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1
Perl, Andras, Adam Bartos, Brian Niland, and David Fernandez. "Transaldolase Deficiency Enhances the Development of Experimental Autoimmune Encephalomyelitis (123.46)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 123.46. http://dx.doi.org/10.4049/jimmunol.188.supp.123.46.
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Abstract Transaldolase (TAL) regulates mitochondrial hyperpolarization (MHP), a reversible step of T-cell activation. Here, we investigated the role of TAL in T-cell mediated experimental autoimmune encephalomyelitis (EAE), a mouse model multiple sclerosis. Direct immunization with myelin oligodendrocyte glycoprotein peptide 35-55 (MOG35-55) elicited EAE in TAL-deficient (TAL-/-) mice at an accelerated rate relative to wild-type littermates (TAL+/+; 2-way ANOVA, p=0.0005). Adoptive transfer of MOG35-55 peptide-immunized TAL-/- lymphoblasts triggered EAE in naïve Rag2-/- recipients at a 2.10±0.42 greater higher degree relative to TAL+/+ lymphoblast (p < 0.0001). The increased potency of TAL-/- lymphoblasts was associated with an expansion of CD4+ T cells (62.74±4.48) as compared to TAL+/+ controls (57.34±4.48, p=0.007). In contrast, the frequency of CD4+/CD25+/Foxp3+ regulatory T cells was reduced in TAL-/- mice (2.91 ± 1.02%) relative to TAL+/+ littermates (3.64 ± 1.02%),; p=0.002) In vivo administration of N-acetylcysteine (NAC) reversed the skewing of CD4+ effector and regulatory T cells and ameliorated the EAE disease score in NAC-treated TAL-/- mice (p<0.05). These data identify the metabolic control of MHP by TAL, as a novel checkpoint of T cells lineage specification that affects the expansion of effector and regulatory CD4+ T cells and thus modulates the onset and severity of EAE. This checkpoint is redox-controlled and represents a target for therapeutic intervention with NAC.
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Song, Congfeng, and Bing Yang. "Mutagenesis of 18 Type III Effectors Reveals Virulence Function of XopZPXO99 in Xanthomonas oryzae pv. oryzae." Molecular Plant-Microbe Interactions® 23, no. 7 (July 2010): 893–902. http://dx.doi.org/10.1094/mpmi-23-7-0893.
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Xanthomonas oryzae pv. oryzae depends on a type III secretion system (T3SS) to translocate effectors into host cells for its ability to cause bacterial blight of rice. All type III (T3) effectors with known function in X. oryzae pv. oryzae belong to a family of transcription activator-like (TAL) effectors. However, other, non–TAL-related effector genes are present in the genome, although their role in virulence and their mode of action have yet to be elucidated. Here, we report the generation of mutants for 18 non-TAL T3 effector genes and the identification of one that contributes to the virulence of strain PXO99A. XopZPXO99 encodes a predicted 1,414-amino-acid protein of unknown function. PXO99A contains two identical copies of the gene due to a duplication of 212 kb in the genome. Strains with knockout mutations of one copy of XopZPXO99 did not exhibit any visible virulence defect. However, strains with mutations in both copies of XopZPXO99 displayed reduced virulence in terms of lesion length and bacterial multiplication compared with PXO99A. The introduction of one genomic copy of XopZPXO99 restores the mutant to full virulence. Transient expression of XopZPXO99 in Nicotiana benthamiana leaves suppresses host basal defense, which is otherwise induced by a T3SS mutant of PXO99A, suggesting a role for XopZPXO99 in interfering with host innate immunity during X. oryzae pv. oryzae infection. XopZPXO99-related genes are found in all Xanthomonas spp. whose genomic sequences have been determined, suggesting a conserved role for this type of effector gene in pathogenesis of Xanthomonas spp. Our results indicate that XopZPXO99 encodes a novel T3 effector and contributes virulence to X. oryzae pv. oryzae strains for bacterial blight of rice.
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Carter, Morgan E., Sara C. D. Carpenter, Zoë E. Dubrow, Mark R. Sabol, Fabio C. Rinaldi, Olga A. Lastovetsky, Stephen J. Mondo, Teresa E. Pawlowska, and Adam J. Bogdanove. "A TAL effector-like protein of an endofungal bacterium increases the stress tolerance and alters the transcriptome of the host." Proceedings of the National Academy of Sciences 117, no. 29 (July 6, 2020): 17122–29. http://dx.doi.org/10.1073/pnas.2003857117.
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Symbioses of bacteria with fungi have only recently been described and are poorly understood. In the symbiosis ofMycetohabitans(formerlyBurkholderia)rhizoxinicawith the fungusRhizopus microsporus, bacterial type III (T3) secretion is known to be essential. Proteins resembling T3-secreted transcription activator-like (TAL) effectors of plant pathogenic bacteria are encoded in the three sequencedMycetohabitansspp. genomes. TAL effectors nuclear-localize in plants, where they bind and activate genes important in disease. The Burkholderia TAL-like (Btl) proteins bind DNA but lack the N- and C-terminal regions, in which TAL effectors harbor their T3 and nuclear localization signals, and activation domain. We characterized a Btl protein, Btl19-13, and found that, despite the structural differences, it can be T3-secreted and can nuclear-localize. Abtl19-13gene knockout did not prevent the bacterium from infecting the fungus, but the fungus became less tolerant to cell membrane stress. Btl19-13 did not alter transcription in a plant-based reporter assay, but 15R. microsporusgenes were differentially expressed in comparisons both of the fungus infected with the wild-type bacterium vs. the mutant and with the mutant vs. a complemented strain. Southern blotting revealedbtlgenes in 14 diverseMycetohabitansisolates. However, banding patterns and available sequences suggest variation, and thebtl19-13phenotype could not be rescued by abtlgene from a different strain. Our findings support the conclusion that Btl proteins are effectors that act on host DNA and play important but varied or possibly host genotype-specific roles in theM. rhizoxinica–R. microsporussymbiosis.
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Sheikh, Taha, Liyuan Zhang, Muhammad Zubair, Alvina Hanif, Ping Li, Ayaz Farzand, Haider Ali, et al. "The Type III Accessory Protein HrpE of Xanthomonas oryzae pv. oryzae Surpasses the Secretion Role, and Enhances Plant Resistance and Photosynthesis." Microorganisms 7, no. 11 (November 18, 2019): 572. http://dx.doi.org/10.3390/microorganisms7110572.
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Many species of plant-pathogenic gram-negative bacteria deploy the type III (T3) secretion system to secrete virulence components, which are mostly characteristic of protein effectors targeting the cytosol of the plant cell following secretion. Xanthomonas oryzae pv. oryzae (Xoo), a rice pathogen causing bacterial blight disease, uses the T3 accessory protein HrpE to assemble the pilus pathway, which in turn secretes transcription activator-like (TAL) effectors. The hrpE gene can execute extensive physiological and pathological functions beyond effector secretion. As evidenced in this study, when the hrpE gene was deleted from the Xoo genome, the bacteria incur seriouimpairments in multiplication, motility, and virulence. The virulence nullification is attributed to reduced secretion and translocation of PthXo1, which is a TAL effector that determines the bacterial virulence in the susceptible rice varieties. When the HrpE protein produced by prokaryotic expression is applied to plants, the recombinant protein is highly effective at inducing the defense response. Moreover, leaf photosynthesis efficiency is enhanced in HrpE-treated plants. These results provide experimental avenues to modulate the plant defense and growth tradeoff by manipulating a bacterial T3 accessory protein.
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Scharenberg, Andrew M. "Genome Editing Toolbox." Blood 124, no. 21 (December 6, 2014): SCI—11—SCI—11. http://dx.doi.org/10.1182/blood.v124.21.sci-11.sci-11.
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Abstract Nucleases capable of making targeted breaks in genomic DNA are a core technology required for genome engineering, an emerging field of technology for making precise alterations in cellular genomes. Over the past ten years, four major platforms have emerged for generation of nucleases able to make targeted DNA breaks with a high degree of efficiency and specificity: homing endonucleases, zinc finger nucleases, transcription activator-like (TAL) effector nucleases, and RNA-guided nucleases. This talk will cover the biochemistry and platform-specific attributes of each type of nuclease, along with evolution/improvements in nucleases and related technologies and aspects of the practical implementation of nuclease technology for gene knockout and gene repair in primary hematopoietic cells. Disclosures Scharenberg: Pregenen Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Cellectis therapeutics: Consultancy.
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Hagen, Kari D., and John C. Meeks. "The Unique Cyanobacterial Protein OpcA Is an Allosteric Effector of Glucose-6-phosphate Dehydrogenase inNostoc punctiformeATCC 29133." Journal of Biological Chemistry 276, no. 15 (January 4, 2001): 11477–86. http://dx.doi.org/10.1074/jbc.m010472200.
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Glucose-6-phosphate dehydrogenase (G6PD), encoded byzwf, is essential for nitrogen fixation and dark heterotrophic growth of the cyanobacteriumNostoc punctiformeATCC 29133. InN. punctiforme,zwfis part of a four-gene operon transcribed in the orderfbp-tal-zwf-opcA. Genetic analyses indicated thatopcAis required for G6PD activity. To define the role ofopcA, the synthesis, aggregation state, and activity of G6PD inN. punctiformestrains expressing different amounts of G6PD and/or OpcA were examined. A single tetrameric form of G6PD was consistently observed for all strains, as well as for recombinantN. punctiformeHis-G6PD purified fromEscherichia coli, regardless of the quantity of OpcA present. However, His-G6PD and the G6PD of strain UCD 351, which lacks OpcA, had low affinities for glucose 6-phosphate (G6P) substrate (Km(app) = 65 and 85 mm, respectively) relative to wild-typeN. punctiformeG6PD (Km(app) = 0.5 mm). Near wild-type affinities for G6P were observed for these enzymes when saturating amounts of His-OpcA- or OpcA-containing extract were added. Kinetic studies were consistent with OpcA acting as an allosteric activator of G6PD. A role in redox modulation of G6PD activity was also indicated, because thioredoxin-mediated inactivation and reactivation of His-G6PD occurred only when His-OpcA was present.
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Li, Yu-Rong, Hua-Song Zou, Yi-Zhou Che, Yi-Ping Cui, Wei Guo, Li-Fang Zou, Subhadeep Chatterjee, Eulandria M. Biddle, Ching-Hong Yang, and Gong-You Chen. "A Novel Regulatory Role of HrpD6 in Regulating hrp-hrc-hpa Genes in Xanthomonas oryzae pv. oryzicola." Molecular Plant-Microbe Interactions® 24, no. 9 (September 2011): 1086–101. http://dx.doi.org/10.1094/mpmi-09-10-0205.
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Xanthomonas oryzae pv. oryzicola, the causal agent of bacterial leaf streak in the model plant rice, possesses a hypersensitive response and pathogenicity (hrp), hrp-conserved (hrc), hrp-associated (hpa) cluster (hrp-hrc-hpa) that encodes a type III secretion system (T3SS) through which T3SS effectors are injected into host cells to cause disease or trigger plant defenses. Mutations in this cluster usually abolish the bacterial ability to cause hypersensitive response in nonhost tobacco and pathogenicity in host rice. In Xanthomonas spp., these genes are generally assumed to be regulated by the key master regulators HrpG and HrpX. However, we present evidence that, apart from HrpG and HrpX, HrpD6 is also involved in regulating the expression of hrp genes. Interestingly, the expression of hpa2, hpa1, hpaB, hrcC, and hrcT is positively controlled by HrpD6. Transcriptional expression assays demonstrated that the expression of the hrcC, hrpD5, hrpE, and hpa3 genes was not completely abolished by hrpG and hrpX mutations. As observed in analysis of their corresponding mutants, HrpG and HrpX exhibit contrasting gene regulation, particularly for hpa2 and hrcT. Other two-component system regulators (Zur, LrpX, ColR/S, and Trh) did not completely inhibit the expression of hrcC, hrpD5, hrpE, and hpa3. Immunoblotting assays showed that the secretion of HrpF, which is an HpaB-independent translocator, is not affected by the mutation in hrpD6. However, the mutation in hrpD6 affects the secretion of an HpaB-dependent TAL effector, AvrXa27. These novel findings suggest that, apart from HrpG and HrpX, HrpD6 plays important roles not only in the regulation of hrp genes but also in the secretion of TAL effectors.
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Phuong Ngoc, Pham, Tran Lan Dai, Do Thi Hanh, Nguyen Quang Huy, and Nguyen Duy Phuong. "Functional characterization of the \(\textit{OsSWEET13 }\) promoter involved in the infection of \(\textit{ Xanthomonas oryzae }\) pv. \(\textit{oryzae (Xoo) }\) in rice cultivar TBR225." Academia Journal of Biology 44, no. 3 (September 27, 2022): 57–65. http://dx.doi.org/10.15625/2615-9023/16759.
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Xanthomonas oryzae pv. oryzae (Xoo) causes severe bacterial leaf blight (BLB) disease to many Vietnamese major rice cultivars, including the TBR225. OsSWEET13 belongs to group III of the OsSWEET gene family encoding sugar transport proteins, which is considered one of the “susceptibility” genes (S genes) necessary for BLB disease. In this study, the rice cultivar TBR225 was determined to be susceptible to 19/20 Vietnamese Xoo isolates collected from the Northern provinces. Two of the three tested isolates (VXO_60 and VXO_96 isolates) were shown to up-regulate OsSWEET13 upon the Xoo infection of the TBR225 cultivar. The TBR225 OsSWEET13 promoter was isolated for sequencing analysis. The isolated DNA fragment was 615 bp in size, contained an effector binding element (EBE) PthXo2 that was recognized by the type III-secretory transcription activator-like (TAL) proteins of the Xoo. This promoter showed a similarity of more than 99% to the published OsSWEET13 promoter sequences (AP014967.1 and CP018167.1). Our findings are basic for the generation of highyielding rice varieties with resistance to BLB disease by genetic engineering in Vietnam.
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Evans, R., and T. Duffy. "The immunological basis of tumor rejection: the absolute dependence of the effector arm on sensitized T cells after chemoimmunotherapy of a murine sarcoma." Journal of Immunology 134, no. 6 (June 1, 1985): 4255–60. http://dx.doi.org/10.4049/jimmunol.134.6.4255.
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Abstract The mechanisms of tumor rejection were investigated by using a therapeutic model system involving treatment of C57BL/6J (B6) mice bearing the syngeneic MCA/76-9 or the unrelated MCA/76-64 sarcomas with cytoxan and tumor-sensitized T lymphocytes. Separated tumor-associated T lymphocytes (TAL) and tumor-associated macrophages (TAM) isolated from the regressing tumors 8 to 10 days after combination therapy expressed relatively specific cytotoxicity in vitro, whereas the unseparated tumor-associated cells (TAC), consisting of a mixture of TAL and TAM, expressed nonspecific cytotoxicity. TAM-mediated cytotoxicity was not dependent on the presence of TAL, as shown by T cell depletion of TAM or TAC cultures with the use of monoclonal anti-Thy-1 or anti-Lyt-2 antibody and complement. In contrast, the nonspecific cytotoxicity was dependent on the presence of T cells. In vivo assays using the Winn test failed to confirm certain aspects of the in vitro data. Without exception, the TAC inhibited tumor growth in an immunologically specific manner, having no effect on the growth of the unrelated B6 sarcoma. T cell depletion completely abrogated in vivo cytotoxicity. Specificity of tumor growth inhibition was confirmed in a bystander experiment in which TAC were mixed with both tumor cell types and were injected into recipient B6 mice. Tumors grew under these conditions, but the tumor that grew consisted only of those tumor cells toward which TAC cytotoxicity was not specifically directed. A bioassay indicated that the specifically immune antitumor effects at the site of regression were initiated between days 3 and 7 after combination therapy. By days 7 and 9, few tumorigenic stem cells could be detected at the tumor site. However, T cell depletion of the TAC isolated on days 8 to 10 resulted in enhanced tumor growth when the depleted TAC were injected into recipient mice. The conclusions reached were that tumor rejection was absolutely dependent on T cell participation at the tumor site, and that if TAM were involved, they required the presence of TAL and did not express nonspecific antitumor cytotoxicity. Indeed, the accelerated tumor growth seen in the absence of TAL suggested the possibility that TAM were growth stimulatory.
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Li, Yu-Rong, Yi-Zhou Che, Hua-Song Zou, Yi-Ping Cui, Wei Guo, Li-Fang Zou, Eulandria M. Biddle, Ching-Hong Yang, and Gong-You Chen. "Hpa2 Required by HrpF To Translocate Xanthomonas oryzae Transcriptional Activator-Like Effectors into Rice for Pathogenicity." Applied and Environmental Microbiology 77, no. 11 (April 8, 2011): 3809–18. http://dx.doi.org/10.1128/aem.02849-10.
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ABSTRACTXanthomonas oryzaepv. oryzicola, the causative agent of bacterial leaf streak, injects a plethora of effectors through the type III secretion system (T3SS) into rice cells to cause disease. The T3SS, encoded by thehrpgenes, is essential for the pathogen to elicit the hypersensitive response (HR) in nonhost tobacco and for pathogenicity in host rice. Whether or not a putative lytic transglycosylase, Hpa2, interacts with a translocon protein, HrpF, to facilitate bacterial pathogenicity remains unknown. Here we demonstrated that both thehpa2andhrpFgenes are required for the pathogenicity ofX. oryzaepv. oryzicola strain RS105 in rice but not for HR induction in tobacco. The expression ofhpa2was positively regulated by HrpG and HrpD6 but not by HrpX.In vivosecretion and subcellular localization analyses confirmed that Hpa2 secretion is dependent on HpaB (a T3SS exit protein) and that Hpa2 binds to the host cell membrane. Protein-protein assays demonstrated that Hpa2 interacts with HrpF.In plantatranslocation of AvrXa10 indicated that the mutation inhpa2andhrpFinhibits the injection of the HpaB-dependent transcriptional activator-like (TAL) effector into rice. These findings suggest that Hpa2 and HrpF form a complex to translocate T3S effectors into plant cells for pathogenesis in host rice.
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Liang, Xiaoye, Tong-Tong Pei, Hao Li, Hao-Yu Zheng, Han Luo, Yang Cui, Ming-Xuan Tang, Ya-Jie Zhao, Ping Xu, and Tao Dong. "VgrG-dependent effectors and chaperones modulate the assembly of the type VI secretion system." PLOS Pathogens 17, no. 12 (December 1, 2021): e1010116. http://dx.doi.org/10.1371/journal.ppat.1010116.
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The type VI secretion system (T6SS) is a spear-like nanomachine found in gram-negative pathogens for delivery of toxic effectors to neighboring bacterial and host cells. Its assembly requires a tip spike complex consisting of a VgrG-trimer, a PAAR protein, and the interacting effectors. However, how the spike controls T6SS assembly remains elusive. Here we investigated the role of three VgrG-effector pairs in Aeromonas dhakensis strain SSU, a clinical isolate with a constitutively active T6SS. By swapping VgrG tail sequences, we demonstrate that the C-terminal ~30 amino-acid tail dictates effector specificity. Double deletion of vgrG1&2 genes (VgrG3+) abolished T6SS secretion, which can be rescued by ectopically expressing chimeric VgrG3 with a VgrG1/2-tail but not the wild type VgrG3. In addition, deletion of effector-specific chaperones also severely impaired T6SS secretion, despite the presence of intact VgrG and effector proteins, in both SSU and Vibrio cholerae V52. We further show that SSU could deliver a V. cholerae effector VasX when expressing a plasmid-borne chimeric VgrG with VasX-specific VgrG tail and chaperone sequences. Pull-down analyses show that two SSU effectors, TseP and TseC, could interact with their cognate VgrGs, the baseplate protein TssK, and the key assembly chaperone TssA. Effectors TseL and VasX could interact with TssF, TssK and TssA in V. cholerae. Collectively, we demonstrate that chimeric VgrG-effector pairs could bypass the requirement of heterologous VgrG complex and propose that effector-stuffing inside the baseplate complex, facilitated by chaperones and the interaction with structural proteins, serves as a crucial structural determinant for T6SS assembly.
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Krueger, Peter D., Brandon Burbach, Deepali Malhotra, Jim Miller, and Marc K. Jenkins. "CD28 signals through tyrosine residues in its cytoplasmic tail to promote CD4+ T cell clonal expansion during infection." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 128.11. http://dx.doi.org/10.4049/jimmunol.196.supp.128.11.
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Abstract CD28 is required for maximal proliferation of CD4+ T cells stimulated through their TCRs. Polyclonal peptide: MHCII-specific CD4+ T cells in mice lacking CD28 or its cytoplasmic tail produced one tenth as many effector and memory cells as wild-type T cells after bacterial infection. However, mutations in the canonical signaling sites, the membrane proximal YMNM and distal PYAP sequences, located in the cytoplasmic tail failed to suppress T cell expansion, suggesting additional sequences are sufficient for signaling. We therefore tested the contribution of the four tyrosine (4Y) residues in the cytoplasmic tail by establishing bone marrow chimeras in which CD28-deficient donor cells were first transduced with either wild-type CD28-CFP or mutated CD28-4Y-YFP and subsequently transferred to irradiated congenically mismatched CD28-sufficient mice. CD28-4Y MHCII-specific CD4+T cells produced one tenth as many effector cells as wild-type CD28-CFP cells after infection with bacterial expressing antigenic peptides. These results implicate that the tyrosine residues located in the cytoplasmic tail are required for CD28 signal transduction in effector CD4+ T cells in vivo.
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Torruellas Garcia, Julie, Franco Ferracci, Michael W. Jackson, Sabrina S. Joseph, Isabelle Pattis, Lisa R. W. Plano, Wolfgang Fischer, and Gregory V. Plano. "Measurement of Effector Protein Injection by Type III and Type IV Secretion Systems by Using a 13-Residue Phosphorylatable Glycogen Synthase Kinase Tag." Infection and Immunity 74, no. 10 (October 2006): 5645–57. http://dx.doi.org/10.1128/iai.00690-06.
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ABSTRACT Numerous bacterial pathogens use type III secretion systems (T3SSs) or T4SSs to inject or translocate virulence proteins into eukaryotic cells. Several different reporter systems have been developed to measure the translocation of these proteins. In this study, a peptide tag-based reporter system was developed and used to monitor the injection of T3S and T4S substrates. The glycogen synthase kinase (GSK) tag is a 13-residue phosphorylatable peptide tag derived from the human GSK-3β kinase. Translocation of a GSK-tagged protein into a eukaryotic cell results in host cell protein kinase-dependent phosphorylation of the tag, which can be detected with phosphospecific GSK-3β antibodies. A series of expression plasmids encoding Yop-GSK fusion proteins were constructed to evaluate the ability of the GSK tag to measure the injection of Yops by the Yersinia pestis T3SS. GSK-tagged YopE, YopH, LcrQ, YopK, YopN, and YopJ were efficiently phosphorylated when translocated into HeLa cells. Similarly, the injection of GSK-CagA by the Helicobacter pylori T4SS into different cell types was measured via phosphorylation of the GSK tag. The GSK tag provides a simple method to monitor the translocation of T3S and T4S substrates.
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Lowe, Devin B., Michael H. Shearer, Cynthia A. Jumper, Robert K. Bright, and Ronald C. Kennedy. "Fcγ Receptors Play a Dominant Role in Protective Tumor Immunity against a Virus-Encoded Tumor-Specific Antigen in a Murine Model of Experimental Pulmonary Metastases." Journal of Virology 81, no. 3 (November 15, 2006): 1313–18. http://dx.doi.org/10.1128/jvi.01943-06.
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ABSTRACT Simian virus 40 (SV40) large tumor antigen (Tag) represents a virus-encoded tumor-specific antigen expressed in many types of human cancers and a potential immunologic target for antitumor responses. Fc receptors are important mediators in the regulation and execution of host effector mechanisms against conditions including infectious diseases, autoimmunity, and cancer. By examining tumor protection in SV40 Tag-immunized wild-type BALB/c mice using an experimental pulmonary metastasis model, we attempted to address whether engagement of the immunoglobulin G Fc receptors (FcγRs) on effector cells is necessary to mediate antitumor responses. All immunized BALB/c FcγR−/− knockout mice developed anti-SV40 Tag antibody responses prior to experimental challenge with a tumorigenic cell line expressing SV40 Tag. However, all mice deficient in the activating FcγRI (CD64) and FcγRIII (CD16) were unable to mount protective immunologic responses against tumor challenge and developed tumor lung foci. In contrast, mice lacking the inhibitory receptor FcγRII (CD32) demonstrated resistance to tumorigenesis. These results underscore the importance of effector cell populations expressing FcγRI/III within this murine tumor model system, and along with the production of a specific humoral immune response, antibody-dependent cell-mediated cytotoxicity (ADCC) may be a functioning mechanism of tumor clearance. Additionally, these data demonstrate the potential utility of ADCC as a viable approach for targeting vaccination strategies that promote FcγRI/III scavenging pathways against cancer.
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Colovic, Radoje, Marko Kaitovic, and Stojan Latincic. "Pancreatic tail pseudocyst of type II treated with resection of the tail of the pancreas and splenectomy." Srpski arhiv za celokupno lekarstvo 139, no. 11-12 (2011): 812–14. http://dx.doi.org/10.2298/sarh1112812c.
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Introduction. Pancreatic pseudocysts of type II are postnecrotic cysts that appear during an acute-on-chronic pancreatitis. In case that surgical treatment is necessary, as a rule it is performed using internal drainage operations. Pancreatic resections are rarely indicated. Case Outline. The authors present a 34 year-old man with a long-lasting history of moderate alcohol consumption in whom an episode of drinking caused an acute-on-chronic pancreatitis so that a 7 cm in diameter cyst was developed inside the tail of the pancreas causing left subcostal pain, mild pleural effusion and pain in the left shoulder. At operation almost entirely inside the tail of the pancreas a cyst of type II unsuitable for internal drainage operation was found so that a spared resection of the tail of the pancreas and splenectomy were carried out. The post-operative recovery was prolonged due to recurrent left pleural effusion requiring punctions, mild suppurative secretion from the splenic fossa and transient postsplenectomy thrombocytosis. Six months after surgery the patient is in good condition and with normal findings. Conclusion. Although rare, pancreatic cysts of type II may be unsuitable for internal drainage operations so that resection of the effected part of the pancreas could be a much better solution than external drainage.
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Park, Jin-Sil, Sung-Min Kim, Sun-Hee Hwang, Si-Young Choi, Ji Ye Kwon, Seung-Ki Kwok, Mi-La Cho, and Sung-Hwan Park. "Combinatory treatment using tacrolimus and a STAT3 inhibitor regulate Treg cells and plasma cells." International Journal of Immunopathology and Pharmacology 32 (January 1, 2018): 205873841877872. http://dx.doi.org/10.1177/2058738418778724.
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Systemic lupus erythematosus (SLE; lupus) is a prototypical autoimmune disease characterized by circulating autoantibodies to nuclear antigens and immune complex deposition, resulting in damage to target organs. To investigate the effects of tacrolimus (TAC) on effector T cells and B cells, we examined its involvement in the development of effector T cells, germinal center (GC) B cells, and plasma cells in an in vitro system using wild-type (WT) and lupus-prone mice. The population of T helper (Th) 1, Th2, and Th17 cells interleukin (IL)-17-producing T (Th17) cells and the production of interferon-γ and interleukin-17A IL-17A were suppressed by TAC. TAC also reduced the population of regulatory T (Treg) cells; however, a combination treatment with the signal transducer and activator of transcription 3 (STAT3) inhibitor STA-21 promoted the population of Treg cells. TAC also suppressed the populations of GC B cells and plasma cells synergistically with STA-21. These findings suggest that the application of TAC with a STAT3 signal inhibitor may provide benefits in SLE treatment.
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Fei, Chenjie, Myron A. Zwozdesky, and James L. Stafford. "A Fish Leukocyte Immune-Type Receptor Uses a Novel Intracytoplasmic Tail Networking Mechanism to Cross-Inhibit the Phagocytic Response." International Journal of Molecular Sciences 21, no. 14 (July 21, 2020): 5146. http://dx.doi.org/10.3390/ijms21145146.
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Channel catfish (Ictalurus punctatus) leukocyte immune-type receptors (IpLITRs) are a family of immunoregulatory proteins shown to regulate several innate immune cell effector responses, including phagocytosis. The precise mechanisms of IpLITR-mediated regulation of the phagocytic process are not entirely understood, but we have previously shown that different IpLITR-types use classical as well as novel pathways for controlling immune cell-mediated target engulfment. To date, all functional assessments of IpLITR-mediated regulatory actions have focused on the independent characterization of select IpLITR-types in transfected cells. As members of the immunoglobulin superfamily, many IpLITRs share similar extracellular Ig-like domains, thus it is possible that various IpLITR actions are influenced by cross-talk mechanisms between different IpLITR-types; analogous to the paired innate receptor paradigm in mammals. Here, we describe in detail the co-expression of different IpLITR-types in the human embryonic AD293 cell line and examination of their receptor cross-talk mechanisms during the regulation of the phagocytic response using imaging flow cytometry, confocal microscopy, and immunoprecipitation protocols. Overall, our data provides interesting new insights into the integrated control of phagocytosis via the antagonistic networking of independent IpLITR-types that requires the selective recruitment of inhibitory signaling molecules for the initiation and sustained cross-inhibition of phagocytosis.
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Perota, A., I. Lagutina, C. Quadalti, R. Duchi, P. Turini, G. Crotti, S. Colleoni, et al. "203 SINGLE-STEP GENE EDITING OF 3 XENOANTIGENS IN PORCINE FIBROBLASTS USING PROGRAMMABLE NUCLEASES." Reproduction, Fertility and Development 29, no. 1 (2017): 210. http://dx.doi.org/10.1071/rdv29n1ab203.
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Programmable nucleases (ZFN, Tal Effector Nucleases, and CRISPR) opened a new era for mammal genome editing, in particular for the pigs used for xenotransplantation. Multiple gene editing events are required both for knockout (KO) of xenoantigens and for targeted integration of human protective genes (Perota et al. 2016 J. Genet. Genomics 43, 233–23). The objective of the present work was to edit selected pig lines to KO the enzymes coding for the most relevant xenoantigens (i.e. GGTA1, CMAH, and B4GalNT2), combining Talens and CRISPR/Cas9 technologies to magnetic beads selection (Li et al. 2013 Xenotransplantation 22, 20–31). Primary porcine adult fibroblasts were transfected using Nucleofector (V-024 program). In a single reaction 2 × 106 fibroblasts were co-transfected using 2 different sets of TALENS (4 μg/set) specific for CMAH (Conchon et al., 2013) and GGTA1 (Perota et al., 2015) genes together with B4GalNT2-specific CRISPR/Cas9 expression vector (2 μg; pX330-B4GalNT2; Estrada et al., 2015). Eight days post-transfection (DPT), Gal–/– cells were selected initially using biotin-conjugated IB4 lectin (Sigma, St. Louis, MO, USA) and magnetic beads (Dynabeads M-280, Thermo Fisher Scientific, Waltham, MA, USA). The selected cells were then plated on 150-mm Petri dishes (200 cells/dish) and cultured for 10 days. Selected colonies were expanded for PCR analysis and cryopreserved for somatic cell nuclear transfer (SCNT). All colonies were analysed by PCR for CMAH gene and their resulting products were digested with HindIII (HindIII-RFLP). Colonies that lost wild-type HindIII as a consequence of Talens effected deletion were PCR characterised for GGTA1, selecting those that had detectable Indels after gel electrophoresis and finally analysed by PCR for B4GalNT2. All PCR products were validated by sequencing for all the 3 genes of interest (TopoTA, Thermo Fisher Scientific). Selected colonies were used as nuclear donors for SCNT (Lagutina et al., 2006). Eight DPT we obtained 3.45 ×106 cells. About 6.0 × 103 Gal-negative cells (0.17%) were collected from the supernatant after magnetic beads separation. Eighteen DPT, 120 colonies were picked up and their HindIII-RFLP analyses on CMAH gene revealed that 22 colonies (18.3%) were KO for both CMAH alleles. Of these 22 colonies following electrophoretic analyses of GGTA1-PCR products, 13 colonies had detectable Indels. These 13 colonies were finally PCR analysed and sequenced for B4GalNT2 and sequenced. Final sequencing results confirmed that 2 colonies (1.6%) resulted in KO for the 3 genes. Three different zona-free SCNT experiments were done and 579 reconstructed embryos were obtained. On Day 7, 322 morulae or blastocysts (56%) were transferred in 3 synchronised sows and 2 (66%) became pregnant. In conclusion, after gene editing with programmable nucleases, combining beads-mediated selection with well-designed molecular analyses, we developed a multistep assay that can be used efficiently to detect desired gene edited events in cell colonies suitable for the SCNT. Embryos generated after SCNT were able to establish pregnancies at a high rate. This work is supported by European FP7 grants Translink (n° 603049) and Xenoislet (n° 601827).
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Xu, W., J. L. Coll, and E. D. Adamson. "Rescue of the mutant phenotype by reexpression of full-length vinculin in null F9 cells; effects on cell locomotion by domain deleted vinculin." Journal of Cell Science 111, no. 11 (June 1, 1998): 1535–44. http://dx.doi.org/10.1242/jcs.111.11.1535.
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Vinculin plays a role in signaling between integrins and the actin cytoskeleton. We reported earlier that F9-derived cells lacking vinculin are less spread, less adhesive, and move two times faster than wild-type F9 cells. Expression of intact vinculin in null cells restored all wild-type characteristics. In contrast, expression of the head (90 kDa) fragment exaggerated mutant characteristics, especially locomotion, which was double that of vinculin null cells. Expression of the tail domain also had a marked effect on locomotion in the opposite direction, reducing it to very low levels. The expression of the head plus tail domains together (no covalent attachment) effected a partial rescue towards wild-type phenotype, thus indicating that reexpressed polypeptides may be in their correct location and are interacting normally. Therefore, we conclude that: (1) the head domain is part of the locomotory force of the cell, modulated by the tail, and driven by the integrin/matrix connection; (2) intact vinculin is required for normal regulation of cell behavior, suggesting that vinculin head-tail interactions control cell adhesion, spreading, lamellipodia formation and locomotion.
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Takashima, Katsunori, Hiroshi Miyake, Rika A. Furuta, Jun-Ichi Fujisawa, Yuji Iizawa, Naoyuki Kanzaki, Mitsuru Shiraishi, Kenji Okonogi, and Masanori Baba. "Inhibitory Effects of Small-Molecule CCR5 Antagonists on Human Immunodeficiency Virus Type 1 Envelope-Mediated Membrane Fusion and Viral Replication." Antimicrobial Agents and Chemotherapy 45, no. 12 (December 1, 2001): 3538–43. http://dx.doi.org/10.1128/aac.45.12.3538-3543.2001.
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ABSTRACT We established a human immunodeficiency virus type 1 (HIV-1) envelope (Env)-mediated membrane fusion assay and examined the small-molecule CCR5 antagonist TAK-779 and its derivatives for their inhibitory effects on HIV-1 Env-mediated membrane fusion and viral replication. The membrane fusion assay is based on HIV-1 long terminal repeat-directed β-d-galactosidase reporter gene expression in CD4- and CCR5-expressed HeLa (MAGI-CCR5) cells after cocultivation with effector 293T cells expressing HIV-1 Env. Inhibition of HIV-1 replication was also determined in MAGI-CCR5 cells infected with the corresponding cell-free HIV-1. TAK-779 effectively suppressed R5 HIV-1 (strain JR-FL) Env-mediated membrane fusion as well as viral replication. Its 50% inhibitory concentrations (IC50s) for membrane fusion and viral replication were 0.87 ± 0.11 and 1.4 ± 0.1 nM, respectively. These values corresponded well to the IC50 for 125I-RANTES (regulated on activation, T cell expressed, and secreted) binding to CCR5 (1.4 nM). The inhibitory effects of 18 TAK-779 derivatives on membrane fusion differed from one compound to another. However, there was a close correlation among their inhibitory effects on membrane fusion, viral replication, and RANTES binding. The correlation coefficient between their IC50s for membrane fusion and viral replication was 0.881. Furthermore, since this assay depends on Env expressed in the effector cells, it is also applicable to the evaluation of CXCR4 antagonists. These results indicate that the HIV-1 Env-mediated membrane fusion assay is a useful tool for the evaluation of entry inhibitors.
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Davila, Eduardo, Degui Geng, Ratika Srivastava, Adam Riker, and Svetomir Markovic. "Amplifying TLR-MyD88 signals within tumor-specific T-cells enhances antitumor activity to low concentrations of subdominant tumor-antigens (101.35)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 101.35. http://dx.doi.org/10.4049/jimmunol.184.supp.101.35.
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Abstract There is a dire need to understand the cellular signals that can potentiate T-cell responses to weakly immunogenic tumor antigens (TAg) and to tumors expressing suboptimal levels of these antigens. We examined the anti-tumor activity and survival of TLR2-MyD88-stimulated tumor-specific CD8 T-cells derived from melanoma patients and TAg-specific T-cell receptor transgenic pmel mice. TLR2 engagement on pmel CD8 T-cells, but not on TLR2-/-pmel or MyD88-/-pmel T-cells, reduced the activation threshold to a subdominant TAg, resulting in increased production of effector molecules and cytotoxicity. Wild-type or MyD88-/- mice treated with pmel T-cells and TLR2 ligand, but not TLR2-/-pmel or MyD88-/-pmel T-cells, showed significant tumor regression of an established melanoma tumor. Over-expressing TLR2 in pmel T-cells eradicated established tumors and four-times fewer cells were needed to generate anti-tumor responses. The enhanced anti-tumor activity was associated with improved survival and increased effector function of TLR2-MyD88-stimulated T-cells. Activating TLR-MyD88 signals in patient-derived T-cells reduced the activation threshold to several weakly immunogenic TAgs, resulting in increased cytokine production, expansion and cytotoxicity. These data highlight the physiological importance of activating TLR-MyD88 signals within tumor-reactive T-lymphocytes for enhancing their longevity and augmenting effector function against suboptimal levels of weakly-immunogenic antigens.
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Nakamura, Akito, Keli Song, Stephen Grossman, Kristina Xega, Yuhong Zhang, Allison Berger, Allison Berger, Gary Shapiro, and Dennis Huszar. "552 SUMOylation inhibitor TAK-981 activates NK cells and macrophages via Type I interferon signaling and shows synergistic activity in combination with rituximab and daratumumab in preclinical models." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A588. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0552.
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BackgroundTAK-981 is a first-in-class small molecule inhibitor of the SUMO activating enzyme in Phase 1 clinical trials. SUMOylation has previously been implicated in the regulation of innate immune responses and expression of Type I interferons,1 and ex vivo treatment of human and mouse immune cells with TAK-981 results in transcriptional upregulation of IFN-beta and Type I IFN receptor (IFNAR) signaling. We previously showed that TAK-981 increases NK cell activation and M1 macrophage polarization, leading to enhanced ADCC and ADCP in the presence of rituximab.2In vivo, TAK-981 induces IFNAR-dependent antitumor activity and synergizes with rituximab in xenograft-bearing mice.2 3 Here we investigated the mechanism of synergistic activity with rituximab and evaluated the combination of TAK-981 with daratumumab, another therapeutic mAb.MethodsThe role of effector function of rituximab in the mechanism of synergy with TAK-981 was evaluated in OCI-Ly10-bearing SCID mice treated with TAK-981 and the LALA-PG version of rituximab, in which mutations in the Fc region prevent FcγR binding. The combination of TAK-981 and rituximab was also evaluated in OCI-Ly10 tumor-bearing mice in which macrophages and/or NK cells were depleted with clodronate and anti-asialo GM1. TAK-981 in combination with daratumumab was evaluated in two CD38+ xenograft models, Daudi (Burkitt’s lymphoma) and LP-1 (multiple myeloma). To test ADCP activity, Daudi-KILR cells were incubated with human monocyte-derived macrophages (hMDM) treated with TAK-981 in the presence or absence of rituximab or daratumumab, with or without a neutralizing antibody to IFNAR2.ResultsUnlike rituximab, LALA-PG mutated rituximab did not synergize with TAK-981 in OCI-Ly10 tumor-bearing mice, indicating a requirement for Fc effector function. Depletion of macrophages with clodronate or NK cells with anti-asialo GM1 lessened the anti-tumor effect of the TAK-981 and rituximab combination, while dual depletion of macrophages and NK cells had a greater impact. TAK-981 showed synergistic activity in combination with daratumumab in two CD38+ xenograft models, Daudi and LP-1. In vitro, TAK-981-treated hMDM showed increased phagocytic activity against Daudi cells, and this effect was further enhanced in the presence of rituximab or daratumumab but prevented by a neutralizing antibody to IFNAR2.ConclusionsIn preclinical models, TAK-981 synergizes with rituximab through a mechanism involving Type I-IFN dependent enhancement of ADCC and ADCP, and the combination of TAK-981 with daratumumab is also synergistic.ReferencesDecque A, Joffre O, Magalhaes JG, Cossec J-C, Blecher-Gonen R, Lapaquette P, Silvin A, Manel N, Joubert P-E, Seeler J-S, Albert ML, Amit I, Amigorena S, Dejean A. Sumoylation coordinates the repression of inflammatory and anti-viral gene-expression programs during innate sensing. Nat Immunol 2016;17:140–149.Nakamura A, Grossman S, Song K, Idamakanti N, Shaprio G, Huszar D. Inhibition of SUMOylation by TAK-981 induces antitumor innate immune responses by modulating macrophage and NK cell function through Type I IFN pathway activation [abstract]. In: Proceedings of the American Association forCancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Cancer Res 2019;79(13 Suppl):Abstract nr 1523.Huszar D. TAK-981: A first-in-class SUMOylation inhibitor in phase 1 clinical trials promotes a Type I interferon response and antitumor immunity in preclinical models. AACR Annual Meeting 2019, American Association for Cancer Research; Mar 29-Apr 03; Atlanta, GA, US. Session DDT01.
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Gerges, Rafik R., and Barry J. Vickery. "Optimum design of pendulum-type tuned mass dampers." Structural Design of Tall and Special Buildings 14, no. 4 (2005): 353–68. http://dx.doi.org/10.1002/tal.273.
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Sajedi, Seyed Omid, Seyed Rasoul Mirghaderi, and Farhad Keshavarzi. "Frame-type load bearing system for long-span cantilevers." Structural Design of Tall and Special Buildings 27, no. 9 (February 13, 2018): e1469. http://dx.doi.org/10.1002/tal.1469.
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Hsu, H. L., J. T. Cheng, Q. Chen, and R. Baer. "Enhancer-binding activity of the tal-1 oncoprotein in association with the E47/E12 helix-loop-helix proteins." Molecular and Cellular Biology 11, no. 6 (June 1991): 3037–42. http://dx.doi.org/10.1128/mcb.11.6.3037-3042.1991.
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Almost 30% of patients with T-cell acute lymphoblastic leukemia (T-ALL) bear structural alterations of tal-1, a presumptive proto-oncogene that encodes sequences homologous to the helix-loop-helix (HLH) DNA-binding and dimerization domain. Analysis of the tal-1 gene product reveals that its HLH domain mediates protein-protein interactions with either of the ubiquitously expressed HLH proteins E47 and E12. The resultant tal-1/E47 and tal-1/E12 heterodimers specifically recognize the E-box DNA sequence motif found in eucaryotic transcriptional enhancers. Hence, the tal-1 protein shares biochemical properties with other tissue-specific HLH proteins that control cell type determination during myogenesis (e.g., MyoD1) and neurogenesis (e.g., achaete-scute). The data suggest that HLH heterodimers involving tal-1 may function in vivo as transcriptional regulatory factors that influence cell type determination during hematopoietic development.
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Hsu, H. L., J. T. Cheng, Q. Chen, and R. Baer. "Enhancer-binding activity of the tal-1 oncoprotein in association with the E47/E12 helix-loop-helix proteins." Molecular and Cellular Biology 11, no. 6 (June 1991): 3037–42. http://dx.doi.org/10.1128/mcb.11.6.3037.
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Almost 30% of patients with T-cell acute lymphoblastic leukemia (T-ALL) bear structural alterations of tal-1, a presumptive proto-oncogene that encodes sequences homologous to the helix-loop-helix (HLH) DNA-binding and dimerization domain. Analysis of the tal-1 gene product reveals that its HLH domain mediates protein-protein interactions with either of the ubiquitously expressed HLH proteins E47 and E12. The resultant tal-1/E47 and tal-1/E12 heterodimers specifically recognize the E-box DNA sequence motif found in eucaryotic transcriptional enhancers. Hence, the tal-1 protein shares biochemical properties with other tissue-specific HLH proteins that control cell type determination during myogenesis (e.g., MyoD1) and neurogenesis (e.g., achaete-scute). The data suggest that HLH heterodimers involving tal-1 may function in vivo as transcriptional regulatory factors that influence cell type determination during hematopoietic development.
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Mandili, Giorgia, Claudia Curcio, Sara Bulfamante, Laura Follia, Giulio Ferrero, Emanuela Mazza, Moitza Principe, et al. "In pancreatic cancer, chemotherapy increases antitumor responses to tumor-associated antigens and potentiates DNA vaccination." Journal for ImmunoTherapy of Cancer 8, no. 2 (October 2020): e001071. http://dx.doi.org/10.1136/jitc-2020-001071.
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BackgroundPancreatic ductal adenocarcinoma (PDA) is an almost incurable tumor that is mostly resistant to chemotherapy (CT). Adaptive immune responses to tumor-associated antigens (TAA) have been reported, but immunotherapy (IT) clinical trials have not yet achieved any significant increase in survival, confirming the suppressive environment of PDA. As CT has immune-modulating properties, we investigated the effect of gemcitabine (GEM) in antitumor effector responses to TAA in patients with PDA.MethodsThe IgG antibody repertoire in patients with PDA before and after CT was profiled by serological proteome analysis and ELISA and their ability to activate complement-dependent cytotoxicity (CDC) was measured. Peripheral T cells were stimulated in vitro with recombinant TAA, and specific proliferation, IFN-γ/IL-10 and CD8+/Treg ratios were measured. Mice that spontaneously developed PDA were treated with GEM and inoculated with an ENO1 (α−Enolase) DNA vaccine. In some experimental groups, the effect of depleting CD4, CD8 and B cells by specific antibodies was also evaluated.ResultsCT increased the number of TAA recognized by IgG and their ability to activate CDC. Evaluation of the IFN-γ/IL-10 ratio and CD8+/Treg ratios revealed that CT treatment shifted T cell responses to ENO1, G3P (glyceraldheyde-3-phosphate dehydrogenase), K2C8 (keratin, type II cytoskeletal 8) and FUBP1 (far upstream binding protein 1), four of the most recognized TAA, from regulatory to effector. In PDA mice models, treatment with GEM prior to ENO1 DNA vaccination unleashed CD4 antitumor activity and strongly impaired tumor progression compared with mice that were vaccinated or GEM-treated alone.ConclusionsOverall, these data indicate that, in PDA, CT enhances immune responses to TAA and renders them suitable targets for IT.
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Jana, Špulerová, Dobrovodská Marta, Šatalová Barbora, and Kanka Róbert. "Small Woodlands and Trees in Traditional Agricultural Landscapes of Slovakia." Journal of Landscape Ecology 10, no. 2 (November 1, 2017): 63–77. http://dx.doi.org/10.1515/jlecol-2017-0014.
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Abstract The studies focused on distribution and characteristic of small woodlands and trees as a typical feature of traditional agricultural landscapes (TAL) in Slovakia are missing or are rather local. The source data for this study was obtained from the national inventory of TAL performed in 2010-2012 in Slovakia, where woody vegetation was considered as one of the landscape elements creating mosaic of TAL. Based on the types of woodland present, which endow the landscape with a distinctive character and structure, we have divided TAL into five subtypes: 1) TAL with low occurrence of woodland – not more than 10 % of the site covered by woods, 2) TAL with spatial woodland formation, 3) TAL with solitaire trees dominant, 4) TAL with lines of trees or shrubs dominant, and 5) TAL with small woodland dominant. The proportion of woodland was relatively low, as TAL with low occurrence of woodland (36 %) was the most extended subtype of TAL. The most common dominant woodland structure was lines of trees and shrubs, with significant occurrence in TAL of arable-land and grassland and TAL with dispersed settlement. They tended to occur on typical agrarian relief forms. Our evaluation was supported by statistical analyses focused on the relationships between woodland type on agrarian relief forms (mostly balks) and their biotic and abiotic characteristics (type of agrarian relief form, content of skeleton, width, height, its continuity, as well as continuity of wood cover)
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KENYON, F., M. WELSH, J. PARKINSON, C. WHITTON, M. L. BLAXTER, and D. P. KNOX. "Expressed sequence tag survey of gene expression in the scab mite Psoroptes ovis – allergens, proteases and free-radical scavengers." Parasitology 126, no. 5 (May 2003): 451–60. http://dx.doi.org/10.1017/s0031182003003044.
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Psoroptes ovis, the causative agent of sheep scab, is an important ectoparasitic mite infecting sheep, goats and cattle. Infection is characterized by an extensive dermatitis, scab formation and intense itching. Initial focal lesions spread outwards, coalesce and may extend over the whole body. The host response to infestation has all the characteristics of an immediate-type hypersensitivity reaction but the mite antigens and allergens which initiate this response are almost completely undefined. Here, 507 randomly selected cDNAs derived from a mixed population of P. ovis were sequenced and the resultant nucleotide sequences subjected to Cluster analysis and Blast searches. This analysis yielded 280 clusters of which 49 had >1 sequence with 24 showing significant Blast X homology to another protein in the databases. There were 231 sequences which appeared on one occasion and 109 of these showed significant Blast X homology to other sequences in the databases. This analysis identified homologues of 9 different types of allergens which have been characterized in other allergic conditions such as responses to house dust mites. It also identified a number of cysteine proteases which may contribute to lesion development as well as several free-radical scavenging enzymes which may protect the mite from host immune effector responses.
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Kalkan, Erol, and S. Bahadir Yüksel. "Pros and cons of multistory RC tunnel-form (box-type) buildings." Structural Design of Tall and Special Buildings 17, no. 3 (September 2008): 601–17. http://dx.doi.org/10.1002/tal.368.
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EL FAR, Oussama, and Heinrich BETZ. "G-protein-coupled receptors for neurotransmitter amino acids: C-terminal tails, crowded signalosomes." Biochemical Journal 365, no. 2 (July 15, 2002): 329–36. http://dx.doi.org/10.1042/bj20020481.
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G-protein-coupled receptors (GPCRs) represent a superfamily of highly diverse integral membrane proteins that transduce external signals to different subcellular compartments, including nuclei, via trimeric G-proteins. By differential activation of diffusible Gα and membrane-bound Gβγ subunits, GPCRs might act on both cytoplasmic/intracellular and plasma-membrane-bound effector systems. The coupling efficiency and the plasma membrane localization of GPCRs are regulated by a variety of interacting proteins. In this review, we discuss recently disclosed protein interactions found with the cytoplasmic C-terminal tail regions of two types of presynaptic neurotransmitter receptors, the group III metabotropic glutamate receptors and the γ-aminobutyric acid type-B receptors (GABABRs). Calmodulin binding to mGluR7 and other group III mGluRs may provide a Ca2+-dependent switch for unidirectional (Gα) versus bidirectional (Gα and Gβγ) signalling to downstream effector proteins. In addition, clustering of mGluR7 by PICK1 (protein interacting with C-kinase 1), a polyspecific PDZ (PSD-95/Dlg1/ZO-1) domain containing synaptic organizer protein, sheds light on how higher-order receptor complexes with regulatory enzymes (or ‘signalosomes') could be formed. The interaction of GABABRs with the adaptor protein 14-3-3 and the transcription factor ATF4 (activating transcription factor 4) suggests novel regulatory pathways for G-protein signalling, cytoskeletal reorganization and nuclear gene expression: processes that may all contribute to synaptic plasticity.
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Hao, Xiao-Yan, Hong-Nan Li, Gang Li, and Toshio Makino. "Experimental investigation of steel structure with innovative H-type steel unbuckling braces." Structural Design of Tall and Special Buildings 23, no. 14 (August 29, 2013): 1064–82. http://dx.doi.org/10.1002/tal.1108.
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Kim, Sang Bum, Young Hak Lee, and Andrew Scanlon. "Comparative study of structural material quantities of multi-storey linear-type residential buildings." Structural Design of Tall and Special Buildings 18, no. 6 (October 2009): 673–86. http://dx.doi.org/10.1002/tal.463.
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Patra-Kneuer, Maria, Akito Nakamura, Keli Song, Stephen Grossman, Andrea Polzer, Carmen Ginzel, Stefan Steidl, Allison J. Berger, Igor Proscurshim, and Christina Heitmüller. "The Sumoylation Inhibitor TAK-981 in Combination with the CD19-Targeting Antibody Tafasitamab Shows Enhanced Anti-Tumor Activity in Preclinical B-Cell Lymphoma Models." Blood 138, Supplement 1 (November 5, 2021): 2268. http://dx.doi.org/10.1182/blood-2021-150718.
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Abstract Introduction TAK-981 is a first-in-class small molecule inhibitor of the SUMO activating enzyme currently in Phase I/II clinical trials. TAK-981 has been shown to increase NK cell activation and M1 macrophage polarization via upregulation of Type I interferon (IFN) signaling, leading to enhanced antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) in combination with rituximab (Nakamura 2019, AACR). Tafasitamab (MOR208) is a CD19-targeting antibody with enhanced Fc effector function mediating ADCC, ADCP and direct cytotoxic activities against B-lymphoma cells. Based on the Phase II clinical study L-MIND (Salles et al., 2020 and Duell et al., 2021), tafasitamab in combination with lenalidomide received accelerated approval by the Food and Drug Administration for the treatment of transplant-ineligible adult patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Due to the potential for TAK-981 to enhance the activity of tafasitamab via activation of innate effector cells, we aimed to investigate the effects of this drug combination on ADCC, ADCP and tumor cell viability in vitro. Additionally, combinatorial activity of TAK-981 plus tafasitamab was evaluated in lymphoma xenograft models. Methods A panel of 9 aggressive lymphoma cell lines was analyzed (7 DLBCL and 2 Burkitt lymphoma). For ADCC, PBMC effector cells from healthy human donors were pre-treated with 0.1 or 1 µM TAK-981 or dimethyl sulfoxide (DMSO) control for 24 hours. Tumor cells were incubated with/without 1 nM tafasitamab in the presence of TAK-981 pretreated PBMCs at effector-to-target (E:T) ratios of 5:1 to 10:1 for 2 hours. Degranulation of NK cells was determined via CD107a surface expression after co-incubation of TAK-981 pre-treated PBMCs with tumor cells and 0.1 or 10 nM tafasitamab for 3 hours. Cytokine levels in the supernatant were investigated upon incubation of PBMCs with lymphoma cells, 1 µM TAK-981 and/or 10 nM tafasitamab for 24 hours. For the ADCP assays, in vitro differentiated macrophages were treated with 1 µM TAK-981 for 24 hours. Next, macrophages were incubated with lymphoma cells and 1 or 10 nM tafasitamab at an E:T ratio of 2:1 for 3 hours. For cell viability assays, tumor cells were treated with 1-1000 nM TAK-981 and/or 5 nM tafasitamab for 24 hours in the absence of effector cells. Cytotoxicity, phagocytosis, degranulation and cytokine release were analyzed by flow cytometry. Cell viability was assessed by determination of ATP levels. For in vivo analysis, effects of TAK-981 (7.5 mg/kg IV twice weekly) in combination with tafasitamab (3, 10 or 20 mg/kg IP twice weekly) on tumor growth were evaluated in Daudi and WSU-DLCL2 xenograft models of Burkitt lymphoma and DLBCL grown in SCID mice. Results In ADCC experiments, increased cytotoxicity was observed upon combination treatment with TAK-981 and tafasitamab compared to the respective mono treatments in 5/8 tested lymphoma cell lines (Daudi, SU-DHL-2, SU-DHL-6, TMD8, OCI-LY10). Moreover, TAK-981 plus tafasitamab enhanced degranulation of NK cells and cytokine release compared to mono treatments. In ADCP assays, combination of TAK-981 and tafasitamab resulted in increased phagocytosis rates in comparison to mono treatments in 2/2 tested cell lines (Daudi, Ramos). Cell viability analysis revealed a combination benefit by increased direct cytotoxic effects against SU-DHL-6 cells. Finally, TAK-981 and tafasitamab were investigated in Daudi and WSU-DLCL2 xenograft models with 3 weeks of dosing. In the Daudi model, the combination treatments of TAK-981 with 10 or 20 mg/kg tafasitamab performed better than either treatment alone, and in the WSU-DLCL2 model, the combination treatments of TAK-981 with 3, 10 or 20 mg/kg tafasitamab performed better than the single agent treatments. Conclusions The combination of TAK-981 with tafasitamab significantly enhanced anti-tumor effects compared to the respective monotherapies in vitro and in vivo. These preclinical data support a clinical evaluation of this drug combination in patients with lymphoma including aggressive subtypes such as Burkitt lymphoma and DLBCL. The study was funded by MorphoSys AG and Takeda Development Center Americas, Inc. Disclosures Patra-Kneuer: MorphoSys AG: Current Employment. Nakamura: Takeda Development Center Americas, Inc.: Current Employment. Song: Takeda Pharmaceuticals International Co.: Current Employment. Grossman: Takeda Development Center, Cambridge MA: Current Employment. Polzer: MorphoSys: Current Employment. Ginzel: MorphoSys: Current Employment. Steidl: MorphoSys AG: Current Employment. Berger: Takeda Development Center Americas, Inc.: Current Employment. Proscurshim: Takeda Pharmaceuticals: Current Employment, Current holder of individual stocks in a privately-held company. Heitmüller: MorphoSys AG: Current Employment.
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Kusumgar, Sheela, D. P. Agrawal, and Prabhakar Sharma. "Radiocarbon Chronology and Magnetic Susceptibility Variation in Kumaon Lake Sediments." Radiocarbon 31, no. 03 (1989): 957–64. http://dx.doi.org/10.1017/s0033822200012583.
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This study was carried out to determine time controls of erosion and sedimentation in the catchment area and lakes of the Naini Tal district in the Kumaon Himalayas. We present here our preliminary data from five lakes, Beon Tal, Garud Tal, Sukha Tal, Bhim Tal and Kamal Tal (Naukuchia Tal). A number of 14C dates are now available to estimate the sedimentation rate of the five lakes and magnetic susceptibility (xL; xfd) variation to determine the signature of sediment source. High xfd values indicate a higher proportion of soil component generally characterized by a slower rate of deposition, and low xfd values with a higher rate of sedimentation indicate rock-debris-derived sediment. A 14C chronology enables us to estimate the mean sedimentation rate whereas rock magnetic properties help us to characterize the type of source responsible for sedimentation.
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Youn, Jeehee, Jin Chen, Shreevrat Goenka, Mark A. Aronica, Ana L. Mora, Victor Correa, James R. Sheller, and Mark Boothby. "In Vivo Function of an Interleukin 2 Receptor β Chain (IL-2Rβ)/IL-4Rα Cytokine Receptor Chimera Potentiates Allergic Airway Disease." Journal of Experimental Medicine 188, no. 10 (November 16, 1998): 1803–16. http://dx.doi.org/10.1084/jem.188.10.1803.
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Strength of T cell receptor (TCR) signaling, coreceptors, costimulation, antigen-presenting cell type, and cytokines all play crucial roles in determining the efficiency with which type 2 T lymphocytes (Th2, Tc2) develop from uncommitted precursors. To investigate in vivo regulatory mechanisms that control the population of type 2 T cells and disease susceptibility, we have created lines of transgenic mice in which expression of a chimeric cytokine receptor (the mouse interleukin 2 receptor β chain [IL-2Rβ] extracellular domain fused to the cytoplasmic tail of IL-4Rα) is targeted to the T lymphoid lineage using the proximal lck promoter. This chimera transduced IL-4–specific signals in response to IL-2 binding and dramatically enhanced type 2 responses (IL-4, IL-5, and immunoglobulin E production) upon in vitro TCR stimulation or in vivo antigen challenge. Thus, type 2 effector function was augmented by IL-4 signals transduced through a chimeric receptor expressed in a T cell–specific manner. This influence was sufficient for establishment of antigen-induced allergic airway hyperresponsiveness on a disease-resistant background (C57BL/6).
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Kandziora, Frank, Matti Scholz, Andreas Pingel, Philipp Schleicher, Ulas Yildiz, Patrick Kluger, Matthias Pumberger, Andreas Korge, and Klaus John Schnake. "Treatment of Atlas Fractures: Recommendations of the Spine Section of the German Society for Orthopaedics and Trauma (DGOU)." Global Spine Journal 8, no. 2_suppl (September 2018): 5S—11S. http://dx.doi.org/10.1177/2192568217726304.
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Study Design: Narrative review and expert recommendation. Objectives: To establish treatment recommendations for atlas fractures based on the knowledge of the experts of the Spine Section of the German Society for Orthopaedics and Trauma. Methods: Neither high-level evidence studies comparing conservative and operative management nor studies matching different operative treatment strategies exist. This recommendation summarizes the knowledge of the experts of the Spine Section of the German Society for Orthopaedics and Trauma with regard to the treatment of atlas fractures. Results: Most atlas fractures are the result of compression forces. A valuable morphological classification system has been described by Gehweiler. For an adequate diagnosis, a computed tomography is mandatory. To distinguish between stable and unstable type 3 injuries, it is necessary to evaluate the integrity of the transverse atlantal ligament (TAL) with magnetic resonance imaging and to classify the TAL lesions. The majority of atlas fractures are stable and will be successfully managed conservatively. Unstable atlas fractures (type 3b and sagittal split type 4 fractures) should be treated by surgical stabilization. Unstable atlas fractures (type 3b) with a midsubstance ligamentous disruption or severely dislocated ligamentous bony avulsions of the TAL can successfully be treated by a C1/2 fusion. Unstable atlas fractures (type 3b) with a moderately dislocated ligamentous bony avulsion of the TAL and sagittal split type 4 fractures may be treated by atlas osteosynthesis only. Conclusions: Whereas the majority of atlas fractures can be managed conservatively, in specific fracture patterns surgical treatment strategies have become the standard of care.
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Barančok, Peter, and Mária Barančoková. "Historical changes in dispersed kopanitse land type and changes in use of agricultural land on Kysuce region example." Ekológia (Bratislava) 35, no. 4 (December 1, 2016): 371–91. http://dx.doi.org/10.1515/eko-2016-0030.
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Abstract Territory of Kysuce is characterised by a high proportion of the traditional agricultural landscape (TAL), which occupy almost 12% of the area. Two types of TAL were allocated here. The first type is represented by TAL with dispersed settlement. The second type is represented by TAL of arable land and grassland landscape. The largest representation has typical forms of anthropogenic relief (FAR). TALs represent the most diverse mosaic of man-made habitats and natural habitats too. In the past, there were the largest representations of arable land and regularly mown meadows. Currently, these areas are dominated by abandoned meadows (fallow meadows), occasionally grazed pastures and meadows. Arable land is represented only minimally. The large part of areas is overgrown by non-forest woody vegetation or passes to the forest vegetation. In this process of landscape changes, significant changes in biodiversity of the areas are realised. Successively, the species of segetal and ruderal vegetation are less represented and species of forest vegetation obtained greater representation. In the process of mapping and evaluation, FAR - shape and orientation of plots, types of balks and some of their basic characteristics - were monitored.
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Nagakubo, Toshiki. "Biological Functions and Applications of Virus-Related Bacterial Nanoparticles: A Review." International Journal of Molecular Sciences 23, no. 5 (February 26, 2022): 2595. http://dx.doi.org/10.3390/ijms23052595.
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Accumulating evidence suggests that microorganisms produce various nanoparticles that exhibit a variety of biological functions. The structure of these bacterial nanoparticles ranges from membrane vesicles composed of membrane lipids to multicomponent proteinaceous machines. Of bacterial nanoparticles, bacterial phage tail-like nanoparticles, associated with virus-related genes, are found in bacteria from various environments and have diverse functions. Extracellular contractile injection systems (eCISs), a type of bacterial phage tail-like nanostructure, have diverse biological functions that mediate the interactions between the producer bacteria and target eukaryote. Known gram-negative bacterial eCISs can act as protein translocation systems and inject effector proteins that modulate eukaryotic cellular processes by attaching to the target cells. Further investigation of the functions of eCISs will facilitate the application of these nanomachines as nano-sized syringes in the field of nanomedicine and vaccine development. This review summarises the recent progress in elucidating the structures and biological functions of nanoparticles that resemble the tail components of phages that infect bacteria and discusses directions for future research to improve the clinical applicability of virus-related bacterial nanoparticles.
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Wilson, Jarad, Eugene Lin, Christopher Pack, Annette Hadley, and Aron Lukacher. "IFN-γ exerts antiviral activity against polyomavirus infection (42.14)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 42.14. http://dx.doi.org/10.4049/jimmunol.184.supp.42.14.
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Abstract CD8 T cells use both cytolytic and noncytolytic effector mechanisms to eliminate infectious pathogens. Using the mouse polyoma virus (MPyV) system, we have previously shown that TNFa, Fas/FasL, and the perforin/granzyme pathways are dispensable for viral control and susceptibility to MPyV-induced tumors. Here, we investigated whether IFN-γ may be an important effector mechanism for limiting viral burden and tumorigenesis. Using Western analyses for early region nonstructural viral T antigens, as well as FACS analyses of cells infected by a novel recombinant MPyV carrying an intra-T antigen HA epitope tag, we found that IFN-γ reduces expression of viral T antigens in a dose-dependent fashion. Compared to MPyV-infected wild type C57BL/6 mice, IFN-γ receptor KO mice had a 1-log higher viral load during acute infection in most organs, as well as during the persistent phase of MPyV infection; notably, 3-log higher viral genome copies were present in the kidneys, a major site of persistence by both murine and human polyomaviruses. This increase in viral burden was not due to a lack of responding cells, as fully functional virus-specific CD8 T cells were found during the entire course of infection in IFN-γR KO mice at levels similar to those seen in wild type mice. Studies are underway to determine if IFN-γ receptor KO mice are susceptible to PyV tumorigenesis and to investigate the importance of IFN-γ as a critical CD8 antiviral effector function in MPyV infection.
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Park, Tae-Won, Lan Chung, and Jinkoo Kim. "Seismic performance evaluation of tall and nonseismic-designed wall-type structures by shaking table tests." Structural Design of Tall and Special Buildings 20, no. 3 (November 25, 2009): 314–26. http://dx.doi.org/10.1002/tal.558.
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Studamire, Barbara, Gavrielle Price, Neal Sugawara, James E. Haber, and Eric Alani. "Separation-of-Function Mutations inSaccharomyces cerevisiae MSH2 That Confer Mismatch Repair Defects but Do Not Affect Nonhomologous-Tail Removal during Recombination." Molecular and Cellular Biology 19, no. 11 (November 1, 1999): 7558–67. http://dx.doi.org/10.1128/mcb.19.11.7558.
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ABSTRACT Yeast Msh2p forms complexes with Msh3p and Msh6p to repair DNA mispairs that arise during DNA replication. In addition to their role in mismatch repair (MMR), the MSH2 and MSH3gene products are required to remove 3′ nonhomologous DNA tails during genetic recombination. The mismatch repair genes MSH6,MLH1, and PMS1, whose products interact with Msh2p, are not required in this process. We have identified mutations in MSH2 that do not disrupt genetic recombination but confer a strong defect in mismatch repair. Twenty-four msh2mutations that conferred a dominant negative phenotype for mismatch repair were isolated. A subset of these mutations mapped to residues in Msh2p that were analogous to mutations identified in human nonpolyposis colorectal cancer msh2 kindreds. Approximately half of the these MMR-defective mutations retained wild-type or nearly wild-type activity for the removal of nonhomologous DNA tails during genetic recombination. The identification of mutations in MSH2 that disrupt mismatch repair without affecting recombination provides a first step in dissecting the Msh-effector protein complexes that are thought to play different roles during DNA repair and genetic recombination.
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Boch, J., H. Scholze, S. Schornack, A. Landgraf, S. Hahn, S. Kay, T. Lahaye, A. Nickstadt, and U. Bonas. "Breaking the Code of DNA Binding Specificity of TAL-Type III Effectors." Science 326, no. 5959 (October 29, 2009): 1509–12. http://dx.doi.org/10.1126/science.1178811.
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Rojo, Susana, Christopher C. Stebbins, Mary E. Peterson, David Dombrowicz, Nicolai Wagtmann, and Eric O. Long. "Natural Killer Cells and Mast Cells from gp49B Null Mutant Mice Are Functional." Molecular and Cellular Biology 20, no. 19 (October 1, 2000): 7178–82. http://dx.doi.org/10.1128/mcb.20.19.7178-7182.2000.
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ABSTRACT Immune responses are controlled by a combination of positive and negative cellular signals. Effector cells in the immune system express inhibitory receptors that serve to limit effector cell expansion and to protect the host from autoreactivity. gp49B is a receptor of unknown function that is expressed on activated mast cells and natural killer (NK) cells and whose cytoplasmic tail endows it with inhibitory potential. To gain insight into the function of gp49B in mice, we disrupted the gp49B gene by homologous recombination. gp49B0 mice were born at expected ratios, were healthy and fertile, and displayed normal long-term survival rates. gp49B0 mice showed no defect in NK or mast cell development. Furthermore, NK and mast cells from the gp49B0mice showed activation properties in vitro similar to those of cells isolated from wild-type mice. Therefore, gp49B is not critical for the development, expansion, and maturation of mast cells and NK cells in vivo. The healthy status of gp49B0 mice makes them suitable for testing the role of gp49B in immune responses to infectious agents.
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Goldfarb, AN, and K. Lewandowska. "Inhibition of cellular differentiation by the SCL/tal oncoprotein: transcriptional repression by an Id-like mechanism." Blood 85, no. 2 (January 15, 1995): 465–71. http://dx.doi.org/10.1182/blood.v85.2.465.465.
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Abstract In cases of T-cell acute lymphoblastic leukemia (T-ALL), the basic helix-loop-helix (bHLH) oncogene SCL/tal undergoes frequent rearrangements activating ectopic expression. Despite the compelling epidemiological association of SCL/tal expression with T-ALL, no specific transforming function has been attributable to the protein product. However, investigators have recently demonstrated that forced overexpression of SCL/tal can block monocytic differentiation of M1 murine myeloid leukemia cells. Thus, inappropriate expression of wild- type SCL/tal protein may in part account for the maturation arrest phenotype observed in T-ALL cells. In this study, ectopic expression of the SCL/tal gene blocked the differentiation of C2C12 muscle precursor cells. Characterization of the mechanism of differentiation blockade showed that the SCL/tal protein repressed transcriptional activation by the myogenic bHLH factor MyoD. Protein interaction analysis showed that SCL/tal and MyoD compete for common partners (E bHLH proteins) but do not directly bind one other. A model is thus proposed in which ectopic SCL/tal protein, by its ability to titrate out E proteins, prevents the formation of bHLH complexes that drive cellular differentiation: the “Id-like” mechanism.
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Goldfarb, AN, and K. Lewandowska. "Inhibition of cellular differentiation by the SCL/tal oncoprotein: transcriptional repression by an Id-like mechanism." Blood 85, no. 2 (January 15, 1995): 465–71. http://dx.doi.org/10.1182/blood.v85.2.465.bloodjournal852465.
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In cases of T-cell acute lymphoblastic leukemia (T-ALL), the basic helix-loop-helix (bHLH) oncogene SCL/tal undergoes frequent rearrangements activating ectopic expression. Despite the compelling epidemiological association of SCL/tal expression with T-ALL, no specific transforming function has been attributable to the protein product. However, investigators have recently demonstrated that forced overexpression of SCL/tal can block monocytic differentiation of M1 murine myeloid leukemia cells. Thus, inappropriate expression of wild- type SCL/tal protein may in part account for the maturation arrest phenotype observed in T-ALL cells. In this study, ectopic expression of the SCL/tal gene blocked the differentiation of C2C12 muscle precursor cells. Characterization of the mechanism of differentiation blockade showed that the SCL/tal protein repressed transcriptional activation by the myogenic bHLH factor MyoD. Protein interaction analysis showed that SCL/tal and MyoD compete for common partners (E bHLH proteins) but do not directly bind one other. A model is thus proposed in which ectopic SCL/tal protein, by its ability to titrate out E proteins, prevents the formation of bHLH complexes that drive cellular differentiation: the “Id-like” mechanism.
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Seifi, Ali, Abdollah Hosseini, Mohammad Sadegh Marefat, and Mohammad Khanmohammadi. "Seismic retrofitting of old-type RC columns with different lap splices by NSM GFRP and steel bars." Structural Design of Tall and Special Buildings 27, no. 2 (September 15, 2017): e1413. http://dx.doi.org/10.1002/tal.1413.
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Hu, Rongpan, Youlin Xu, Xiao Lu, Chaodong Zhang, Qilin Zhang, and Jiemin Ding. "Integrated multi-type sensor placement and response reconstruction method for high-rise buildings under unknown seismic loading." Structural Design of Tall and Special Buildings 27, no. 6 (March 5, 2018): e1453. http://dx.doi.org/10.1002/tal.1453.
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Barclay, Zoë, Louise Dickson, Derek N. Robertson, Melanie S. Johnson, Pamela J. Holland, Roberta Rosie, Liting Sun, Sue Fleetwood-Walker, Eve M. Lutz, and Rory Mitchell. "5-HT2A receptor signalling through phospholipase D1 associated with its C-terminal tail." Biochemical Journal 436, no. 3 (May 27, 2011): 651–60. http://dx.doi.org/10.1042/bj20101844.
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The 5-HT2AR (5-hydroxytryptamine-2A receptor) is a GPCR (G-protein-coupled receptor) that is implicated in the actions of hallucinogens and represents a major target of atypical antipsychotic agents. In addition to its classical signalling though PLC (phospholipase C), the receptor can activate several other pathways, including ARF (ADP-ribosylation factor)-dependent activation of PLD (phospholipase D), which appears to be achieved through a mechanism independent of heterotrimeric G-proteins. In the present study we show that wild-type and inactive constructs of PLD1 (but not PLD2) respectively facilitate and inhibit ARF-dependent PLD signalling by the 5-HT2AR. Furthermore we demonstrate that PLD1 specifically co-immunoprecipitates with the receptor and binds to a distal site in GST (glutathione transferase) fusion protein constructs of its C-terminal tail which is distinct from the ARF-interaction site, thereby suggesting the existence of a functional ARF–PLD signalling complex directly associated with this receptor. This reveals the spatial co-ordination of an important GPCR, transducer and effector into a physical complex that is likely to reinforce the impact of receptor activation on a heterotrimeric G-protein-independent signalling pathway. Signalling of this receptor through such non-canonical pathways may be important to its role in particular disorders.
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Banki, K., E. Colombo, F. Sia, D. Halladay, D. H. Mattson, A. H. Tatum, P. T. Massa, P. E. Phillips, and A. Perl. "Oligodendrocyte-specific expression and autoantigenicity of transaldolase in multiple sclerosis." Journal of Experimental Medicine 180, no. 5 (November 1, 1994): 1649–63. http://dx.doi.org/10.1084/jem.180.5.1649.
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Although the etiology of multiple sclerosis (MS) is unknown, there is compelling evidence that its pathogenesis is mediated through the immune system. Molecular mimicry, i.e., crossreactivity between self-antigens and viral proteins, has been implicated in the initiation of autoimmunity and MS. Based on homology to human T cell lymphotropic virus type I (HTLV-I) a novel human retrotransposon was cloned and found to constitute an integral part of the coding sequence of the human transaldolase gene (TAL-H). TAL-H is a key enzyme of the nonoxidative pentose phosphate pathway (PPP) providing ribose-5-phosphate for nucleic acid synthesis and NADPH for lipid biosynthesis. Another fundamental function of the PPP is to maintain glutathione at a reduced state and, consequently, to protect sulfhydryl groups and cellular integrity from oxygen radicals. Immunohistochemical analyses of human brain sections and primary murine brain cell cultures demonstrated that TAL is expressed selectively in oligodendrocytes at high levels, possibly linked to production of large amounts of lipids as a major component of myelin, and to the protection of the vast network of myelin sheaths from oxygen radicals. High-affinity autoantibodies to recombinant TAL-H were detected in serum (25/87) and cerebrospinal fluid (15/20) of patients with MS. By contrast, TAL-H antibodies were absent in 145 normal individuals and patients with other autoimmune and neurological diseases. In addition, recombinant TAL-H stimulated proliferation and caused aggregate formation of peripheral blood lymphocytes from patients with MS. Remarkable amino acid sequence homologies were noted between TAL-H and core proteins of human retroviruses. Presence of crossreactive antigenic epitopes between recombinant TAL-H and HTLV-I/human immunodeficiency virus type 1 (HIV-1) gas proteins was demonstrated by Western blot analysis. The results suggest that molecular mimicry between viral core proteins and TAL-H may play a role in breaking immunological tolerance and leading to a selective destruction of oligodendrocytes in MS.