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242 results on '"Rudel, T."'

1. Deprivation of arginine and lysine interferes with growth of patient-derived tumor xenografts

Author

Wolkersdorfer, A.M., primary, Bergmann, B., additional, Adelmann, J., additional, Ebbinghaus, M., additional, Günther, E., additional, Gutmann, M., additional, Hahn, L., additional, Hurwitz, R., additional, Lühmann, T., additional, Schueler, J., additional, Schmidt, L., additional, Teifel, M., additional, Meinel, L., additional, and Rudel, T., additional

Published
2023
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2. Innovative vaccine approaches-a Keystone Symposia report

Author

Cable, J, Rappuoli, R, Klemm, EJ, Kang, G, Mutreja, A, Wright, GJ, Pizza, M, Castro, SA, Hoffmann, JP, Alter, G, Carfi, A, Pollard, AJ, Krammer, F, Gupta, RK, Wagner, CE, Machado, V, Modjarrad, K, Corey, L, Gilbert, PB, Dougan, G, Lurie, N, Bjorkman, PJ, Chiu, C, Nemes, E, Gordon, SB, Steer, AC, Rudel, T, Blish, CA, Sandberg, JT, Brennan, K, Klugman, KP, Stuart, LM, Madhi, SA, Karp, CL, Cable, J, Rappuoli, R, Klemm, EJ, Kang, G, Mutreja, A, Wright, GJ, Pizza, M, Castro, SA, Hoffmann, JP, Alter, G, Carfi, A, Pollard, AJ, Krammer, F, Gupta, RK, Wagner, CE, Machado, V, Modjarrad, K, Corey, L, Gilbert, PB, Dougan, G, Lurie, N, Bjorkman, PJ, Chiu, C, Nemes, E, Gordon, SB, Steer, AC, Rudel, T, Blish, CA, Sandberg, JT, Brennan, K, Klugman, KP, Stuart, LM, Madhi, SA, and Karp, CL

Abstract

The rapid development of COVID-19 vaccines was the result of decades of research to establish flexible vaccine platforms and understand pathogens with pandemic potential, as well as several novel changes to the vaccine discovery and development processes that partnered industry and governments. And while vaccines offer the potential to drastically improve global health, low-and-middle-income countries around the world often experience reduced access to vaccines and reduced vaccine efficacy. Addressing these issues will require novel vaccine approaches and platforms, deeper insight how vaccines mediate protection, and innovative trial designs and models. On June 28-30, 2021, experts in vaccine research, development, manufacturing, and deployment met virtually for the Keystone eSymposium "Innovative Vaccine Approaches" to discuss advances in vaccine research and development.

Published
2022

7. Inhibitors of retrograde trafficking active against ricin and Shiga toxins also protect cells from several viruses, Chlamydiales and Leishmania

Author

Gupta, N., Noël, R., Goudet, A., Hinsinger, K., Michau, A., Pons, V., Abdelkafi, H., Secher, T., Shima, A., Shtanko, O., Sakurai, Y., Cojean, S., Pomel, S., Liévin-le Moal, V., Leignel, V., Herweg, J.-a., Fischer, A., Johannes, L., Harrison, Kate, Beard, Philippa M., Clayette, P., Le Grand, R., Rayner, J.o., Rudel, T., Vacus, J., Loiseau, P.m., Davey, R.a., Oswald, E., Cintrat, J.-c., Barbier, J., and Gillet, D.

Subjects
Emerging infectious diseases, endocrine system, Biothreat agents, Ricin toxin, High-throughput cell-based assays, Retrograde cell transport, Shiga-like toxins, Bioterrorism
Abstract

Medical countermeasures to treat biothreat agent infections require broad-spectrum therapeutics that do not induce agent resistance. A cell-based high-throughput screen (HTS) against ricin toxin combined with hit optimization allowed selection of a family of compounds that meet these requirements. The hit compound Retro-2 and its derivatives have been demonstrated to be safe in vivo in mice even at high doses. Moreover, Retro-2 is an inhibitor of retrograde transport that affects syntaxin-5-dependent toxins and pathogens. As a consequence, it has a broad-spectrum activity that has been demonstrated both in vitro and in vivo against ricin, Shiga toxin-producing O104:H4 entero-hemorrhagic E. coli and Leishmania sp. and in vitro against Ebola, Marburg and poxviruses and Chlamydiales. An effect is anticipated on other toxins or pathogens that use retrograde trafficking and syntaxin-5. Since Retro-2 targets cell components of the host and not directly the pathogen, no selection of resistant pathogens is expected. These lead compounds need now to be developed as drugs for human use.

Published
2017
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8. Transcriptional landscape and essential genes of Neisseria gonorrhoeae

Author

Remmele, C., Xian, Y., Albrecht, M., Faulstich, M., Fraunholz, M., Heinrichs, E., Dittrich, M., Müller, T., Reinhardt, R., and Rudel, T.

Subjects
Genes, Essential, RNA, Untranslated, Genes, Bacterial, Riboswitch, ddc:570, RNA, Antisense, Genomics, Transcription Initiation Site, Promoter Regions, Genetic, Transcriptome, Neisseria gonorrhoeae
Abstract

The WHO has recently classified Neisseria gonorrhoeae as a super-bacterium due to the rapid spread of antibiotic resistant derivatives and an overall dramatic increase in infection incidences. Genome sequencing has identified potential genes, however, little is known about the transcriptional organization and the presence of non-coding RNAs in gonococci. We performed RNA sequencing to define the transcriptome and the transcriptional start sites of all gonococcal genes and operons. Numerous new transcripts including 253 potentially non-coding RNAs transcribed from intergenic regions or antisense to coding genes were identified. Strikingly, strong antisense transcription was detected for the phase-variable opa genes coding for a family of adhesins and invasins in pathogenic Neisseria, that may have regulatory functions. Based on the defined transcriptional start sites, promoter motifs were identified. We further generated and sequenced a high density Tn5 transposon library to predict a core of 827 gonococcal essential genes, 133 of which have no known function. Our combined RNA-Seq and Tn-Seq approach establishes a detailed map of gonococcal genes and defines the first core set of essential gonococcal genes.

Published
2014

9. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018

Author

Galluzzi, L, Vitale, I, Aaronson, SA, Abrams, JM, Adam, D, Agostinis, P, Alnemri, ES, Altucci, L, Amelio, I, Andrews, DW, Annicchiarico-Petruzzelli, M, Antonov, AV, Arama, E, Baehrecke, EH, Barlev, NA, Bazan, NG, Bernassola, F, Bertrand, MJM, Bianchi, K, Blagosklonny, MV, Blomgren, K, Borner, C, Boya, P, Brenner, C, Campanella, M, Candi, E, Carmona-Gutierrez, D, Cecconi, F, Chan, FK-M, Chandel, NS, Cheng, EH, Chipuk, JE, Cidlowski, JA, Ciechanover, A, Cohen, GM, Conrad, M, Cubillos-Ruiz, JR, Czabotar, PE, D'Angiolella, V, Dawson, TM, Dawson, VL, De laurenzi, V, De Maria, R, Debatin, K-M, DeBerardinis, RJ, Deshmukh, M, Di Daniele, N, Di Virgilio, F, Dixit, VM, Dixon, SJ, Duckett, CS, Dynlacht, BD, El-Deiry, WS, Elrod, JW, Fimia, GM, Fulda, S, Garcia-Saez, AJ, Garg, AD, Garrido, C, Gavathiotis, E, Golstein, P, Gottlieb, E, Green, DR, Greene, LA, Gronemeyer, H, Gross, A, Hajnoczky, G, Hardwick, JM, Harris, IS, Hengartner, MO, Hetz, C, Ichijo, H, Jaattela, M, Joseph, B, Jost, PJ, Juin, PP, Kaiser, WJ, Karin, M, Kaufmann, T, Kepp, O, Kimchi, A, Kitsis, RN, Klionsky, DJ, Knight, RA, Kumar, S, Lee, SW, Lemasters, JJ, Levine, B, Linkermann, A, Lipton, SA, Lockshin, RA, Lopez-Otin, C, Lowe, SW, Luedde, T, Lugli, E, MacFarlane, M, Madeo, F, Malewicz, M, Malorni, W, Manic, G, Marine, J-C, Martin, SJ, Martinou, J-C, Medema, JP, Mehlen, P, Meier, P, Melino, S, Miao, EA, Molkentin, JD, Moll, UM, Munoz-Pinedo, C, Nagata, S, Nunez, G, Oberst, A, Oren, M, Overholtzer, M, Pagano, M, Panaretakis, T, Pasparakis, M, Penninger, JM, Pereira, DM, Pervaiz, S, Peter, ME, Piacentini, M, Pinton, P, Prehn, JHM, Puthalakath, H, Rabinovich, GA, Rehm, M, Rizzuto, R, Rodrigues, CMP, Rubinsztein, DC, Rudel, T, Ryan, KM, Sayan, E, Scorrano, L, Shao, F, Shi, Y, Silke, J, Simon, H-U, Sistigu, A, Stockwell, BR, Strasser, A, Szabadkai, G, Tait, SWG, Tang, D, Tavernarakis, N, Thorburn, A, Tsujimoto, Y, Turk, B, Vanden Berghe, T, Vandenabeele, P, Heiden, MGV, Villunger, A, Virgin, HW, Vousden, KH, Vucic, D, Wagner, EF, Walczak, H, Wallach, D, Wang, Y, Wells, JA, Wood, W, Yuan, J, Zakeri, Z, Zhivotovsky, B, Zitvogel, L, Melino, G, Kroemer, G, Galluzzi, L, Vitale, I, Aaronson, SA, Abrams, JM, Adam, D, Agostinis, P, Alnemri, ES, Altucci, L, Amelio, I, Andrews, DW, Annicchiarico-Petruzzelli, M, Antonov, AV, Arama, E, Baehrecke, EH, Barlev, NA, Bazan, NG, Bernassola, F, Bertrand, MJM, Bianchi, K, Blagosklonny, MV, Blomgren, K, Borner, C, Boya, P, Brenner, C, Campanella, M, Candi, E, Carmona-Gutierrez, D, Cecconi, F, Chan, FK-M, Chandel, NS, Cheng, EH, Chipuk, JE, Cidlowski, JA, Ciechanover, A, Cohen, GM, Conrad, M, Cubillos-Ruiz, JR, Czabotar, PE, D'Angiolella, V, Dawson, TM, Dawson, VL, De laurenzi, V, De Maria, R, Debatin, K-M, DeBerardinis, RJ, Deshmukh, M, Di Daniele, N, Di Virgilio, F, Dixit, VM, Dixon, SJ, Duckett, CS, Dynlacht, BD, El-Deiry, WS, Elrod, JW, Fimia, GM, Fulda, S, Garcia-Saez, AJ, Garg, AD, Garrido, C, Gavathiotis, E, Golstein, P, Gottlieb, E, Green, DR, Greene, LA, Gronemeyer, H, Gross, A, Hajnoczky, G, Hardwick, JM, Harris, IS, Hengartner, MO, Hetz, C, Ichijo, H, Jaattela, M, Joseph, B, Jost, PJ, Juin, PP, Kaiser, WJ, Karin, M, Kaufmann, T, Kepp, O, Kimchi, A, Kitsis, RN, Klionsky, DJ, Knight, RA, Kumar, S, Lee, SW, Lemasters, JJ, Levine, B, Linkermann, A, Lipton, SA, Lockshin, RA, Lopez-Otin, C, Lowe, SW, Luedde, T, Lugli, E, MacFarlane, M, Madeo, F, Malewicz, M, Malorni, W, Manic, G, Marine, J-C, Martin, SJ, Martinou, J-C, Medema, JP, Mehlen, P, Meier, P, Melino, S, Miao, EA, Molkentin, JD, Moll, UM, Munoz-Pinedo, C, Nagata, S, Nunez, G, Oberst, A, Oren, M, Overholtzer, M, Pagano, M, Panaretakis, T, Pasparakis, M, Penninger, JM, Pereira, DM, Pervaiz, S, Peter, ME, Piacentini, M, Pinton, P, Prehn, JHM, Puthalakath, H, Rabinovich, GA, Rehm, M, Rizzuto, R, Rodrigues, CMP, Rubinsztein, DC, Rudel, T, Ryan, KM, Sayan, E, Scorrano, L, Shao, F, Shi, Y, Silke, J, Simon, H-U, Sistigu, A, Stockwell, BR, Strasser, A, Szabadkai, G, Tait, SWG, Tang, D, Tavernarakis, N, Thorburn, A, Tsujimoto, Y, Turk, B, Vanden Berghe, T, Vandenabeele, P, Heiden, MGV, Villunger, A, Virgin, HW, Vousden, KH, Vucic, D, Wagner, EF, Walczak, H, Wallach, D, Wang, Y, Wells, JA, Wood, W, Yuan, J, Zakeri, Z, Zhivotovsky, B, Zitvogel, L, Melino, G, and Kroemer, G

Abstract

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.

Published
2018

11. Requirements for the import of neisserial Omp85 into the outer membrane of human mitochondria

Author

Ott, C., Utech, M., Goetz, M., Rudel, T., and Vera Kozjak-Pavlovic

Subjects
PorB, PEI, polyethylenimine, Recombinant Fusion Proteins, lcsh:Life, lcsh:QR1-502, SAM, sorting and assembly machinery, Porins, BN, blue native, β-barrel, S2, lcsh:Microbiology, Protein Structure, Secondary, ddc:570, HEK-293T, human embryonic kidney 293T, Escherichia coli, mitochondrion, Humans, POTRA domain, Original Paper, IMS, intermembrane space, Escherichia coli Proteins, SDHA, succinate dehydrogenase A, Neisseria gonorrhoeae, Mitochondria, Protein Structure, Tertiary, lcsh:QH501-531, POTRA, polypeptide-transport associated, Protein Transport, HEK293 Cells, Mitochondrial Membranes, TOM, translocase of the outer mitochondrial membrane, OMM, outer mitochondrial membrane, Omp85, BAM, β-barrel assembly machinery, IMM, inner mitochondrial membrane, Bacterial Outer Membrane Proteins, HeLa Cells
Abstract

β-Barrel proteins are present only in the outer membranes of Gram-negative bacteria, chloroplasts and mitochondria. Fungal mitochondria were shown to readily import and assemble bacterial β-barrel proteins, but human mitochondria exhibit certain selectivity. Whereas enterobacterial β-barrel proteins are not imported, neisserial ones are. Of those, solely neisserial Omp85 is integrated into the outer membrane of mitochondria. In this study, we wanted to identify the signal that targets neisserial β-barrel proteins to mitochondria. We exchanged parts of neisserial Omp85 and PorB with their Escherichia coli homologues BamA and OmpC. For PorB, we could show that its C-terminal quarter can direct OmpC to mitochondria. In the case of Omp85, we could identify several amino acids of the C-terminal β-sorting signal as crucial for mitochondrial targeting. Additionally, we found that at least two POTRA (polypeptide-transport associated) domains and not only the β-sorting signal of Omp85 are needed for its membrane integration and function in human mitochondria. We conclude that the signal that directs neisserial β-barrel proteins to mitochondria is not conserved between these proteins. Furthermore, a linear mitochondrial targeting signal probably does not exist. It is possible that the secondary structure of β-barrel proteins plays a role in directing these proteins to mitochondria.

Published
2013

13. Essential versus accessory aspects of cell death: Recommendations of the NCCD 2015

Author

Galluzzi, L., Bravo-San Pedro, J. M., Vitale, Ilio, Aaronson, S. A., Abrams, J. M., Adam, D., Alnemri, E. S., Altucci, L., Andrews, D., Annicchiarico-Petruzzelli, M., Baehrecke, E. H., Bazan, N. G., Bertrand, M. J., Bianchi, K., Blagosklonny, M. V., Blomgren, K., Borner, C., Bredesen, D. E., Brenner, C., Campanella, M., Candi, E., Cecconi, F., Chan, F. K., Chandel, N. S., Cheng, E. H., Chipuk, J. E., Cidlowski, J. A., Ciechanover, A., Dawson, T. M., Dawson, V. L., De Laurenzi, V., De Maria Marchiano, Ruggero, Debatin, K. -M., Di Daniele, N., Dixit, V. M., Dynlacht, B. D., El-Deiry, W. S., Fimia, G. M., Flavell, R. A., Fulda, S., Garrido, C., Gougeon, M. -L., Green, D. R., Gronemeyer, H., Hajnoczky, G., Hardwick, J. M., Hengartner, M. O., Ichijo, H., Joseph, B., Jost, P. J., Kaufmann, T., Kepp, O., Klionsky, D. J., Knight, R. A., Kumar, S., Lemasters, J. J., Levine, B., Linkermann, A., Lipton, S. A., Lockshin, R. A., López-Otín, C., Lugli, E., Madeo, F., Malorni, W., Marine, J. -C., Martin, S. J., Martinou, J. -C., Medema, Jan Paul, Meier, P., Melino, S., Mizushima, N., Moll, U., Muñoz-Pinedo, C., Nuñez, G., Oberst, A., Panaretakis, T., Penninger, J. M., Peter, M. E., Piacentini, M., Calzavara Pinton, Piergiacomo, Prehn, J. H., Puthalakath, H., Rabinovich, G. A., Ravichandran, K. S., Rizzuto, R., Rodrigues, C. M., Rubinsztein, D. C., Rudel, T., Shi, Y., Simon, H. -U., Stockwell, B. R., Szabadkai, G., Tait, S. W., Tang, H. L., Tavernarakis, N., Tsujimoto, Y., Vanden Berghe, T., Vandenabeele, P., Villunger, A., Wagner, E. F., Walczak, H., White, E., Wood, W. G., Yuan, J., Zakeri, Z., Zhivotovsky, B., Melino, G., Kroemer, G., Vitale, I., De Maria Marchiano, R. (ORCID:0000-0003-2255-0583), Medema, J. P., Calzavara Pinton, P., Galluzzi, L., Bravo-San Pedro, J. M., Vitale, Ilio, Aaronson, S. A., Abrams, J. M., Adam, D., Alnemri, E. S., Altucci, L., Andrews, D., Annicchiarico-Petruzzelli, M., Baehrecke, E. H., Bazan, N. G., Bertrand, M. J., Bianchi, K., Blagosklonny, M. V., Blomgren, K., Borner, C., Bredesen, D. E., Brenner, C., Campanella, M., Candi, E., Cecconi, F., Chan, F. K., Chandel, N. S., Cheng, E. H., Chipuk, J. E., Cidlowski, J. A., Ciechanover, A., Dawson, T. M., Dawson, V. L., De Laurenzi, V., De Maria Marchiano, Ruggero, Debatin, K. -M., Di Daniele, N., Dixit, V. M., Dynlacht, B. D., El-Deiry, W. S., Fimia, G. M., Flavell, R. A., Fulda, S., Garrido, C., Gougeon, M. -L., Green, D. R., Gronemeyer, H., Hajnoczky, G., Hardwick, J. M., Hengartner, M. O., Ichijo, H., Joseph, B., Jost, P. J., Kaufmann, T., Kepp, O., Klionsky, D. J., Knight, R. A., Kumar, S., Lemasters, J. J., Levine, B., Linkermann, A., Lipton, S. A., Lockshin, R. A., López-Otín, C., Lugli, E., Madeo, F., Malorni, W., Marine, J. -C., Martin, S. J., Martinou, J. -C., Medema, Jan Paul, Meier, P., Melino, S., Mizushima, N., Moll, U., Muñoz-Pinedo, C., Nuñez, G., Oberst, A., Panaretakis, T., Penninger, J. M., Peter, M. E., Piacentini, M., Calzavara Pinton, Piergiacomo, Prehn, J. H., Puthalakath, H., Rabinovich, G. A., Ravichandran, K. S., Rizzuto, R., Rodrigues, C. M., Rubinsztein, D. C., Rudel, T., Shi, Y., Simon, H. -U., Stockwell, B. R., Szabadkai, G., Tait, S. W., Tang, H. L., Tavernarakis, N., Tsujimoto, Y., Vanden Berghe, T., Vandenabeele, P., Villunger, A., Wagner, E. F., Walczak, H., White, E., Wood, W. G., Yuan, J., Zakeri, Z., Zhivotovsky, B., Melino, G., Kroemer, G., Vitale, I., De Maria Marchiano, R. (ORCID:0000-0003-2255-0583), Medema, J. P., and Calzavara Pinton, P.

Abstract

Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as 'accidental cell death' (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. 'Regulated cell death' (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death.

Published
2015

14. LivestockPlus - The sustainable intensification of forage-based agricultural systems to improve livelihoods and ecosystem services in the tropics

Author

Rao, I., Peters, M., Castro, A., Schultze-Kraft, R., White, D., Fisher, M., Miles, J., Lascano, C., Blümmel, M., Bungenstab, D., Tapasco, J., Hyman, G., Bolliger, A., Paul, B., Van Der Hoek, R., Maass, B., Tiemann, T., Cuchillo, M., Douxchamps, S., Villanueva, C., Rincón, A., Ayarza, M., Rosenstock, T., Subbarao, G., Arango, J., Cardoso, J., Worthington, M., Chirinda, N., Notenbaert, A., Jenet, A., Schmidt, A., Vivas, N., Lefroy, R., Fahrney, K., Guimarães, E., Tohme, J., Cook, Simon, Herrero, M., Chacón, M., Searchinger, T., Rudel, T., Rao, I., Peters, M., Castro, A., Schultze-Kraft, R., White, D., Fisher, M., Miles, J., Lascano, C., Blümmel, M., Bungenstab, D., Tapasco, J., Hyman, G., Bolliger, A., Paul, B., Van Der Hoek, R., Maass, B., Tiemann, T., Cuchillo, M., Douxchamps, S., Villanueva, C., Rincón, A., Ayarza, M., Rosenstock, T., Subbarao, G., Arango, J., Cardoso, J., Worthington, M., Chirinda, N., Notenbaert, A., Jenet, A., Schmidt, A., Vivas, N., Lefroy, R., Fahrney, K., Guimarães, E., Tohme, J., Cook, Simon, Herrero, M., Chacón, M., Searchinger, T., and Rudel, T.

Abstract

© 2015. As global demand for livestock products (such as meat, milk and eggs) is expected to double by 2050, necessary in-creases to future production must be reconciled with negative environmental impacts that livestock cause. This paper describes the LivestockPlus concept and demonstrates how the sowing of improved forages can lead to the sustainable intensification of mixed crop-forage-livestock-tree systems in the tropics by producing multiple social, economic and environmental benefits. Sustainable intensification not only improves the productivity of tropical forage-based systems but also reduces the ecological footprint of livestock production and generates a diversity of ecosystem services (ES) such as improved soil quality and reduced erosion, sedimentation and greenhouse gas (GHG) emissions. Integrating improved grass and legume forages into mixed production systems (crop-livestock, tree-livestock, crop-tree-livestock) can restore degraded lands and enhance system resilience to drought and waterlogging associated with climate change. When properly managed tropical forages accumulate large amounts of carbon in soil, fix atmospheric nitrogen (legumes), inhibit nitrification in soil and reduce nitrous oxide emissions (grasses), and reduce GHG emissions per unit livestock product. The LivestockPlus concept is defined as the sustainable intensification of forage-based systems, which is based on 3 interrelated intensification processes: genetic intensification - the development and use of superior grass and legume cultivars for increased livestock productivity; ecological intensification - the development and application of improved farm and natural resource management practices; and socio-economic intensification - the improvement of local and national institutions and policies, which enable refinements of technologies and support their enduring use. Increases in livestock productivity will require coordinated efforts to develop supportive government, non-gover

Published
2015

15. The Use of High-Throughput DNA Sequencing in the Investigation of Antigenic Variation: Application to Neisseria Species

Author

Rudel, T, Davies, JK, Harrison, PF, Lin, Y-H, Bartley, S, Khoo, CA, Seemann, T, Ryan, CS, Kahler, CM, Hill, SA, Rudel, T, Davies, JK, Harrison, PF, Lin, Y-H, Bartley, S, Khoo, CA, Seemann, T, Ryan, CS, Kahler, CM, and Hill, SA

Abstract

Antigenic variation occurs in a broad range of species. This process resembles gene conversion in that variant DNA is unidirectionally transferred from partial gene copies (or silent loci) into an expression locus. Previous studies of antigenic variation have involved the amplification and sequencing of individual genes from hundreds of colonies. Using the pilE gene from Neisseria gonorrhoeae we have demonstrated that it is possible to use PCR amplification, followed by high-throughput DNA sequencing and a novel assembly process, to detect individual antigenic variation events. The ability to detect these events was much greater than has previously been possible. In N. gonorrhoeae most silent loci contain multiple partial gene copies. Here we show that there is a bias towards using the copy at the 3' end of the silent loci (copy 1) as the donor sequence. The pilE gene of N. gonorrhoeae and some strains of Neisseria meningitidis encode class I pilin, but strains of N. meningitidis from clonal complexes 8 and 11 encode a class II pilin. We have confirmed that the class II pili of meningococcal strain FAM18 (clonal complex 11) are non-variable, and this is also true for the class II pili of strain NMB from clonal complex 8. In addition when a gene encoding class I pilin was moved into the meningococcal strain NMB background there was no evidence of antigenic variation. Finally we investigated several members of the opa gene family of N. gonorrhoeae, where it has been suggested that limited variation occurs. Variation was detected in the opaK gene that is located close to pilE, but not at the opaJ gene located elsewhere on the genome. The approach described here promises to dramatically improve studies of the extent and nature of antigenic variation systems in a variety of species.

Published
2014

16. Essential versus accessory aspects of cell death: recommendations of the NCCD 2015

Author

Galluzzi, L, Bravo-San Pedro, Jm, Vitale, I, Aaronson, Sa, Abrams, Jm, Adam, D, Alnemri, E, Altucci, L, Andrews, D, Annicchiarico-Petruzzelli, M, Baehrecke, Eh, Bazan, Ng, Bertrand, Mj, Bianchi, K, Blagosklonny, Mv, Blomgren, K, Borner, C, Bredesen, De, Brenner, C, Campanella, M, Candi, E, Cecconi, F, Chan, Fk, Chandel, N, Cheng, Eh, Chipuk, Je, Cidlowski, Ja, Ciechanover, A, Dawson, Tm, Dawson, Vl, De Laurenzi, V, De Maria Marchiano, Ruggero, Debatin, Km, Di Daniele, N, Dixit, Vm, Dynlacht, Bd, El-Deiry, W, Fimia, Gm, Flavell, Ra, Fulda, S, Garrido, C, Gougeon, Ml, Green, Dr, Gronemeyer, H, Hajnoczky, G, Hardwick, Jm, Hengartner, Mo, Ichijo, H, Joseph, B, Jost, Pj, Kaufmann, T, Kepp, O, Klionsky, Dj, Knight, Ra, Kumar, S, Lemasters, Jj, Levine, B, Linkermann, A, Lipton, Sa, Lockshin, Ra, López-Otín, C, Lugli, E, Madeo, F, Malorni, W, Marine, Jc, Martin, Sj, Martinou, Jc, Medema, Jan Paul, Meier, P, Melino, S, Mizushima, N, Moll, U, Muñoz-Pinedo, C, Nuñez, G, Oberst, A, Panaretakis, T, Penninger, Jm, Peter, Me, Piacentini, M, Calzavara Pinton, Piergiacomo, Prehn, Jh, Puthalakath, H, Rabinovich, Ga, Ravichandran, K, Rizzuto, R, Rodrigues, Cm, Rubinsztein, Dc, Rudel, T, Shi, Y, Simon, Hu, Stockwell, Br, Szabadkai, G, Tait, Sw, Tang, Hl, Tavernarakis, N, Tsujimoto, Y, Vanden Berghe, T, Vandenabeele, P, Villunger, A, Wagner, Ef, Walczak, H, White, E, Wood, Wg, Yuan, J, Zakeri, Z, Zhivotovsky, B, Melino, G, Kroemer, G., De Maria Marchiano R (ORCID:0000-0003-2255-0583), Medema JP, Calzavara Pinton P, Galluzzi, L, Bravo-San Pedro, Jm, Vitale, I, Aaronson, Sa, Abrams, Jm, Adam, D, Alnemri, E, Altucci, L, Andrews, D, Annicchiarico-Petruzzelli, M, Baehrecke, Eh, Bazan, Ng, Bertrand, Mj, Bianchi, K, Blagosklonny, Mv, Blomgren, K, Borner, C, Bredesen, De, Brenner, C, Campanella, M, Candi, E, Cecconi, F, Chan, Fk, Chandel, N, Cheng, Eh, Chipuk, Je, Cidlowski, Ja, Ciechanover, A, Dawson, Tm, Dawson, Vl, De Laurenzi, V, De Maria Marchiano, Ruggero, Debatin, Km, Di Daniele, N, Dixit, Vm, Dynlacht, Bd, El-Deiry, W, Fimia, Gm, Flavell, Ra, Fulda, S, Garrido, C, Gougeon, Ml, Green, Dr, Gronemeyer, H, Hajnoczky, G, Hardwick, Jm, Hengartner, Mo, Ichijo, H, Joseph, B, Jost, Pj, Kaufmann, T, Kepp, O, Klionsky, Dj, Knight, Ra, Kumar, S, Lemasters, Jj, Levine, B, Linkermann, A, Lipton, Sa, Lockshin, Ra, López-Otín, C, Lugli, E, Madeo, F, Malorni, W, Marine, Jc, Martin, Sj, Martinou, Jc, Medema, Jan Paul, Meier, P, Melino, S, Mizushima, N, Moll, U, Muñoz-Pinedo, C, Nuñez, G, Oberst, A, Panaretakis, T, Penninger, Jm, Peter, Me, Piacentini, M, Calzavara Pinton, Piergiacomo, Prehn, Jh, Puthalakath, H, Rabinovich, Ga, Ravichandran, K, Rizzuto, R, Rodrigues, Cm, Rubinsztein, Dc, Rudel, T, Shi, Y, Simon, Hu, Stockwell, Br, Szabadkai, G, Tait, Sw, Tang, Hl, Tavernarakis, N, Tsujimoto, Y, Vanden Berghe, T, Vandenabeele, P, Villunger, A, Wagner, Ef, Walczak, H, White, E, Wood, Wg, Yuan, J, Zakeri, Z, Zhivotovsky, B, Melino, G, Kroemer, G., De Maria Marchiano R (ORCID:0000-0003-2255-0583), Medema JP, and Calzavara Pinton P

Abstract

Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as 'accidental cell death' (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. 'Regulated cell death' (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death.

Published
2014

17. Essential versus accessory aspects of cell death: recommendations of the NCCD 2015

Author

Galluzzi, L, primary, Bravo-San Pedro, J M, additional, Vitale, I, additional, Aaronson, S A, additional, Abrams, J M, additional, Adam, D, additional, Alnemri, E S, additional, Altucci, L, additional, Andrews, D, additional, Annicchiarico-Petruzzelli, M, additional, Baehrecke, E H, additional, Bazan, N G, additional, Bertrand, M J, additional, Bianchi, K, additional, Blagosklonny, M V, additional, Blomgren, K, additional, Borner, C, additional, Bredesen, D E, additional, Brenner, C, additional, Campanella, M, additional, Candi, E, additional, Cecconi, F, additional, Chan, F K, additional, Chandel, N S, additional, Cheng, E H, additional, Chipuk, J E, additional, Cidlowski, J A, additional, Ciechanover, A, additional, Dawson, T M, additional, Dawson, V L, additional, De Laurenzi, V, additional, De Maria, R, additional, Debatin, K-M, additional, Di Daniele, N, additional, Dixit, V M, additional, Dynlacht, B D, additional, El-Deiry, W S, additional, Fimia, G M, additional, Flavell, R A, additional, Fulda, S, additional, Garrido, C, additional, Gougeon, M-L, additional, Green, D R, additional, Gronemeyer, H, additional, Hajnoczky, G, additional, Hardwick, J M, additional, Hengartner, M O, additional, Ichijo, H, additional, Joseph, B, additional, Jost, P J, additional, Kaufmann, T, additional, Kepp, O, additional, Klionsky, D J, additional, Knight, R A, additional, Kumar, S, additional, Lemasters, J J, additional, Levine, B, additional, Linkermann, A, additional, Lipton, S A, additional, Lockshin, R A, additional, López-Otín, C, additional, Lugli, E, additional, Madeo, F, additional, Malorni, W, additional, Marine, J-C, additional, Martin, S J, additional, Martinou, J-C, additional, Medema, J P, additional, Meier, P, additional, Melino, S, additional, Mizushima, N, additional, Moll, U, additional, Muñoz-Pinedo, C, additional, Nuñez, G, additional, Oberst, A, additional, Panaretakis, T, additional, Penninger, J M, additional, Peter, M E, additional, Piacentini, M, additional, Pinton, P, additional, Prehn, J H, additional, Puthalakath, H, additional, Rabinovich, G A, additional, Ravichandran, K S, additional, Rizzuto, R, additional, Rodrigues, C M, additional, Rubinsztein, D C, additional, Rudel, T, additional, Shi, Y, additional, Simon, H-U, additional, Stockwell, B R, additional, Szabadkai, G, additional, Tait, S W, additional, Tang, H L, additional, Tavernarakis, N, additional, Tsujimoto, Y, additional, Vanden Berghe, T, additional, Vandenabeele, P, additional, Villunger, A, additional, Wagner, E F, additional, Walczak, H, additional, White, E, additional, Wood, W G, additional, Yuan, J, additional, Zakeri, Z, additional, Zhivotovsky, B, additional, Melino, G, additional, and Kroemer, G, additional

Published
2014
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18. Attachment and Invasion of Neisseria meningitidis to Host Cells Is Related to Surface Hydrophobicity, Bacterial Cell Size and Capsule

Author

Rudel, T, Bartley, SN, Tzeng, Y-L, Heel, K, Lee, CW, Mowlaboccus, S, Seemann, T, Lu, W, Lin, Y-H, Ryan, CS, Peacock, C, Stephens, DS, Davies, JK, Kahler, CM, Rudel, T, Bartley, SN, Tzeng, Y-L, Heel, K, Lee, CW, Mowlaboccus, S, Seemann, T, Lu, W, Lin, Y-H, Ryan, CS, Peacock, C, Stephens, DS, Davies, JK, and Kahler, CM

Abstract

We compared exemplar strains from two hypervirulent clonal complexes, strain NMB-CDC from ST-8/11 cc and strain MC58 from ST-32/269 cc, in host cell attachment and invasion. Strain NMB-CDC attached to and invaded host cells at a significantly greater frequency than strain MC58. Type IV pili retained the primary role for initial attachment to host cells for both isolates regardless of pilin class and glycosylation pattern. In strain MC58, the serogroup B capsule was the major inhibitory determinant affecting both bacterial attachment to and invasion of host cells. Removal of terminal sialylation of lipooligosaccharide (LOS) in the presence of capsule did not influence rates of attachment or invasion for strain MC58. However, removal of either serogroup B capsule or LOS sialylation in strain NMB-CDC increased bacterial attachment to host cells to the same extent. Although the level of inhibition of attachment by capsule was different between these strains, the regulation of the capsule synthesis locus by the two-component response regulator MisR, and the level of surface capsule determined by flow cytometry were not significantly different. However, the diplococci of strain NMB-CDC were shown to have a 1.89-fold greater surface area than strain MC58 by flow cytometry. It was proposed that the increase in surface area without changing the amount of anchored glycolipid capsule in the outer membrane would result in a sparser capsule and increase surface hydrophobicity. Strain NMB-CDC was shown to be more hydrophobic than strain MC58 using hydrophobicity interaction chromatography and microbial adhesion-to-solvents assays. In conclusion, improved levels of adherence of strain NMB-CDC to cell lines was associated with increased bacterial cell surface and surface hydrophobicity. This study shows that there is diversity in bacterial cell surface area and surface hydrophobicity within N. meningitidis which influence steps in meningococcal pathogenesis.

Published
2013

19. Guidelines for the use and interpretation of assays for monitoring cell death in higher eukaryotes

Author

Galluzzi, L., Aaronson, S. A., Abrams, J., Alnemri, E. S., Andrews, D. W., Baehrecke, E. H., Bazan, N. G., Blagosklonny, M. V., Blomgren, K., Borner, C., Bredesen, D. E., Brenner, C., Castedo, M., Cidlowski, J. A., Ciechanover, A., Cohen, G. M., De Laurenzi, V., De Maria Marchiano, Ruggero, Deshmukh, M., Dynlacht, B. D., El-Deiry, W. S., Flavell, R. A., Fulda, S., Garrido, C., Golstein, P., Gougeon, M. -L., Green, D. R., Gronemeyer, H., Hajnóczky, G., Hardwick, J. M., Hengartner, M. O., Ichijo, H., Jäättelä, M., Kepp, O., Kimchi, A., Klionsky, D. J., Knight, R. A., Kornbluth, S., Kumar, S., Levine, B., Lipton, S. A., Lugli, E., Madeo, F., Malorni, W., Marine, J. -C. W., Martin, S. J., Medema, Jan Paul, Mehlen, P., Melino, G., Moll, U. M., Morselli, E., Nagata, S., Nicholson, D. W., Nicotera, P., Nuñez, G., Oren, M., Penninger, J., Pervaiz, S., Peter, M. E., Piacentini, M., Prehn, J. H. M., Puthalakath, H., Rabinovich, G. A., Rizzuto, R., Rodrigues, C. M. P., Rubinsztein, D. C., Rudel, T., Scorrano, L., Simon, H. -U., Steller, H., Tschopp, J., Tsujimoto, Y., Vandenabeele, P., Vitale, Ilio, Vousden, K. H., Youle, R. J., Yuan, J., Zhivotovsky, B., Kroemer, G., De Maria Marchiano, R. (ORCID:0000-0003-2255-0583), Medema, J. P., Vitale, I., Galluzzi, L., Aaronson, S. A., Abrams, J., Alnemri, E. S., Andrews, D. W., Baehrecke, E. H., Bazan, N. G., Blagosklonny, M. V., Blomgren, K., Borner, C., Bredesen, D. E., Brenner, C., Castedo, M., Cidlowski, J. A., Ciechanover, A., Cohen, G. M., De Laurenzi, V., De Maria Marchiano, Ruggero, Deshmukh, M., Dynlacht, B. D., El-Deiry, W. S., Flavell, R. A., Fulda, S., Garrido, C., Golstein, P., Gougeon, M. -L., Green, D. R., Gronemeyer, H., Hajnóczky, G., Hardwick, J. M., Hengartner, M. O., Ichijo, H., Jäättelä, M., Kepp, O., Kimchi, A., Klionsky, D. J., Knight, R. A., Kornbluth, S., Kumar, S., Levine, B., Lipton, S. A., Lugli, E., Madeo, F., Malorni, W., Marine, J. -C. W., Martin, S. J., Medema, Jan Paul, Mehlen, P., Melino, G., Moll, U. M., Morselli, E., Nagata, S., Nicholson, D. W., Nicotera, P., Nuñez, G., Oren, M., Penninger, J., Pervaiz, S., Peter, M. E., Piacentini, M., Prehn, J. H. M., Puthalakath, H., Rabinovich, G. A., Rizzuto, R., Rodrigues, C. M. P., Rubinsztein, D. C., Rudel, T., Scorrano, L., Simon, H. -U., Steller, H., Tschopp, J., Tsujimoto, Y., Vandenabeele, P., Vitale, Ilio, Vousden, K. H., Youle, R. J., Yuan, J., Zhivotovsky, B., Kroemer, G., De Maria Marchiano, R. (ORCID:0000-0003-2255-0583), Medema, J. P., and Vitale, I.

Abstract

Cell death is essential for a plethora of physiological processes, and its deregulation characterizes numerous human diseases. Thus, the in-depth investigation of cell death and its mechanisms constitutes a formidable challenge for fundamental and applied biomedical research, and has tremendous implications for the development of novel therapeutic strategies. It is, therefore, of utmost importance to standardize the experimental procedures that identify dying and dead cells in cell cultures and/or in tissues, from model organisms and/or humans, in healthy and/or pathological scenarios. Thus far, dozens of methods have been proposed to quantify cell death-related parameters. However, no guidelines exist regarding their use and interpretation, and nobody has thoroughly annotated the experimental settings for which each of these techniques is most appropriate. Here, we provide a nonexhaustive comparison of methods to detect cell death with apoptotic or nonapoptotic morphologies, their advantages and pitfalls. These guidelines are intended for investigators who study cell death, as well as for reviewers who need to constructively critique scientific reports that deal with cellular demise. Given the difficulties in determining the exact number of cells that have passed the point-of-no-return of the signaling cascades leading to cell death, we emphasize the importance of performing multiple, methodologically unrelated assays to quantify dying and dead cells.

Published
2009

22. Guidelines for the use and interpretation of assays for monitoring cell death in higher eukaryotes

Author

Galluzzi, L, primary, Aaronson, S A, additional, Abrams, J, additional, Alnemri, E S, additional, Andrews, D W, additional, Baehrecke, E H, additional, Bazan, N G, additional, Blagosklonny, M V, additional, Blomgren, K, additional, Borner, C, additional, Bredesen, D E, additional, Brenner, C, additional, Castedo, M, additional, Cidlowski, J A, additional, Ciechanover, A, additional, Cohen, G M, additional, De Laurenzi, V, additional, De Maria, R, additional, Deshmukh, M, additional, Dynlacht, B D, additional, El-Deiry, W S, additional, Flavell, R A, additional, Fulda, S, additional, Garrido, C, additional, Golstein, P, additional, Gougeon, M-L, additional, Green, D R, additional, Gronemeyer, H, additional, Hajnóczky, G, additional, Hardwick, J M, additional, Hengartner, M O, additional, Ichijo, H, additional, Jäättelä, M, additional, Kepp, O, additional, Kimchi, A, additional, Klionsky, D J, additional, Knight, R A, additional, Kornbluth, S, additional, Kumar, S, additional, Levine, B, additional, Lipton, S A, additional, Lugli, E, additional, Madeo, F, additional, Malorni, W, additional, Marine, J-CW, additional, Martin, S J, additional, Medema, J P, additional, Mehlen, P, additional, Melino, G, additional, Moll, U M, additional, Morselli, E, additional, Nagata, S, additional, Nicholson, D W, additional, Nicotera, P, additional, Nuñez, G, additional, Oren, M, additional, Penninger, J, additional, Pervaiz, S, additional, Peter, M E, additional, Piacentini, M, additional, Prehn, J H M, additional, Puthalakath, H, additional, Rabinovich, G A, additional, Rizzuto, R, additional, Rodrigues, C M P, additional, Rubinsztein, D C, additional, Rudel, T, additional, Scorrano, L, additional, Simon, H-U, additional, Steller, H, additional, Tschopp, J, additional, Tsujimoto, Y, additional, Vandenabeele, P, additional, Vitale, I, additional, Vousden, K H, additional, Youle, R J, additional, Yuan, J, additional, Zhivotovsky, B, additional, and Kroemer, G, additional

Published
2009
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24. Signal transduction pathways induced by virulence factors of Neisseria gonorrhoeae

Author

Popp, A, Billker, Oliver, Rudel, T, Popp, A, Billker, Oliver, and Rudel, T

Abstract

The obligate human pathogen Neisseria gonorrhoeae infects a variety of human tissues. In recent years, several host cell receptors for the major bacterial adhesins have been identified. While the knowledge of the molecular mechanism of colonisation has helped to understand special aspects of the infection, like the explicit tropism of gonococci for human tissues, the long-term consequences of engaging these receptors are still unknown. A variety of signalling pathways initiated by the activated receptors and by bacterial proteins transferred to the infected cell have been defined which include lipid second messenger, protein kinases, proteases and GTPases. These pathways control important steps of the infection, such as tight adhesion and invasion, the induction of cytokine release, and apoptosis. The detailed knowledge of bacteria-induced signalling pathways could allow the design of new therapeutic approaches which might be advantageous over the classical antibiotics therapy.

Published
2001
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25. Targeting of the pro-apoptotic VDAC-like porin (PorB) of Neisseria gonorrhoeae to mitochondria of infected cells

Author

Müller, Anne; https://orcid.org/0000-0002-1368-8276, Günther, D, Brinkmann, V, Hurwitz, R, Meyer, T F, Rudel, T, Müller, Anne; https://orcid.org/0000-0002-1368-8276, Günther, D, Brinkmann, V, Hurwitz, R, Meyer, T F, and Rudel, T

Abstract

Infection of cell cultures with Neisseria gonorrhoeae results in apoptosis that is mediated by the PorB porin. During the infection process porin translocates from the outer bacterial membrane into host cell membranes where its channel activity is regulated by nucleotide binding and voltage-dependent gating, features that are shared by the mitochondrial voltage-dependent anion channel (VDAC). Here we show that porin is selectively and efficiently transported to mitochondria of infected cells. Prevention of porin translocation also blocked the induction of apoptosis. Mitochondria of cells treated with porin both in vitro and in vivo were depleted of cytochrome c and underwent permeability transition. Overexpression of Bcl-2 blocked porin-induced apoptosis. The release of cytochrome c occurred independently of active caspases but was completely prevented by Bcl-2. Our data suggest that the Neisseria porin can, like its eukaryotic homologue, function at the mitochondrial checkpoint to mediate apoptosis.

Published
2000

26. Neisserial porin (PorB) causes rapid calcium influx in target cells and induces apoptosis by the activation of cysteine proteases

Author

Müller, Anne; https://orcid.org/0000-0002-1368-8276, Günther, D, Düx, F, Naumann, M, Meyer, T F, Rudel, T, Müller, Anne; https://orcid.org/0000-0002-1368-8276, Günther, D, Düx, F, Naumann, M, Meyer, T F, and Rudel, T

Abstract

The porin (PorB) of Neisseria gonorrhoeae is an intriguing bacterial factor owing to its ability to translocate from the outer bacterial membrane into host cell membranes where it modulates the infection process. Here we report on the induction of programmed cell death after prolonged infection of epithelial cells with pathogenic Neisseria species. The underlying mechanism we propose includes translocation of the porin, a transient increase in cytosolic Ca2+ and subsequent activation of the Ca2+ dependent protease calpain as well as proteases of the caspase family. Blocking the porin channel by ATP eliminates the Ca2+ signal and also abolishes its pro-apoptotic function. The neisserial porins share structural and functional homologies with the mitochondrial voltage-dependent anion channels (VDAC). The neisserial porin may be an analogue or precursor of the ancient permeability transition pore, the putative central regulator of apoptosis.

Published
1999

31. Requirement of caspase-mediated cleavage of c-Abl during stress-induced apoptosis.

Author

Machuy, N, Rajalingam, K, and Rudel, T

Subjects
PROTEIN-tyrosine kinases, CELL cycle, APOPTOSIS, CELL death, TUMOR necrosis factors, SMALL interfering RNA
Abstract

c-Abl protein tyrosine kinase plays an important role in cell cycle control and apoptosis. Furthermore, induction of apoptosis correlates with the activation of c-Abl. Here, we demonstrate the cleavage of c-Abl by caspases during apoptosis. Caspases separate c-Abl into functional domains including a Src-kinase, a fragment containing nuclear import sequences, a fragment with an actin-binding domain and nuclear export sequence. Caspase cleavage increases the kinase activity of c-Abl as demonstrated by in vitro kinase assays as well as by auto- and substrate phosphorylation. Cells in which c-Abl expression was knocked down by RNA interference resisted cisplatin- but not TNFa-induced apoptosis. A similar selective resistance against cisplatin-induced apoptosis was observed when cleavage resistant c-Abl was overexpressed in treated cells. Our data suggest the selective requirement of c-Abl cleavage by caspases for stress-induced, but not for TNFa-induced apoptosis.Cell Death and Differentiation (2004) 11, 290-300. doi:10.1038/sj.cdd.4401336 Published online 5 December 2003 [ABSTRACT FROM AUTHOR]

Published
2004
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32. Neisseria gonorrhoeae porin modifies the oxidative burst of human professional phagocytes.

Author

Lorenzen, D R, Günther, D, Pandit, J, Rudel, T, Brandt, E, and Meyer, T F

Abstract

A hallmark of infection with the gram-negative bacterium Neisseria gonorrhoeae is the local infiltration and subsequent activation of polymorphonuclear neutrophils. Several gonococcal outer membrane proteins are involved in the interaction with and the activation of these phagocytes, including gonococcal porin, the most abundant protein in the outer membrane. Previous work suggests that this porin plays a role in various cellular processes, including inhibiting neutrophils activation and phagosome maturation in professional phagocytes. Here we investigated the ability of porin to modify the oxidative metabolism of human peripheral blood neutrophils and monocytes in response to particulate stimuli (including live gonococci) and soluble agents. The activation of the oxidative metabolism was determined by chemiluminescence amplified with either luminol or lucigenin. We found that treatment of the phagocytes with porin inhibits the release of reactive oxygen species measured as luminol-enhanced chemiluminescence in response to zymosan, latex particles, and gonococci. The engulfment of these particles was not, however, affected by porin treatment. Similar effects of porin on the chemiluminescence response were observed in cytochalasin B-treated neutrophils exposed to the soluble chemotactic peptide N-formylmethionyl-leucyl-phenylalanine. This indicates that porin selectively inhibits granule fusion with those cellular membranes that are in direct contact with porin, namely, the phagosomal and plasma membranes. This porin-induced downregulation of oxidative metabolism may be a potent mechanism by which gonococci modulate oxygen-dependent reactions by activated phagocytes at inflammation sites.

Published
2000

34. Review: Emissions Trading: An Exercise on Reforming Pollution Policy, Urbanization in the World-Economy, Communities in Crisis, a Systems Approach to Social Impact Assessment: Two Alaskan Case Studies, Concorde and Dissent: Explaining High Technology Project Failures in Britain and France, Analytical Urban Geography: Spatial Patterns and Theories, People in Cities: The Urban Environment and its Effects, Cities in Crisis: The Political Economy of Urban Development in Post-War Britain, Basic Methods of Policy Analysis and Planning

Author

O'Riordan, T, King, A D, Kellerman, A, Solomon, B D, Hall, P, Rushton, G, Rudel, T K, Lovering, J, and De Cola, L

Published
1986
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35. Roles of PilC and PilE proteins in pilus-mediated adherence of Neisseria gonorrhoeae and Neisseria meningitidis to human erythrocytes and endothelial and epithelial cells.

Author

Scheuerpflug, I, Rudel, T, Ryll, R, Pandit, J, and Meyer, T F

Abstract

Unlike other type 4 pili, the neisserial pili consist of at least two distinct proteins, the highly variable major subunit PilE forming the pilus fiber and the tip-associated adhesin PilC. PilC protein purified either from gonococci or from Escherichia coli interacted with different human epithelial cell lines, primary epithelial and endothelial cells. The binding of PilC protein efficiently prevented the attachment of piliated Neisseria gonorrhoeae and Neisseria meningitidis to these cell types. Fluorescent beads coated with pili prepared from piliated wild-type N. gonorrhoeae also adhered to these cells, in contrast to beads coated with pili prepared from a piliated PilC-deficient mutant. In the latter case, the binding of fluorescent beads was restored after pretreatment of the pilus-loaded beads with purified PilC. Piliated wild-type N. gonorrhoeae, the piliated PilC-deficient mutant, and N. gonorrhoeae pili assembled in Pseudomonas aeruginosa agglutinated human erythrocytes, while nonpiliated gonococci did not. Consistently, purified PilC did not agglutinate or bind to human erythrocytes, suggesting that N. gonorrhoeae PilE is responsible for pilus-mediated hemagglutination.

Published
1999

36. Crowds and Strategies for Avoiding Them in a Densely Settled Region

Author

Rudel, T K

Abstract

In this paper, data from interviews with residents of the New York metropolitan area are used to examine the relationship between crowding and the adoption of strategies for avoiding crowds. The analyses reveal major differences between recreational and maintenance activities in the frequency with which participants experience crowding and plan to avoid it. Stage in the life cycle and the population density of the place of residence predict the frequency with which individuals encounter crowded conditions. Plans for avoiding crowds are closely linked with the individual's experience of crowding, especially in recreational activities. The implications of these findings for research and policy are briefly explored.

Published
1985
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38. Guidelines for the use and interpretation of assays for monitoring cell death in higher eukaryotes

Author

Green, D. R., Morselli, E., Cidlowski, J. A., Bazan, N. G., Rudel, T., Zhivotovsky, B., Cohen, G. M., Youle, R. J., Kornbluth, S., Hardwick, J. M., Martin, S. J., De Laurenzi, V., Lugli, E., De Maria, R., Penninger, J., Deshmukh, M., Kumar, S., Andrews, D. W., Kimchi, A., Kroemer, G., Scorrano, L., Dynlacht, B. D., Melino, G., Madeo, F., Piacentini, M., Hajnóczky, G., Peter, M. E., Aaronson, S. A., Tsujimoto, Y., Rizzuto, R., Medema, J. P., Nicotera, P., El-Deiry, W. S., Nuñez, G., Jäättelä, M., Hengartner, M. O., Rodrigues, C. M.P., Marine, J. C.W., Ciechanover, A., Yuan, J., Alnemri, E. S., Rubinsztein, D. C., Fulda, S., Rabinovich, G. A., Galluzzi, L., Garrido, C., Malorni, W., Blomgren, K., Levine, B., Puthalakath, H., Nicholson, D. W., Vitale, I., Golstein, P., Knight, R. A., Castedo, M., Abrams, J., Mehlen, P., Vousden, K. H., Ichijo, H., Vandenabeele, P., Simon, H. U., Bredesen, D. E., Moll, U. M., Prehn, J. H.M., Klionsky, D. J., Gronemeyer, H., Flavell, R. A., Gougeon, M. L., Nagata, S., Steller, H., Kepp, O., Borner, C., Pervaiz, S., Baehrecke, E. H., Brenner, C., Oren, M., Lipton, S. A., Tschopp, J., and Blagosklonny, M. V.

Subjects
3. Good health
Abstract

Cell death is essential for a plethora of physiological processes, and its deregulation characterizes numerous human diseases. Thus, the in-depth investigation of cell death and its mechanisms constitutes a formidable challenge for fundamental and applied biomedical research, and has tremendous implications for the development of novel therapeutic strategies. It is, therefore, of utmost importance to standardize the experimental procedures that identify dying and dead cells in cell cultures and/or in tissues, from model organisms and/or humans, in healthy and/or pathological scenarios. Thus far, dozens of methods have been proposed to quantify cell death-related parameters. However, no guidelines exist regarding their use and interpretation, and nobody has thoroughly annotated the experimental settings for which each of these techniques is most appropriate. Here, we provide a nonexhaustive comparison of methods to detect cell death with apoptotic or nonapoptotic morphologies, their advantages and pitfalls. These guidelines are intended for investigators who study cell death, as well as for reviewers who need to constructively critique scientific reports that deal with cellular demise. Given the difficulties in determining the exact number of cells that have passed the point-of-no-return of the signaling cascades leading to cell death, we emphasize the importance of performing multiple, methodologically unrelated assays to quantify dying and dead cells.

42. Host glycoprotein Gp96 and scavenger receptor SREC interact with PorB of disseminating Neisseria gonorrhoeae in an epithelial invasion pathway

Author

Cindy Rechner, Hansjörg Schild, Christiane Kühlewein, Anne Müller, Thomas Rudel, University of Zurich, and Rudel, T

Subjects
Serotype, Cancer Research, MICROBIO, 2405 Parasitology, Porins, Biology, medicine.disease_cause, Endoplasmic Reticulum, Microbiology, Bacterial Adhesion, law.invention, Gonorrhea, law, Virology, Immunology and Microbiology(all), medicine, Animals, Humans, Scavenger receptor, Receptor, Molecular Biology, Cells, Cultured, chemistry.chemical_classification, Membrane Glycoproteins, 10061 Institute of Molecular Cancer Research, 2404 Microbiology, Epithelial Cells, Neisseria gonorrhoeae, Scavenger Receptors, Class F, chemistry, Porin, 2406 Virology, Recombinant DNA, 570 Life sciences, biology, Parasitology, Glycoprotein, Bacterial outer membrane, Protein Binding
Abstract

Neisseria gonorrhoeae expresses numerous surface proteins that mediate bacterial adherence and invasion during infection. Gonococci expressing serotype A of the major outer membrane porin PorB (PorB(IA)) are frequently isolated from patients with severe disseminating infections. PorB(IA) triggers efficient adherence and invasion under low phosphate conditions mimicking systemic bloodstream infections. Here, we identify the human heat shock glycoprotein Gp96 and the scavenger receptor SREC as PorB(IA)-specific receptors. Gonococci expressing PorB(IA), but not those expressing PorB serotype B instead, bind to purified native or recombinant Gp96. Depletion of Gp96 from host cells prevented adherence but significantly triggered gonococcal invasion. Furthermore, such invasion was blocked by chemical inhibitors of scavenger receptors, and we identified SREC as the scavenger receptor involved in PorB(IA)-dependent invasion. Thus, we establish Gp96 as an anti-invasion factor and SRECs as receptors mediating host cell entry of highly invasive disseminating gonococci.

Published
2007

43. Designing the Aplysia punctata Arginine-Depleting Enzyme for Tumor Targeting.

Author

Wolkersdorfer AM, Endo Y, Kehrein J, Kappus M, Hattori S, Gutmann M, Rudel T, Caliskan N, Lühmann T, Kato Y, and Meinel L

Subjects
Animals, Humans, Mice, Cell Line, Tumor, Female, Amino Acid Oxidoreductases metabolism, Amino Acid Oxidoreductases genetics, Xenograft Model Antitumor Assays, Polyethylene Glycols chemistry, Mice, Nude, Receptor, ErbB-2 metabolism, Receptor, ErbB-2 genetics, Aplysia, Arginine metabolism
Abstract

l-Amino acid oxidases (LAAO) deaminate amino acids to α-keto acids and generate hydrogen peroxide, a reactive oxygen species (ROS) with potential value for cancer therapy. We recombinantly expressed the LAAO from Aplysia punctata , called APIT (Cuvier 1803). The resulting wild-type APIT (APIT wt ) was conjugated to polyethylene glycol (APIT-PEG). Furthermore, an APIT mutant with an affibody targeting the human epidermal growth factor receptor 2 (HER2; zHER2-APIT) was genetically engineered resulting in a binding affinity K D of ∼ 2.2 nM to the HER2 receptor ectodomain. Further, we evaluated if the APIT and tumor-targeted APIT can be used as an APIT-drug conjugate by covalently amidating the lysine residues on the protein surface. However, for the HER2-targeted APIT, the affibody contains lysines as well, and amidation of these lysines could have impaired the affibody's affinity to the HER2 receptor. Therefore, we designed a lysine-free variant of the tumor-targeting part of zHER2-APIT using an in silico mutation analysis, suggesting the replacement of the lysines of the affibody by arginine or alanine. This new variant is referred to as zHER2(K-del)-APIT. To simulate a covalent drug loading to APIT and the targeting constructs, we attached biotin by amidation. Biotin-zHER2(K-del)-APIT successfully allowed binding to HER2-positive but not HER2-negative cells in vitro . The biodistribution of these novel constructs was tested in xenografted mice with a HER2-positive and negative tumor in each animal. The zHER2(K-del)-APIT lost its ability to target HER2-positive tumors despite the in vitro data suggesting otherwise. The zHER2-APIT accumulated within the HER2-positive tumors but not in the negative tumors. APIT-PEG had increased uptake in HER2-positive and negative tumors compared to APIT wt , which can be attributed to a prolonged serum half-life achieved by PEGylation, due to the absence of any tumor-targeting effect. These biodistribution studies point to HER2-targeting LAAOs for cancer therapy and PEGylation increasing tumor accumulation.

Published
2025
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44. A Multicellular In Vitro Model of the Human Intestine with Immunocompetent Features Highlights Host-Pathogen Interactions During Early Salmonella Typhimurium Infection.

Author

Damigos S, Caliskan A, Wajant G, Giddins S, Moldovan A, Kuhn S, Putz E, Dandekar T, Rudel T, Westermann AJ, and Zdzieblo D

Abstract

Studying the molecular basis of intestinal infections caused by enteric pathogens at the tissue level is challenging, because most human intestinal infection models have limitations, and results obtained from animals may not reflect the human situation. Infections with Salmonella enterica serovar Typhimurium (STm) have different outcomes between organisms. 3D tissue modeling of primary human material provides alternatives to animal experimentation, but epithelial co-culture with immune cells remains difficult. Macrophages, for instance, contribute to the immunocompetence of native tissue, yet their incorporation into human epithelial tissue models is challenging. A 3D immunocompetent tissue model of the human small intestine based on decellularized submucosa enriched with monocyte-derived macrophages (MDM) is established. The multicellular model recapitulated in vivo-like cellular diversity, especially the induction of GP2 positive microfold (M) cells. Infection studies with STm reveal that the pathogen physically interacts with these M-like cells. MDMs show trans-epithelial migration and phagocytosed STm within the model and the levels of inflammatory cytokines are induced upon STm infection. Infected epithelial cells are shed into the supernatant, potentially reflecting an intracellular reservoir of invasion-primed STm. Together, the 3D model of the human intestinal epithelium bears potential as an alternative to animals to identify human-specific processes underlying enteric bacterial infections., (© 2025 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Published
2025
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45. Linkage-specific ubiquitin binding interfaces modulate the activity of the chlamydial deubiquitinase Cdu1 towards poly-ubiquitin substrates.

Author

Schlötzer J, Schmalix A, Hügelschäffer S, Rieger D, Sauer F, Tully MD, Rudel T, Wiesner S, and Kisker C

Subjects
Substrate Specificity, Humans, Protein Binding, Deubiquitinating Enzymes metabolism, Ubiquitin metabolism, Ubiquitination, Chlamydia Infections metabolism, Chlamydia Infections microbiology, Chlamydia trachomatis metabolism, Polyubiquitin metabolism, Bacterial Proteins metabolism, Bacterial Proteins genetics
Abstract

The chlamydial deubiquitinase Cdu1 of the obligate intracellular human pathogenic bacterium Chlamydia trachomatis plays important roles in the maintenance of chlamydial infection. Despite the structural similarities shared with its homologue Cdu2, both DUBs display remarkable differences in their enzymatic activity towards poly-UB chain substrates. Whereas Cdu1 is highly active towards K48- and K63- poly-UB chains, Cdu2 activity is restricted mostly to mono-UB substrates. Here, we shed light on the molecular mechanisms of the differential activity and the substrate specificity of Cdu1 to better understand the cellular processes it is involved in, including infection-related events. We found that the strikingly elevated activity of Cdu1 relative to its paralogue Cdu2 can be attributed to an N-terminally extended α-helix, which has not been observed in Cdu2. Moreover, by employing isothermal titration calorimetry and nuclear magnetic resonance spectroscopy, we demonstrate the differential recognition of K48- and K63-linked poly-UB substrates by Cdu1. Whereas K63-linked poly-UB substrates appear to be recognized by Cdu1 with only two independent ubiquitin interaction sites, up to four different binding interfaces are present for K48-linked ubiquitin chains. Combined, our data suggest that Cdu1 possesses a poly-UB chain directed activity that may enable its function as a multipurpose DUB with a broad substrate specificity., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Schlötzer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Published
2024
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46. Interactions of SARS-CoV-2 with Human Target Cells-A Metabolic View.

Author

Eisenreich W, Leberfing J, Rudel T, Heesemann J, and Goebel W

Subjects
Humans, Host-Pathogen Interactions, Glycolysis, Virus Replication, Pentose Phosphate Pathway, Citric Acid Cycle, SARS-CoV-2 metabolism, SARS-CoV-2 physiology, COVID-19 metabolism, COVID-19 virology
Abstract

Viruses are obligate intracellular parasites, and they exploit the cellular pathways and resources of their respective host cells to survive and successfully multiply. The strategies of viruses concerning how to take advantage of the metabolic capabilities of host cells for their own replication can vary considerably. The most common metabolic alterations triggered by viruses affect the central carbon metabolism of infected host cells, in particular glycolysis, the pentose phosphate pathway, and the tricarboxylic acid cycle. The upregulation of these processes is aimed to increase the supply of nucleotides, amino acids, and lipids since these metabolic products are crucial for efficient viral proliferation. In detail, however, this manipulation may affect multiple sites and regulatory mechanisms of host-cell metabolism, depending not only on the specific viruses but also on the type of infected host cells. In this review, we report metabolic situations and reprogramming in different human host cells, tissues, and organs that are favorable for acute and persistent SARS-CoV-2 infection. This knowledge may be fundamental for the development of host-directed therapies.

Published
2024
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47. Trifunctional sphingomyelin derivatives enable nanoscale resolution of sphingomyelin turnover in physiological and infection processes via expansion microscopy.

Author

Rühling M, Kersting L, Wagner F, Schumacher F, Wigger D, Helmerich DA, Pfeuffer T, Elflein R, Kappe C, Sauer M, Arenz C, Kleuser B, Rudel T, Fraunholz M, and Seibel J

Subjects
Humans, Fluorescence Resonance Energy Transfer methods, HeLa Cells, Chlamydia Infections metabolism, Chlamydia Infections microbiology, Microscopy methods, Sphingomyelins metabolism, Sphingomyelin Phosphodiesterase metabolism, Chlamydia trachomatis metabolism, Cell Membrane metabolism
Abstract

Sphingomyelin is a key molecule of sphingolipid metabolism, and its enzymatic breakdown is associated with various infectious diseases. Here, we introduce trifunctional sphingomyelin derivatives that enable the visualization of sphingomyelin distribution and sphingomyelinase activity in infection processes. We demonstrate this by determining the activity of a bacterial sphingomyelinase on the plasma membrane of host cells using a combination of Förster resonance energy transfer and expansion microscopy. We further use our trifunctional sphingomyelin probes to visualize their metabolic state during infections with Chlamydia trachomatis and thereby show that chlamydial inclusions primarily contain the cleaved forms of the molecules. Using expansion microscopy, we observe that the proportion of metabolized molecules increases during maturation from reticulate to elementary bodies, indicating different membrane compositions between the two chlamydial developmental forms. Expansion microscopy of trifunctional sphingomyelins thus provides a powerful microscopy tool to analyze sphingomyelin metabolism in cells at nanoscale resolution., (© 2024. The Author(s).)

Published
2024
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48. Infection of human organoids supports an intestinal niche for Chlamydia trachomatis.

Author

Hovhannisyan P, Stelzner K, Keicher M, Paprotka K, Neyazi M, Pauzuolis M, Ali WM, Rajeeve K, Bartfeld S, and Rudel T

Subjects
Humans, Intestinal Mucosa microbiology, Epithelial Cells microbiology, Antigens, Bacterial metabolism, Bacterial Proteins, Chlamydia trachomatis physiology, Organoids microbiology, Organoids pathology, Chlamydia Infections microbiology
Abstract

Several reports suggest that intestinal tissue may be a natural niche for Chlamydia trachomatis infection and a reservoir for persistent infections in the human body. Due to the human specificity of the pathogen and the lack of suitable host models, there is limited knowledge on this topic. In our study, we modelled the course of the chlamydial infection in human primary gastrointestinal (GI) epithelial cells originating from patient-derived organoids. We show that GI cells are resistant to apical infection and C. trachomatis needs access to the basolateral membrane to establish an infection. Transmission electron microscopy analysis reveals the presence of both normal as well as aberrant chlamydial developmental forms in the infected cells, suggesting a possible cell-type specific nature of the infection. Furthermore, we show that the plasmid-encoded Pgp3 is an important virulence factor for the infection of human GI cells. This is the first report of C. trachomatis infection in human primary intestinal epithelial cells supporting a possible niche for chlamydial infection in the human intestinal tissue., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Hovhannisyan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Published
2024
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49. The JMU-SalVac-System: A Novel, Versatile Approach to Oral Live Vaccine Development.

Author

Iwanowitsch A, Diessner J, Bergmann B, and Rudel T

Abstract

Salmonella enterica Serovar Typhi Ty21a (Ty21a) is the only licensed oral vaccine against typhoid fever. Due to its excellent safety profile, it has been used as a promising vector strain for the expression of heterologous antigens for mucosal immunization. As the efficacy of any bacterial live vector vaccine correlates with its ability to express and present sufficient antigen, the genes for antigen expression are traditionally located on plasmids with antibiotic resistance genes for stabilization. However, for use in humans, antibiotic selection of plasmids is not applicable, leading to segregational loss of the antigen-producing plasmid. Therefore, we developed an oral Ty21a-based vaccine platform technology, the JMU-SalVac-system (Julius-Maximilians-Universität Würzburg) in which the antigen delivery plasmids (pSalVac-plasmid-series) are stabilized by a Δ tyrS / tyrS + -based balanced-lethal system (BLS). The system is made up of the chromosomal knockout of the essential tyrosyl-tRNA-synthetase gene ( tyrS ) and the in trans complementation of tyrS on the pSalVac-plasmid. Further novel functional features of the pSalVac-plasmids are the presence of two different expression cassettes for the expression of protein antigens. In this study, we present the construction of vaccine strains with BLS plasmids for antigen expression. The expression of cytosolic and secreted mRFP and cholera toxin subunit B (CTB) proteins as model antigens is used to demonstrate the versatility of the approach. As proof of concept, we show the induction of previously described in vivo inducible promoters cloned into pSalVac-plasmids during infection of primary macrophages and demonstrate the expression of model vaccine antigens in these relevant human target cells. Therefore, antigen delivery strains developed with the JMU-SalVac technology are promising, safe and stable vaccine strains to be used against mucosal infections in humans.

Published
2024
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50. PEGylated Recombinant Aplysia punctata Ink Toxin Depletes Arginine and Lysine and Inhibits the Growth of Tumor Xenografts.

Author

Wolkersdorfer AM, Bergmann B, Adelmann J, Ebbinghaus M, Günther E, Gutmann M, Hahn L, Hurwitz R, Krähmer R, Leenders F, Lühmann T, Schueler J, Schmidt L, Teifel M, Meinel L, and Rudel T

Subjects
Animals, Humans, Mice, Xenograft Model Antitumor Assays, Marine Toxins pharmacology, Marine Toxins therapeutic use, Marine Toxins chemistry, Recombinant Proteins pharmacology, Recombinant Proteins therapeutic use, L-Amino Acid Oxidase pharmacology, L-Amino Acid Oxidase metabolism, L-Amino Acid Oxidase chemistry, Female, Cell Line, Tumor, Arginine pharmacology, Arginine chemistry, Lysine pharmacology, Lysine chemistry, Polyethylene Glycols chemistry, Polyethylene Glycols pharmacology, Aplysia
Abstract

In recent years, a novel treatment method for cancer has emerged, which is based on the starvation of tumors of amino acids like arginine. The deprivation of arginine in serum is based on enzymatic degradation and can be realized by arginine deaminases like the l-amino acid oxidase found in the ink toxin of the sea hare Aplysia punctata . Previously isolated from the ink, the l-amino acid oxidase was described to oxidate the essential amino acids l-lysine and l-arginine to their corresponding deaminated alpha-keto acids. Here, we present the recombinant production and functionalization of the amino acid oxidase Aplysia punctata ink toxin (APIT). PEGylated APIT (APIT-PEG) increased the blood circulation time. APIT-PEG treatment of patient-derived xenografted mice shows a significant dose-dependent reduction of tumor growth over time mediated by amino acid starvation of the tumor. Treatment of mice with APIT-PEG, which led to deprivation of arginine, was well tolerated.

Published
2024
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