression, respectively. Lastly, while some naive PB T cells can acquire NKp30, it is not functional due to the lack of FcεR1γ. Such studies highlight the differences between UCB and PB T cells and challenge the dogma that NCRs are NK cell specific.

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ElTanbouly, Mohamed A., Yanding Zhao, Elizabeth Nowak, Jiannan Li, Evelien Schaafsma, Isabelle Le Mercier, Sabrina Ceeraz, et al. "VISTA is a checkpoint regulator for naïve T cell quiescence and peripheral tolerance." Science 367, no. 6475 (January 16, 2020): eaay0524. http://dx.doi.org/10.1126/science.aay0524.

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Negative checkpoint regulators (NCRs) temper the T cell immune response to self-antigens and limit the development of autoimmunity. Unlike all other NCRs that are expressed on activated T lymphocytes, V-type immunoglobulin domain-containing suppressor of T cell activation (VISTA) is expressed on naïve T cells. We report an unexpected heterogeneity within the naïve T cell compartment in mice, where loss of VISTA disrupted the major quiescent naïve T cell subset and enhanced self-reactivity. Agonistic VISTA engagement increased T cell tolerance by promoting antigen-induced peripheral T cell deletion. Although a critical player in naïve T cell homeostasis, the ability of VISTA to restrain naïve T cell responses was lost under inflammatory conditions. VISTA is therefore a distinctive NCR of naïve T cells that is critical for steady-state maintenance of quiescence and peripheral tolerance.

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Kálmán, Alajos, and László Fábián. "Structural similarities in tetraaryltins described by virtual non-crystallographic rotations or translations: Kitaigorodskii's morphotropism is revisited." Acta Crystallographica Section B Structural Science 63, no. 3 (May 16, 2007): 411–17. http://dx.doi.org/10.1107/s0108768107010968.

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Recently Kálmán [(2005), Acta Cryst. B61, 536–547] revealed that semirigid molecules or their patterns held together e.g. by hydrogen bonds may perform non-crystallographic rotations (through 180, 90° etc.) around themselves whenever a substitution, ring enlargement or isomerization destroys the existing close packing, i.e. the novel substituent or the enlarged ring can no longer fit in the hollows formed between the molecules. In other words, the old and new arrangements of such chemically similar molecules can be converted into each other by virtual rotations. However, when a semirigid molecule without substitution, but under the influence of solvents, temperature etc., is fully or partly rearranged in the solid state, the corresponding non-crystallographic rotation (hereinafter ncr) is real and gives rise to polymorphism. Such polymorphs are hallmarked by full or partial isostructurality and show that ncrs always occur together with isostructurality. First Kitaigorodskii [(1961), Organic Chemical Crystallography, New York: Consultants Bureau] reported on the structural similarity of three tetraaryltins, (p-RC6H4)4Sn, R = H, CH3, CH3O, which is terminated by the larger C2H5O group. A revisit to these structures revealed that the tetragonal → monoclinic conversion termed by Kitaigorodskii as a `morphotropic step' is also performed by an ncr. Similarly, other tetraaryltins in the literature are related by ncrs or the nc translation of the semirigid tetrahedra, or they remain isostructural. Since one of the definitions of morphotropism, a word of Greek origin, is `turn of form', the ncrs of semirigid molecules can be denoted – following Kitaigorodskii – by this word, whereas its alternative definition in the morphological crystallography of `unidirectional changes' [applied by Groth (1870). Ber. Chem. Ges. 3, 449–457] covers the non-crystallographic translations described first in this work.

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32

Hayasaka, Daisuke, Leonid Ivanov, Galina N. Leonova, Akiko Goto, Kentaro Yoshii, Tetsuya Mizutani, Hiroaki Kariwa, and Ikuo Takashima. "Distribution and characterization of tick-borne encephalitis viruses from Siberia and far-eastern Asia." Journal of General Virology 82, no. 6 (June 1, 2001): 1319–28. http://dx.doi.org/10.1099/0022-1317-82-6-1319.

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In this study, tick-borne encephalitis (TBE) viruses from Siberia and far-eastern Asia were characterized in order to determine virus subtype distribution. TBE viruses were isolated from ticks (Ixodes persulcatus) collected in the far-eastern (Khabarovsk and Vladivostok) and Siberian (Irkutsk) regions of Russia in 1999. Phylogenetic analysis showed that isolates formed distinct clusters of far-eastern and Siberian subtypes. There was also a minor difference in antigenicity between the Irkutsk isolates and other TBE virus strains, as demonstrated by the reactivity of monoclonal antibodies. Amino acid alignments of the E gene showed that the Irkutsk isolates had a single amino acid change at position 234 (Q or H); this amino acid position is considered to be a ‘signature’ of Siberian subtype TBE viruses. Strains isolated in Irkutsk also exhibited equivalent or somewhat higher virulence in mice compared with far-eastern TBE virus isolates. All viruses isolated in this study (i.e. far-east Asian and Siberian isolates) have 3′ non-coding regions (NCRs) of almost the same length, which contrasts with the various sizes of 3′NCRs of other TBE viruses strains reported previously. The data presented in this study show that the 3′NCR is uniform among TBE viruses isolated from Siberia and far-eastern Asia and that the 3′NCR is essential for TBE virus growth in tick and/or rodent host cells.

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Costello, Régis T., Simona Sivori, Emanuela Marcenaro, Marina Lafage-Pochitaloff, Marie-Joelle Mozziconacci, Denis Reviron, Jean-Albert Gastaut, Daniela Pende, Daniel Olive, and Alessandro Moretta. "Defective expression and function of natural killer cell–triggering receptors in patients with acute myeloid leukemia." Blood 99, no. 10 (May 15, 2002): 3661–67. http://dx.doi.org/10.1182/blood.v99.10.3661.

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The cytolytic function of natural killer (NK) cells is induced by the engagement of a series of activating receptors and coreceptors some of which have recently been identified and collectively termed natural cytotoxicity receptors (NCRs). Here, we analyzed the cytolytic function of NK cells obtained from patients with acute myeloid leukemia (AML). In sharp contrast with healthy donors, in most (16 of 18) patients with AML the majority of NK cells displayed low NCR surface density (NCRdull). This phenotype correlated with a weak cytolytic activity against autologous leukemic cells that could not be reversed by the monoclonal antibody-mediated disruption of HLA class I/killer immunoglobulinlike receptor interaction. The remaining 2 patients were characterized by NK cells having an NCRbright phenotype. Surprisingly, although displaying NCR-mediated cytolytic activity, these NCRbright NK cells were unable to kill autologous leukemic blasts. Importantly, the leukemic blasts from these 2 patients were also resistant to lysis mediated by normal NCRbrightallogeneic NK cells. Our study suggests that in most instances the inability of NK cells to kill autologous leukemic blasts is consequent to low NCR surface expression. In few cases, however, this failure appears to involve a mechanism of tumor escape based on down-regulation of ligands relevant for NCR-mediated target cell recognition.

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Seymour, Matthew T., Rachel Moser, Matthew Cooper, Sheila Fisher, Karen Poole, and Christopher Nutting. "Growth in head and neck cancer clinical research in the NCRN and NCRI: Expanding opportunities for patients across the United Kingdom." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): e16007-e16007. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e16007.

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e16007 Background: The National Institute for Health Research Cancer Research Network (NCRN) was established in 2001 to benefit patients by improving the coordination, integration and speed of cancer research. Networks were established in England (NCRN), Scotland, Wales and Northern Ireland, supporting recruitment to a national portfolio across the NHS. In a decade recruitment to cancer studies has increased five fold in England to 20% of new incident cases. Head and Neck cancers affect basic functions including breathing and eating; particularly devastating for patients. The NCRI Head and Neck Cancer Clinical Studies Group is one of 23 Groups funded by NCRI members with a UK wide remit to develop a national portfolio of clinical studies. All CSGs include patients and carers as members resulting in active patient involvement in trial design, patient information and strategic direction of the portfolio. Methods: The last decade has seen unprecedented growth in the Head and Neck portfolio, which now includes 43 studies from only three studies in 2003/4. By 2010/11, 95% of UK Cancer Local Research Networks (37 networks) were recruiting to Head and Neck studies from only 2 networks in 2001/2, expanding trial access for patients and developing Head and Neck research expertise in new sites and with new investigators. Results: Numbers of patients participating in Head and Neck studies has grown exponentially. Since 2006/7 UK patient recruitment has risen 15-fold from 126 to 1890, representing almost 25% new incident cases of Head and Neck cancer. Conclusions: Rapid portfolio growth and associated network activity has expanded opportunities for patients with Head and Neck cancer; providing access to new therapeutic agents and treatment modalities, including NIHR CRN-adopted commercial trials and studies in a surgical setting. Participation in studies demonstrating the effectiveness of Intensity Modulated Radiotherapy in reducing xerostomia (including PARSPORT), has supported integration of this technique into cancer service.

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Robertson, LE, YO Huh, JJ Butler, WC Pugh, C. Hirsch-Ginsberg, S. Stass, H. Kantarjian, and MJ Keating. "Response assessment in chronic lymphocytic leukemia after fludarabine plus prednisone: clinical, pathologic, immunophenotypic, and molecular analysis [see comments]." Blood 80, no. 1 (July 1, 1992): 29–36. http://dx.doi.org/10.1182/blood.v80.1.29.29.

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Abstract The goals of this study were to evaluate the response to treatment in chronic lymphocytic leukemia (CLL) according to clinical, pathologic, immunophenotypic, and molecular features, as well as to address the clinical significance of each finding. One hundred fifty-nine CLL patients with either advanced Rai stage III or IV (81 patients) or progressive Rai stage 0 to II (78 patients) were treated with fludarabine (30 mg/m2/d intravenously every day for 5 days) plus prednisone (30 mg/m2/d orally daily for 5 days). Thirty-six patients were previously untreated. The response rates were 12% complete response (CR), 30% nodular complete response (nCR), and 18% partial response (PR). In all patients who achieved a complete response (both CR and nCR) less than 30% of nucleated cells were lymphocytes on marrow aspirate differential analysis; however, nCR patients had residual nodular and/or interstitial lymphocyte involvement on marrow biopsy examination. There was no evidence of leukemic infiltration on marrow biopsy examination in CR patients. With a median follow-up of 35 months, comparison of time to progression in the CR and nCR groups at 2 years showed a projected 87% versus 55% progression-free survival (P less than .03). Residual disease assessment by flow cytometry using simultaneous dual-color staining on blood and marrow lymphocytes was also performed on each patient. Residual disease was determined by the expression of CD5 on B lymphocytes and the monoclonality of surface light-chain expression. After six courses of fludarabine plus prednisone, no residual disease was detected by flow cytometry in 89% of the CRs, 51% of the nCRs, and 19% of the PRs. Clinical residual disease in PR patients with no residual disease detectable by flow cytometry was limited to lymph-adenopathy. Time to progression at 2 years was longer in CR and nCR patients having no residual disease detected by flow cytometry (84% v 39% 2-year progression-free survival, P less than .001). Posttreatment lg gene rearrangement analysis using JH, J kappa, and C lambda probes demonstrated no rearranged bands and a return to the germline configuration in five of seven CRs and two of eight nCRs studied. The molecular studies were concordant with the dual- parameter immunophenotype results and none of the patients who reverted to a germline DNA pattern after treatment have experienced relapse. The absence of detectable minimal residual disease by bone marrow biopsy, dual-color flow cytometry, and lg gene rearrangement analysis is achieveable in CLL with fludarabine and is predictive of the response duration.

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Robertson, LE, YO Huh, JJ Butler, WC Pugh, C. Hirsch-Ginsberg, S. Stass, H. Kantarjian, and MJ Keating. "Response assessment in chronic lymphocytic leukemia after fludarabine plus prednisone: clinical, pathologic, immunophenotypic, and molecular analysis [see comments]." Blood 80, no. 1 (July 1, 1992): 29–36. http://dx.doi.org/10.1182/blood.v80.1.29.bloodjournal80129.

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The goals of this study were to evaluate the response to treatment in chronic lymphocytic leukemia (CLL) according to clinical, pathologic, immunophenotypic, and molecular features, as well as to address the clinical significance of each finding. One hundred fifty-nine CLL patients with either advanced Rai stage III or IV (81 patients) or progressive Rai stage 0 to II (78 patients) were treated with fludarabine (30 mg/m2/d intravenously every day for 5 days) plus prednisone (30 mg/m2/d orally daily for 5 days). Thirty-six patients were previously untreated. The response rates were 12% complete response (CR), 30% nodular complete response (nCR), and 18% partial response (PR). In all patients who achieved a complete response (both CR and nCR) less than 30% of nucleated cells were lymphocytes on marrow aspirate differential analysis; however, nCR patients had residual nodular and/or interstitial lymphocyte involvement on marrow biopsy examination. There was no evidence of leukemic infiltration on marrow biopsy examination in CR patients. With a median follow-up of 35 months, comparison of time to progression in the CR and nCR groups at 2 years showed a projected 87% versus 55% progression-free survival (P less than .03). Residual disease assessment by flow cytometry using simultaneous dual-color staining on blood and marrow lymphocytes was also performed on each patient. Residual disease was determined by the expression of CD5 on B lymphocytes and the monoclonality of surface light-chain expression. After six courses of fludarabine plus prednisone, no residual disease was detected by flow cytometry in 89% of the CRs, 51% of the nCRs, and 19% of the PRs. Clinical residual disease in PR patients with no residual disease detectable by flow cytometry was limited to lymph-adenopathy. Time to progression at 2 years was longer in CR and nCR patients having no residual disease detected by flow cytometry (84% v 39% 2-year progression-free survival, P less than .001). Posttreatment lg gene rearrangement analysis using JH, J kappa, and C lambda probes demonstrated no rearranged bands and a return to the germline configuration in five of seven CRs and two of eight nCRs studied. The molecular studies were concordant with the dual- parameter immunophenotype results and none of the patients who reverted to a germline DNA pattern after treatment have experienced relapse. The absence of detectable minimal residual disease by bone marrow biopsy, dual-color flow cytometry, and lg gene rearrangement analysis is achieveable in CLL with fludarabine and is predictive of the response duration.

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Bubenikova, Jana, Jana Vrabelova, Karla Stejskalova, Jan Futas, Martin Plasil, Petra Cerna, Jan Oppelt, Dana Lobova, Dobromila Molinkova, and Petr Horin. "Candidate Gene Markers Associated with Fecal Shedding of the Feline Enteric Coronavirus (FECV)." Pathogens 9, no. 11 (November 17, 2020): 958. http://dx.doi.org/10.3390/pathogens9110958.

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The Feline coronavirus (FCoV) can cause a fatal disease, the Feline Infectious Peritonitis. Persistent shedders represent the most important source of infection. The role of the host in FCoV fecal shedding is unknown. The objective of this study was to develop gene markers and to test their associations with FCoV shedding patterns. Fecal samples were taken from 57 cats of 12 breeds on the day 0 and after 2, 4 and 12 months. Variation from persistent and/or high-intensity shedding to no shedding was observed. Thirteen immunity-related genes were selected as functional and positional/functional candidates. Positional candidates were selected in a candidate region detected by a GWAS analysis. Tens to hundreds of single nucleotide polymorphisms (SNPs) per gene were identified using next generation sequencing. Associations with different phenotypes were assessed by chi-square and Fisher’s exact tests. SNPs of one functional and one positional candidate (NCR1 and SLX4IP, respectively) and haplotypes of four genes (SNX5, NCR2, SLX4IP, NCR1) were associated with FCoV shedding at pcorected < 0.01. Highly significant associations were observed for extreme phenotypes (persistent/high-intensity shedders and non-shedders) suggesting that there are two major phenotypes associated with different genotypes, highly susceptible cats permanently shedding high amounts of viral particles and resistant non-shedders.

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Marras, Francesco, Federica Bozzano, and Andrea De Maria. "Involvement of Activating NK Cell Receptors and Their Modulation in Pathogen Immunity." Journal of Biomedicine and Biotechnology 2011 (2011): 1–11. http://dx.doi.org/10.1155/2011/152430.

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Natural Killer (NK) cells are endowed with cell-structure-sensing receptors providing inhibitory protection from self-destruction (inhibitory NK receptors, iNKRs, including killer inhibitory receptors and other molecules) and rapid triggering potential leading to functional cell activation by Toll-like receptors (TLRs), cytokine receptors, and activating NK cell receptors including natural cytotoxicity receptors (NCRs, i.e., NKp46, NKp46, and NKp44). NCR and NKG2D recognize ligands on infected cells which may be endogenous or may directly bind to some structures derived from invading pathogens. In this paper, we address the known direct or indirect interactions between activating receptors and pathogens and their expression during chronic HIV and HCV infections.

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Bryant, Juliet E., Pedro F. C. Vasconcelos, Rene C. A. Rijnbrand, J. P. Mutebi, Stephen Higgs, and Alan D. T. Barrett. "Size Heterogeneity in the 3′ Noncoding Region of South American Isolates of Yellow Fever Virus." Journal of Virology 79, no. 6 (March 15, 2005): 3807–21. http://dx.doi.org/10.1128/jvi.79.6.3807-3821.2005.

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ABSTRACT The 3′ noncoding region (3′ NCR) of flaviviruses contains secondary and tertiary structures essential for virus replication. Previous studies of yellow fever virus (YFV) and dengue virus have found that modifications to the 3′ NCR are sometimes associated with attenuation in vertebrate and/or mosquito hosts. The 3′ NCRs of 117 isolates of South American YFV have been examined, and major deletions and/or duplications of conserved RNA structures have been identified in several wild-type isolates. Nineteen isolates (designated YF-XL isolates) from Brazil, Trinidad, and Venezuela, dating from 1973 to 2001, exhibited a 216-nucleotide (nt) duplication, yielding a tandem repeat of conserved hairpin, stem-loop, dumbbell, and pseudoknot structures. YF-XL isolates were found exclusively within one subclade of South American genotype I YFV. One Brazilian isolate exhibited, in addition to the 216-nt duplication, a deletion of a 40-nt repeated hairpin (RYF) motif (YF-XL-ΔRYF). To investigate the biological significance of these 3′ NCR rearrangements, YF-XL-ΔRYF and YF-XL isolates, as well as other South American YFV isolates, were evaluated for three phenotypes: growth kinetics in cell culture, neuroinvasiveness in suckling mice, and ability to replicate and produce disseminated infections in Aedes aegypti mosquitoes. YF-XL-ΔRYF and YF-XL isolates showed growth kinetics and neuroinvasive characteristics comparable to those of typical South American YFV isolates, and mosquito infectivity trials demonstrated that both types of 3′ NCR variants were capable of replication and dissemination in a laboratory-adapted colony of A. aegypti.

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Terra Junior, Orlando Nascimento, Gabriel de Carvalho Maldonado, Guilherme Rohem Alfradique, Vinicius da Cunha Lisboa, Adriano Arnóbio, Dirce Bonfim de Lima, Hilda Rachel Diamond, and Maria Helena Faria Ornellas de Souza. "Study of Natural Cytotoxicity Receptors in Patients with HIV/AIDS and Cancer: A Cross-Sectional Study." Scientific World Journal 2016 (2016): 1–11. http://dx.doi.org/10.1155/2016/2085871.

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The NCR receptors play a fundamental role in the cytotoxicity mediated by NK cells against tumor cells. In the current study, we investigated possible HIV/AIDS-related changes in the expression of the NCR receptors comparing healthy donors, HIV/AIDS patients, and HIV/AIDS patients with cancer (HIV/AIDSWC). The NCRs were quantified in NK cells (NKdimandNKbright) and T lymphocytes from peripheral blood samples by flow cytometry. We found a significant decrease in the frequency of NK cells expressing NKp46 in HIV/AIDS group (p=0.0012). There was a decrease in the frequency of NK cells expressing NKp46 in the HIV/AIDSWC group; however, this was not statistically significant. We found a significant decrease in the frequency of NK cells expressing NKp30 in the HIV/AIDS group (p=0.0144). There was a decrease in the frequency of NK cells expressing NKp30 and in the HIV/AIDSWC group, but this was not statistically significant. There were no changes in the distribution of NK cells and their subtypes in both groups.

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Xu, Xiao-Dong, Jia-Yin Guan, Zi-Yi Zhang, Yu-Rou Cao, Yin-Yin Cai, Kenneth B. Storey, Dan-Na Yu, and Jia-Yong Zhang. "Insight into the Phylogenetic Relationships among Three Subfamilies within Heptageniidae (Insecta: Ephemeroptera) along with Low-Temperature Selection Pressure Analyses Using Mitogenomes." Insects 12, no. 7 (July 19, 2021): 656. http://dx.doi.org/10.3390/insects12070656.

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We determined 15 complete and two nearly complete mitogenomes of Heptageniidae belonging to three subfamilies (Heptageniinae, Rhithrogeninae, and Ecdyonurinae) and six genera (Afronurus, Epeorus, Leucrocuta, Maccaffertium, Stenacron, and Stenonema). Species of Rhithrogeninae and Ecdyonurinae had the same gene rearrangement of CR-I-M-Q-M-ND2, whereas a novel gene rearrangement of CR-I-M-Q-NCR-ND2 was found in Heptageniinae. Non-coding regions (NCRs) of 25–47 bp located between trnA and trnR were observed in all mayflies of Heptageniidae, which may be a synapomorphy for Heptageniidae. Both the BI and ML phylogenetic analyses supported the monophyly of Heptageniidae and its subfamilies (Heptageniinae, Rhithrogeninae, and Ecdyonurinae). The phylogenetic results combined with gene rearrangements and NCR locations confirmed the relationship of the subfamilies as (Heptageniinae + (Rhithrogeninae + Ecdyonurinae)). To assess the effects of low-temperature stress on Heptageniidae species from Ottawa, Canada, we found 27 positive selection sites in eight protein-coding genes (PCGs) using the branch-site model. The selection pressure analyses suggested that mitochondrial PCGs underwent positive selection to meet the energy requirements under low-temperature stress.

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von Strandmann, Elke Pogge, Venkateswara R. Simhadri, Bastian von Tresckow, Stefanie Sasse, Katrin S. Reiners, Hinrich P. Hansen, Achim Rothe, et al. "Tumor Cell-Derived HLA-B-Associated Transkript 3 (BAT3) Is a Ligand for NKp30 and Activates NK Cells." Blood 108, no. 11 (November 16, 2006): 643. http://dx.doi.org/10.1182/blood.v108.11.643.643.

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Abstract Natural-killer (NK)-cells are lymphocytes of the innate immune system, which directly attack tumor and virus-infected cells. They provide a link between innate and adaptive immunity through crosstalk with dendritic cells (DCs) and mediate T-cell activation. Among the activating and inhibitory receptors that regulate NK cell activity, the orphan NKp30 receptor (NCR3, CD337) plays a special role as NKp30 does not only induce target cell lysis but is also crucial for the interaction between NK cells and dendritic cells. However, so far the cellular ligands for NKp30 have remained elusive. Using a yeast two hybrid approach with the extracellular NKp30 sequence as bait we were able to isolate a putative NKp30 ligand from a tumor cDNA library. Sequence analysis revealed that the cDNA encoded for BAT3 (HLA-B-associated transcript 3) which originally had been cloned from the human major histocompatibility complex by chromosome walking and mapped to chromosome 6p21.3 within the HLA complex. BAT3 was described as a nuclear protein characterized by an N-terminal ubiquitin-like region, a polyproline stretch and a highly conserved BAG-(Bcl-2-associated athanogene) domain. Until now, the function of BAT3 in mammals is not clearly defined. With BAT3-specific antibodies and by means of laser scanner microscopy and Western Blotting we demonstrate that tumor cell lines and immature as well as mature DCs express BAT3. Upon co-cultivation with NK cells or exposure to stress signals such as heat shock, we observed that BAT3 translocates from the nucleus to the cell-surface and the protein is released from tumor cells into the extracellular environment. BAT3 binds directly and specifically to NKp30 on NK cells and triggers NK cell-mediated cytokine release and NKp30-dependent cytotoxicity. The inhibition of endogenous BAT3 using polyclonal antibodies prevents tumor rejection in vivo, demonstrating that BAT3 is necessary for the tumor rejection in a xenograft tumor model. Thus, BAT3 is the long sought cellular NKp30 ligand and exhibits a novel mechanism by which a nuclear protein activates NK cells via NKp30-engagement after its release to the cell-surface and the cell environment. The isolation of the first cellular NKp30-ligand provides the basis for a better molecular understanding of NK cell-regulation and allows the development of clinical applications targeting NKp30 for the immunotherapy.

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Nguyen, Jean-Michel, Philippe Juin, Daniel Antonioli, Alexandre Moreau-Gaudry, Mario Campone, and Pascal Jézéquel. "Identification of paclitaxel resistance through a new statistical approach based on a random forest of perfect trees classifcation." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e13513-e13513. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e13513.

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e13513 Background: Predictors of paclitaxel sensitivity in breast cancer published ten years ago, are still pending. The authors showed that paclitaxel pathological complete response (pCR) was in one hand, encountered in aggressive breast tumor with immune response and in another hand, paclitaxel resistance in less aggressive tumor. We have developed a new analysis paradigm, mixing neurons into nodes of trees classification and news class of statistical information based on free-error trees classification. We proposed to reanalyze the Bauer et al’s dataset using this novel approach. Methods: GES22513 dataset including 14 duplicated observations and 54675 anonymized probes was analyzed. A random forest of one million trees whose nodes were composed of neurons including 15 probes, was developped. We selected probes for which a free-error classification was obtained and ranked them according to the inverse of the probability of being a confounding factor and to the inverse of the probability of interacting with another probe. We compared the sets of probes which were necessary to obtain an error-free classification between those associated with a decrease and those associated with an increase of the probability of pCR. Results: Our 15 best ranked predictors were free-error classification for all observations. This includes gene expression of TLCD2, BRCC3, CHI3L2 and PROX1. Their over-expressions were associated with an increase in the probability of pCR, and gene expression of APH1B, ARFGEF1, ARID2, BPGM, CAMK2N1, CCNY, PARM1, PHKA1, PSMD9, SUDS3 (two probes) whose over-expressions are associated with a decrease in the probability of pCR. Ten out of these probes were concordant with Bauer et al’s conclusion. Four probes ( BPGM, PHKA1, CCNY and ARFGEF1) are in contradiction with it. The limited biological information were available for TLCD2. The statistical analysis also showed that TLCD2, BBRCC3, CHI3L2 and PROX1 were altogether positively modulated by eight genes/probes ( CKS1B, ADIG, NCR3, RIN3, NIPAL1, 234422_at, DCLRE1C, SLC17A4). At the opposite, the modulation of genes associated with a decrease in the probability of pCR, was rather heterogeneous and involves many more genes. Conclusions: This preliminary work shows that our statistical approach allows a perfect classification of tumors with and without pCR. Also, it proves that the selected probes/genes are respectively associated with aggressiveness/basal and less aggressiveness/luminal phenotypes. These results need to be validated on an independent cohort.

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Fauriat, Cyril, Sylvaine Just-Landi, Françoise Mallet, Christine Arnoulet, Danielle Sainty, Daniel Olive, and Regis T. Costello. "Deficient expression of NCR in NK cells from acute myeloid leukemia: evolution during leukemia treatment and impact of leukemia cells in NCRdull phenotype induction." Blood 109, no. 1 (August 29, 2006): 323–30. http://dx.doi.org/10.1182/blood-2005-08-027979.

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Abstract Natural killer (NK) cells play an important role in tumor-cell clearance, particularly against leukemia, as shown by killer cell inhibitory receptor (KIR)–mismatched allogeneic stem cell transplantation. Analysis of in vitro IL-2–expanded NK cells from patients with myelocytic/monocytic acute myeloid leukemia (AML-NK cells) has revealed poor cytolytic functions because of deficient expression of pivotal activation molecules—the natural cytotoxicity receptors (NCRs) NKp30, NKp44, and NKp46. To exclude the possibility that this observation was caused by the in vitro amplification of a small NCRdull population, we analyzed the AML-NK phenotype directly, without any in vitro expansion. We first confirmed that the NCRdull phenotype was not an in vitro artifact. Moreover, analysis of a large population of AML patients allowed us to demonstrate that phenotype was not restricted to a French-American-British (FAB) subtype and was not associated with a particular cytogenetic abnormality. Our longitudinal study of AML patients showed that the NCRdull phenotype was acquired during leukemia development because we observed its complete (for NKp46) or partial (for NKp30) reversibility in patients achieving complete remission (CR). Reversibility of the NCRdull phenotype after CR suggested that leukemia cells might be involved in NCR down-regulation. In agreement with this hypothesis, direct contact between leukemic blasts and NK cells (but not leukemia-cell supernatants) induced loss or decrease in NKp30 and NKp46 expression while impeding NKp44 induction by IL-2. We excluded the major implication of TGF-β in NCR down-regulation. Although the clinical antitumor value of NK cells is clearly demonstrated in allogeneic stem cell transplantation, the role of NK cells in autologous transplantation is not proved. Interestingly, we observed a correlation between the NCRdull phenotype and poor survival in AML patients, suggesting that NK-deficient activation caused by NCR down-regulation could play a role in patient outcome. The prognostic value of NCR expression is discussed, and pathophysiologic implication of the NCR phenotype will be further investigated in a larger study.

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Roberts, Robin A., Lisa M. Rimsza, Louis Staudt, Andreas Rosenwald, Wing-Chung Chan, Sandeep Dave, Randy D. Gascoyne, et al. "Gene Expression Differences between Low and High Stage Diffuse Large B Cell Lymphoma (DLBCL)." Blood 108, no. 11 (November 16, 2006): 809. http://dx.doi.org/10.1182/blood.v108.11.809.809.

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Abstract Low stage DLBCL patients have better prognosis than those with advanced disease. We searched for differences in gene expression between disease stages to find correlations with tumor stage as possible therapeutic targets. We used 2 microarray datasets from the Leukemia/Lymphoma Molecular Profiling Project containing nodal and extra-nodal de novo DLBCL samples on Lymphochip (LC), spotted arrays of ~7400 and Affymetrix arrays (Affy) of ~45,000 elements. The Affy dataset was a subset of the LC samples. LC elements were median-centered, log2 transformed; Affy elements were array-centered to a 500 average. We compared average gene expression in stage I vs. III/IV, looking for elements with >2-fold differences between low and high stage, with p<.05, excluding Affy elements with an average <100. 35 stage I and 131 stage III/IV samples were analyzed with LC and 34 stage I and 118 stage III/IV samples with Affy. Differentially expressed genes were searched by NCBI Entrez and Stratagene PathwayArchitect software to find common pathways of regulation. From the LC data, 6 genes were identified as differentially expressed, 5 were higher in stage I, 1 was lower in stage I. For the Affy data, 29 genes were differentially expressed, 11 were higher in stage I, 18 were lower in stage I (Table 1). Differences were rarely >3-fold. A subset of these genes, CTGF (connective tissue growth factor), FN1 (fibronectin), INHBA (activin), POSTN (periostin), THBS1 (thrombospondin), and BCL2, are coregulated and/or coregulatory. Many are expressed in the microenvironment and associated with fibrosis, wound healing and Th2 immune response. The presence of these genes at higher levels and their known associations implied a pathway of TGF-β signaling present mainly in the low stage DLBCL. Although TGF-β levels were not different between stages, differences in localization/activation of TGF-β could account for observed differences. In conclusion, there are a small number of stage-specific gene expression differences in DLBCL, and many of these relate to TGF-β signaling in the microenvironment. CTGF and FN1 were previously identified as key prognostic molecules in DLBCL (Rosenwald et al, NEJM 2002). These differences may relate to different prognoses between DLBCL stages and constitute therapeutic targets. Genes Differentially Expressed by Stage higher in stage I higher in stage III/IV LC Affy LC Affy CTGF CTGF IGHM IBRDC2 (2 elements) SERPINA1 MYBPC1 HTR3A POSTN NCR3 BCL2 FN1 INHBA (2 elements) CRYM THBS1 EMP1 SIX1 KLHL14 MGC23911 PP1665 GPM6A (2 elements) FLJ33069 TUBB IgM rheum. factor RF-TT9 CD1C transcribed locus LOC150568 LOC346887 LOC283454 MGC17624 IMAGE:5311619 transcribed locus (2x)

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Pape, Marieke, Pauline A. J. Vissers, Laurens Beerepoot, Mark I. Van Berge Henegouwen, Sjoerd Lagarde, Stella Mook, David Bertwistle, Laura McDonald, Hanneke W. M. Van Laarhoven, and Rob Verhoeven. "Disease-free and overall survival in nonmetastatic esophageal or gastroesophageal junctional cancer after treatment with curative intent: A nationwide population-based study." Journal of Clinical Oncology 39, no. 3_suppl (January 20, 2021): 246. http://dx.doi.org/10.1200/jco.2021.39.3_suppl.246.

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246 Background: Among patients with potentially curable esophageal cancer (EC) or gastroesophageal junctional cancer (GEJC) treated with curative intent, survival remains poor and around half of these patients have disease recurrence within a few years. This study addresses the need for real-world data on disease-free survival (DFS) and overall survival (OS) in patients with EC or GEJC who underwent potentially curative treatment. Methods: Patients selected from the nationwide Netherlands cancer registry (NCR) had received a primary diagnosis of non-metastatic EC or GEJC (excluding patients with T4b tumors) in 2015 or 2016 and received treatment with curative intent. Curative intent was defined as receiving resection (with or without [neo]adjuvant therapy) or definitive chemoradiotherapy (dCRT) without surgery. DFS and OS were analysed using Kaplan-Meier curves with Log-Rank test from resection date or end of dCRT. A sub-analysis was performed for NCR patients selected to align with the population of the CheckMate-577 phase 3 study of adjuvant nivolumab, i.e. patients with non-cervical stage II/III disease, R0 resection and residual pathological disease after neoadjuvant CRT (nCRT) and surgery. Results: We identified 1916 patients of median age of 67 years and predominantly male (76%). The majority (79%) received surgery and 21% of patients received dCRT. In resected patients, 83% received nCRT, 10% neoadjuvant chemotherapy (with or without adjuvant CRT) and 7% received no (neo)adjuvant treatment. Compared to the resected group, the population receiving dCRT had significantly fewer males (65% vs 78%), a higher median age (72 vs 65 years) and worse performance status. Patients receiving dCRT significantly shorter median DFS (14.2 months) and OS (20.9 months) compared to resected patients (DFS: 26.4 months, p < 0.001; OS: 40.5 months, p < 0.001). The 1- and 3-year DFS probabilities were 68% and 44%, respectively, in resected patients, and 56% and 24%, respectively, in patients receiving dCRT. In patients receiving nCRT followed by surgery, the median DFS and OS were 25.2 and 38.0 months, respectively, and 1- and 3-year DFS probabilities were 67% and 43%, respectively. In the sub-analysis (n = 725) the median DFS and OS were 19.2 and 29.4 months, respectively, and the 1- and 3-year DFS rates were 62% and 36%, respectively. Conclusions: Although patients are treated with curative intent, a considerable amount of patients with non-metastatic EC or GEJC experienced recurrence within two years. Resected patients had a higher DFS and OS compared to patients receiving dCRT.

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Rector, Annabel, Koenraad Van Doorslaer, Mads Bertelsen, Ian K. Barker, Rolf-Arne Olberg, Philippe Lemey, John P. Sundberg, and Marc Van Ranst. "Isolation and cloning of the raccoon (Procyon lotor) papillomavirus type 1 by using degenerate papillomavirus-specific primers." Journal of General Virology 86, no. 7 (July 1, 2005): 2029–33. http://dx.doi.org/10.1099/vir.0.80874-0.

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Partial sequences of a novel papillomavirus were amplified from a cutaneous lesion biopsy of a raccoon (Procyon lotor), by using PCR with degenerate papillomavirus-specific primers. The Procyon lotor papillomavirus type 1 (PlPV-1) DNA was amplified with long template PCR in two overlapping fragments, together encompassing the entire genome, and the complete PlPV-1 genomic sequence was determined. The PlPV-1 genome consists of 8170 bp, and contains the typical papillomaviral open reading frames, encoding five early proteins and two late capsid proteins. Besides the classical non-coding region (NCR1) between the end of L1 and the start of E6, PlPV-1 contains an additional non-coding region (NCR2) of 1065 bp between the early and late protein region, which has previously also been described for the canine oral papillomavirus (COPV) and the Felis domesticus papillomavirus (FdPV-1). Phylogenetic analysis places PlPV-1 together with COPV and FdPV-1 in a monophyletic branch which encompasses the Lambda papillomavirus genus.

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Li, Yili, Qian Wang, and Roy A. Mariuzza. "Structure of the human activating natural cytotoxicity receptor NKp30 bound to its tumor cell ligand B7-H6." Journal of Experimental Medicine 208, no. 4 (March 21, 2011): 703–14. http://dx.doi.org/10.1084/jem.20102548.

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Natural killer (NK) cells are lymphocytes of the innate immune system that participate in the elimination of tumor cells. In humans, the activating natural cytotoxicity receptors (NCRs) NKp30, NKp44, and NKp46 play a major role in NK cell–mediated tumor cell lysis. NKp30 recognizes B7-H6, a member of the B7 family which is expressed on tumor, but not healthy, cells. To understand the basis for tumor surveillance by NCRs, we determined the structure of NKp30, a member of the CD28 family which includes CTLA-4 and PD-1, in complex with B7-H6. The overall organization of the NKp30–B7-H6–activating complex differs considerably from those of the CTLA-4–B7 and PD-1–PD-L T cell inhibitory complexes. Whereas CTLA-4 and PD-1 use only the front β-sheet of their Ig-like domain to bind ligands, NKp30 uses both front and back β-sheets, resulting in engagement of B7-H6 via the side, as well as face, of the β-sandwich. Moreover, B7-H6 contacts NKp30 through the complementarity-determining region (CDR)–like loops of its V-like domain in an antibody-like interaction that is not observed for B7 or PD-L. This first structure of an NCR bound to ligand provides a template for designing molecules to stimulate NKp30-mediated cytolytic activity for tumor immunotherapy.

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Horváth, Beatrix, Ágota Domonkos, Attila Kereszt, Attila Szűcs, Edit Ábrahám, Ferhan Ayaydin, Károly Bóka, et al. "Loss of the nodule-specific cysteine rich peptide, NCR169, abolishes symbiotic nitrogen fixation in the Medicago truncatula dnf7 mutant." Proceedings of the National Academy of Sciences 112, no. 49 (September 23, 2015): 15232–37. http://dx.doi.org/10.1073/pnas.1500777112.

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Host compatible rhizobia induce the formation of legume root nodules, symbiotic organs within which intracellular bacteria are present in plant-derived membrane compartments termed symbiosomes. In Medicago truncatula nodules, the Sinorhizobium microsymbionts undergo an irreversible differentiation process leading to the development of elongated polyploid noncultivable nitrogen fixing bacteroids that convert atmospheric dinitrogen into ammonia. This terminal differentiation is directed by the host plant and involves hundreds of nodule specific cysteine-rich peptides (NCRs). Except for certain in vitro activities of cationic peptides, the functional roles of individual NCR peptides in planta are not known. In this study, we demonstrate that the inability of M. truncatula dnf7 mutants to fix nitrogen is due to inactivation of a single NCR peptide, NCR169. In the absence of NCR169, bacterial differentiation was impaired and was associated with early senescence of the symbiotic cells. Introduction of the NCR169 gene into the dnf7-2/NCR169 deletion mutant restored symbiotic nitrogen fixation. Replacement of any of the cysteine residues in the NCR169 peptide with serine rendered it incapable of complementation, demonstrating an absolute requirement for all cysteines in planta. NCR169 was induced in the cell layers in which bacteroid elongation was most pronounced, and high expression persisted throughout the nitrogen-fixing nodule zone. Our results provide evidence for an essential role of NCR169 in the differentiation and persistence of nitrogen fixing bacteroids in M. truncatula.

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Ta, Malancha, and Sudhanshu Vrati. "Mov34 Protein from Mouse Brain Interacts with the 3′ Noncoding Region of Japanese Encephalitis Virus." Journal of Virology 74, no. 11 (June 1, 2000): 5108–15. http://dx.doi.org/10.1128/jvi.74.11.5108-5115.2000.

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ABSTRACT The plus-sense RNA genome of Japanese encephalitis virus (JEV) contains noncoding regions (NCRs) of 95 and 585 bases at its 5′ and 3′ ends, respectively. The last 83 nucleotides of the 3′-NCR are predicted to form stable stem-loop (SL) structures. The shape of this 3′-SL structure is highly conserved among divergent flaviviruses even though only small stretches of nucleotide sequence contained within these structures are conserved. These SL structures have been predicted to function as cis-acting signals for RNA replication and as such may bind to viral and cellular proteins that may be involved in viral replication. We have studied the interaction of the JEV 3′-NCR RNA with host proteins using gel retardation assays. We show that the JEV 3′-SL structure RNA forms three complexes with proteins from the S100 cytoplasmic extract prepared from the neonatal mouse brain. These complexes could be obtained in the presence of 200 mM KCl, indicating that the RNA-protein interaction may be physiologically relevant. UV-induced cross-linking and Northwestern blotting analyses detected three proteins with apparent molecular masses of 32, 35, and 50 kDa that bound to the JEV 3′-SL structure RNA. Screening of the neonatal mouse brain cDNA library with the JEV 3′-SL structure RNA identified a 36-kDa Mov34 protein interacting with it. Competition experiments using the RNA extracted from JEV virions established that the 36-kDa Mov34 protein indeed bound to the JEV genome. Murine Mov34 belongs to a family of proteins whose members have been shown to be involved in RNA transcription and translation. It is, therefore, likely that the murine Mov34 interaction with JEV 3′-NCR has a role in RNA replication.

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Journal articles on the topic 'NCR3'

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