THIS SECTION LISTS ARTICLES for further study related to each chapter. Many of these fields are rapidly evolving, and new articles are appearing almost daily. Several subjects are more obscure, with review articles that are much older. The articles chosen attempt to give a starting point from a much larger pool of research. Also, each review article has a long list of references.
These articles from the best journals do contain a significant amount of jargon that can be difficult. For example, describing a cellular conversation might include names and acronyms for signal molecules, molecular pathways, receptors, genes, and promoters and inhibitors of genes. A signal might be identified by multiple complex names at the same time. Because of this, I recommend review articles first, but these be may less current than single research articles.
There is a vast literature for many of the chapter subjects, but particularly for T cells, neurons, cancer, pain, and microbes. Also, there is considerable overlap with each of the areas of research. Several of the chapters describe concepts that are relatively recent, and there is less material.
While the book chapters just scratched the surface of cellular signaling activity for each cell described, giving complete bibliographies for all of the details mentioned is beyond the scope of these notes.
Chapter 1: Cells—They Talk About Everything!
This chapter combined four unrelated areas of research that are all proceeding at different rates. The most research has been on cellular clocks, with new findings almost daily in this arena. Several review articles are listed as an introduction. Questions about how cells maintain their appropriate size and their awareness of their own aging are relatively new, and there is limited research available.
How cells communicate about the shape of organs and limbs and where they are located in developing tissue is a new area of research that is quite complex. This chapter introduced chemical gradients, and a review article is listed. Very exciting research on electrical gradients is too complex for this book. For those interested in this new and developing field, I have listed a review article by Michael Levin, one of the pioneers in this research.
Campisi, J., Kapahi P., Lithgow, G. J., Melov, S., Newman, J. C., & Verdin, E. (2019). “From discoveries in ageing research to therapeutics for healthy ageing.” Nature, 571, 183–192. https://doi.org/10.1038/s41586-019-1365-2.
Ginzberg, M. B., Kafri, R., & Kirschner, M. (2015). “Cell biology. On being the right (cell) size.” Science, 348 (6236), 771–775. https://doi.org/10.1126/science.1245075.
Greco, C. M., & Sassone–Corsi, P. (2019). “Circadian blueprint of metabolic pathways in the brain.” Nature Reviews Neuroscience, 20, 71–82. https://doi.org/10.1038/s41583-018-0096-y.
Johnson, C. H., Zhao, C., Xu, Y., & Mori, T. (2017). “Timing the day: what makes bacterial clocks tick?” Nature Reviews Microbiology, 15, 232–242. https://doi.org/10.1038/nrmicro.2016.196.
Lander, A. D. (2013). “How Cells Know Where They Are.” Science, 339 (6122), 923–927. https://doi.org/10.1126/science.1224186.
Levin, M., & Martyniuk, C. J. (2018). “The bioelectric code: An ancient computational medium for dynamic control of growth and form.” BioSystems, 164, 76–93. https://doi.org/10.1016/j.biosystems.2017.08.009.
Si, F., Le Treut, G., Sauls, J. T., Vadia, S., Levin, P. A., & Jun, S. (2019). “Mechanistic Origin of Cell-Size Control and Homeostasis in Bacteria.” Current Biology, 29 (11), 1760–1770. https://doi.org/10.1016/j.cub.2019.04.062.
Willis, L., & Huang, K. C. (2017). “Sizing up the bacterial cell cycle.” Nature Reviews Microbiology, 15, 606–620. https://doi.org/10.1038/nrmicro.2017.79.
Chapter 2: Signals for Migrating White Blood Cells
There is extensive research on newly discovered functions of white blood cells, including their ability to travel in all types of terrain and the signaling that enables their transit. Individual research articles describe how cells move with rapidly changing scaffolds. Details are emerging about how organelles are carried during movement. Multiple studies describe the recently discovered signals for white blood cells to get to infections. Also, an exciting area of research involves white blood cell signals as they die at the site of infections.
Buckley, C. D., & McGettrick, H. M. (2018). “Leukocyte trafficking between stromal compartments: lessons from rheumatoid arthritis.” Nature Reviews Rheumatology, 14, 476–487. https://doi.org/10.1038/s41584-018-0042-4.
de Oliveira, S., Rosowski, E. E., & Huttenlocher, A. (2016). “Neutrophil migration in infection and wound repair: going forward in reverse.” Nature Reviews Immunology, 16, 378–391. https://doi.org/10.1038/nri.2016.49.
Huse, M. (2017). “Mechanical forces in the immune system.” Nature Reviews Immunology, 17, 679–690. https://doi.org/10.1038/nri.2017.74.
Németh, T., Sperandio, M., & Mócsai, A. (2020). “Neutrophils as emerging therapeutic targets.” Nature Reviews Drug Discovery. https://doi.org/10.1038/s41573-019-0054-z.
Soehnlein, O., Steffens, S., Hidalgo, A., & Weber, C. (2017). “Neutrophils as protagonists and targets in chronic inflammation.” Nature Reviews Immunology, 17, 248–259. https://doi.org/10.1038/nri.2017.10.
Vestweber, D. (2015). “How leukocytes cross the vascular Endothelium.” Nature Reviews Immunology, 15, 692–702. https://doi.org/10.1038/nri3908.
Weninger, W., Biro, M., & Jain, R. (2014). “Leukocyte migration in the interstitial space of non-lymphoid organs.” Nature Reviews Immunology, 14, 232–244. https://doi.org/10.1038/nri3641.
Chapter 3: T Cells—Masters of Immunity
It is impossible to represent the extensive research into T cells in a small number of review articles. Articles here were chosen out of a sample of more than fifty. The most important findings are occurring now and are presented not in review articles but as single-study research in a broad range of fields spanning infections, cancer, neuroscience, pain, and psychiatric disorders, among others.
Chapman, N. M., Boothby, M. R., & Chi, H. (2020). “Metabolic coordination of T cell quiescence and activation.” Nature Reviews Immunology, 20, 55–70. https://doi.org/10.1038/s41577-019-0203-y.
de la Roche, M., Asano, Y., & Griffiths, G. M. (2016). “Origins of the cytolytic synapse.” Nature Reviews Immunology, 16, 421–432. https://doi.org/10.1038/nri.2016.54.
Gaud, G., Lesourne, R., & Love, P. (2018). “Regulatory mechanisms in T cell receptor signaling.” Nature Reviews Immunology, 18, 485–497. https://doi.org/10.1038/s41577-018-0020-8.
Kipnis, J., Gadani, S., & Derecki, N. C. (2012). “Pro-cognitive properties of T cells.” Nature Reviews Immunology, 12, 663–669. https://doi.org/10.1038/nri3280.
Klein, L., Kyewski, B., Allen, P. M., & Hogguist, K. A. (2014). “Positive and negative selection of the T cell repertoire: what thymocytes see (and don’t see).” Nature Reviews Immunology, 14, 377–391. https://doi.org/10.1038/nri3667.
Korn, T. & Kallies, A. (2017). “T cell responses in the central nervous system.” Nature Reviews Immunology, 17, 179–194. https://doi.org/10.1038/nri.2016.144.
Li, M. O, & Rudensky, A. Y. (2016). “T cell receptor signaling in the control of regulatory T cell differentiation and function.” Nature Reviews Immunology, 16, 220–233. https://doi.org/10.1038/nri.2016.26.
Love, P. E., & Bhandoola, A. (2011). “Signal integration and crosstalk during thymocyte migration and emigration.” Nature Reviews Immunology, 11, 469–477. https://doi.org/10.1038/nri2989.
Lu, L., Barbi, J., & Pan, F. (2017). “The regulation of immune tolerance by FOXP3.” Nature Reviews Immunology, 17, 703–717. https://doi.org/10.1038/nri.2017.75.
Sasson, S. C., Gordon, C. L., Christo, S. N., Klenerman, P., & Mackay, L. K. (2020). “Local heroes or villains: tissue-resident memory T cells in human health and disease.” Cellular & Molecular Immunology, 17, 113–122. https://doi.org/10.1038/s41423-019-0359-1.
Sharpe, A. H., & Pauken, K. E. (2018). “The diverse functions of the PD1 inhibitory pathway.” Nature Reviews Immunology, 18, 153–167. https://doi.org/10.1038/nri.2017.108.
Takahama, Y., Ohigashi, I., Baik, S., & Anderson, G. (2017). “Generation of diversity in thymic epithelial cells.” Nature Reviews Immunology, 17, 295–305. https://doi.org/10.1038/nri.2017.12.
Chapter 4: Capillaries—the “Brain Centers” of Tissue Development
The complexity of capillary functions is just now emerging. Slowly, the wide range of unique capillaries in each organ is being unearthed. Unlike the literature on T cells, the literature on capillaries is not vast, but studies are unraveling the unique ways that capillaries are linked with nearby organs. A search of recent research should include the unique capillary niches in specific organs and the unusual behavior of pericytes.
Clements, W. K. & Traver, D. (2013). “Signalling pathways that control vertebrate haematopoietic stem cell specification.” Nature Reviews Immunology, 13, 336–348. https://doi.org/10.1038/nri3443.
Crivellato, E., & Ribatti, D. (2006). “Aristotle: the first student of angiogenesis.” Leukemia, 20, 1209–1210. https://doi.org/10.1038/sj.leu.2404256.
Gómez-Gaviro, M. V., Lovell-Badge, R., Fernández-Avilés, F., & Lara-Pezzi, E. (2012). “The vascular stem cell niche.” Journal of Cardiovascular Translational Research, 5, 618–630. https://doi.org/10.1007/s12265-012-9371-x.
Griffin, C. T, & Gao S. (2017). “Building discontinuous liver sinusoidal vessels.” Journal of Clinical Investigation, 127 (3), 790–792. https://doi.org/10.1172/JCI92823.
Hall, C. N., Reynell, C., Gesslein, B., Hamilton, N. B., Mishra, A., Sutherland, B. A., O’Farrell, F. M., Buchan, A. M., Lauritzen, M., & Attwell, D. (2014). “Capillary pericytes regulate cerebral blood flow in health and disease.” Nature, 508, 55–60. https://doi.org/10.1038/nature13165.
Robbins, P. D., & Morelli, A. E. (2014). “Regulation of immune responses by extracellular vesicles.” Nature Reviews Immunology, 14, 195–208. https://doi.org/10.1038/nri3622.
Sivaraj, K. K., & Adams, R. H. (2016). “Blood vessel formation and function in bone.” Development, 143, 2706–2715. https://doi.org/10.1242/dev.136861.
Spadoni, I., Fornasa, G., & Rescigno, M. (2017). “Organ-specific protection mediated by cooperation between vascular and epithelial barriers.” Nature Reviews Immunology, 17, 761–773. https://doi.org/10.1038/nri.2017.100.
Thomas, J. L. “Orchestrating cortical brain development.” Science, 361 (6404), 754–755. https://doi.org/10.1126/science.aau7155.
Chapter 5: Platelets—Much More Than a Plug
It was a big surprise to find that platelets also engage in elaborate signaling as first responders to trauma and infections, and continue to communicate with white blood cells and capillary and tissue cells about fighting microbes. Recent research shows platelet signaling in cancer. This is a slowly evolving literature.
Bye, A. P., Unsworth, A. J., & Gibbins, J. M. (2016). “Platelet signaling: a complex interplay between inhibitory and activatory networks.” Journal of Thrombosis and Haemostasis, 14 (5), 918–930. https://doi.org/10.1111/jth.13302.
Cloutier, N., Allaeys, I., Marcoux, G., Machlus, K. R., Mailhot, B., Zufferey, A., Levesque, T., Becker, Y., Tessandier, N., Melki, I., Zhi, H., Poirier, G., Rondina, M. T., Italiano, J. E., Flamand, L., McKenzie, S. E., Cote, F., Nieswandt, B., Khan, W. I., . . . Boilard, E. (2018). “Platelets release pathogenic serotonin and return to circulation after immune complex mediated sequestration.” Proceedings of the National Academy of Sciences of the United States of America, 115 (7), E11550–E1559. https://doi.org/10.1073/pnas.1720553115.
Estevez, B. & Du, X. (2017). “New Concepts and Mechanisms of Platelet Activation Signaling.” Physiology, 32, 162–177. https://doi.org/10.1152/physiol.00020.2016.
Hamzeh-Cognasse, H., Damien, P., Chabert, A., Pozzetto, B., Cognasse, F., & Garraud, O. (2015). “Platelets and Infections—complex interactions with Bacteria.” Frontiers in Immunology, 6 (82), 1–18. https://doi.org/10.3389/fimmu.2015.00082.
Qiu, Y., Brown, A. C., Myers, D. R., Sakurai, Y., Mannino, R. G., Tran, R., Ahn. B., Hardy, E. T., Kee, M. F., Kumar, S., Bao, G., Barker, T. H., & Lam, W. A. (2014). “Platelet mechanosensing of substrate stiffness during clot formation mediates adhesions, spreading, and activation.” Proceedings of the National Academy of Sciences of the United States of America, 111 (40), 14430–14435. https://doi.org/10.1073/pnas.1322917111.
Sreeramkumar, V., Adrover, J. M., Ballesteros, I., Cuartero, M. I., Rossaint, J., Bilbao, I., Nácher, M., Pitaval, C., Radovanovic, I., Fukui, Y., McEver, R. P., Filippi, M. D., Lizasoain, I., Ruiz-Cabello, J., Zarbock, A., Moro, M. A., & Hidalgo, A. (2014). “Neutrophils scan for activated platelets to initiate inflammation.” Science, 346 (6214), 1234–1238. https://doi.org/10.1126/science.1256478.
Yeaman, M. R. (2014). “Platelets: at the nexus of antimicrobial defense.” Nature Reviews Microbiology, 12, 426–437. https://doi.org/10.1038/nrmicro3269.
Chapter 6: Conversations in the Gut
Research into gut lining cells is vast and evolving rapidly. There is a lot written about the effects of molecules from the gut influencing every other part of the body. These articles introduce conversations of gut lining cells with immune cells and microbes. These subjects overlap articles for the chapter on microbes in the gut.
Burgueño, J. F., & Abreu, M. T. (2020). “Epithelial Toll-like receptors and their role in gut homeostasis and disease.” Nature Reviews Gastroenterology & Hepatology. https://doi.org/10.1038/s41575-019-0261-4.
Clemmensen, C., Müller, T. D., Woods, S. C., Berthoud, H. R., Seeley, R. J., & Tschöp, M. H. (2017). “Gut-Brain Cross-Talk in Metabolic Control.” Cell, 168 (5), 758–774. https://doi.org/10.1016/j.cell.2017.01.025.
Jansen, M. (2019). “Marching out of the crypt: Intestinal epithelial cells actively migrate up the villus, challenging a long-held view.” Science, 365 (6454), 642–643. https://doi.org/10.1126/science.aay5861.
Johansson, M. E. V., & Hansson, G. C. (2016). “Immunological aspects of intestinal mucus and mucins.” Nature Reviews Immunology, 16, 639–649. https://doi.org/10.1038/nri.2016.88.
Koh, A., De Vadder, E., Kovatcheva-Datchary, P., & Bäckhed, F. (2016). “From Dietary Fiber to Host Physiology: Short-Chain Fatty Acids as Key Bacterial Metabolites.” Cell, 165 (6), 1332–1344. https://doi.org/10.1016/j.cell.2016.05.041.
Martens, E. C., Neumann, M., & Desai, M. S. (2018). “Interactions of commensal and pathogenic microorganisms with the intestinal mucosal barrier.” Nature Reviews Microbiology, 16, 457–470. https://doi.org/10.1038/s41579-018-0036-x.
Mowat, A. M., & Agace, W. W. (2014). “Regional specialization within the intestinal immune system.” Nature Reviews Immunology, 14, 667–685. https://doi.org/10.1038/nri3738.
Peterson, L. W. & Artis, D. (2014). “Intestinal epithelial cells: regulators of barrier function and immune homeostasis.” Nature Reviews Immunology, 14, 141–153. https://doi.org/10.1038/nri3608.
Tanoue, T., Atarashi, K., & Honda, K. (2016). “Development and maintenance of intestinal regulatory T cells.” Nature Reviews Immunology, 16, 295–309. https://doi.org/10.1038/nri.2016.36.
Veiga-Fernandes, H., & Mucida, D. (2016). “Neuro-Immune Interactions at Barrier Surfaces.” Cell, 165 (4), 801–811. https://doi.org/10.1016/j.cell.2016.04.041.
Yu, W., Freeland, D. M. H., & Nadeau, K. C. (2016). “Food allergy: immune mechanisms, diagnosis and immunotherapy.” Nature Reviews Immunology, 16, 751–765. https://doi.org/10.1038/nri.2016.111.
Chapter 7: Signaling Across the Skin Landscape
With many very exciting new findings about skin cells and their relation to immune cells and microbes, I have included reviews, as well as several recent single-study research papers. It has only recently been understood that, of all organs, there is the most signaling among immune cells on the skin because of the flat, barren landscape and inability to have lymph follicles nearby to rapidly help the surface. Individual research articles describe unique activity and signaling from fat cells, the behavior of an individual skin cell fighting cancer, how microbes regulate T cells for skin repair, and microbes protecting against cancer. Also included are essays about how skin cells remember and the recently discovered layer called the “interstitium.”
Alcorn, J. F., & Kolls, J. K. (2015). “Killer fat.” Science, 347 (6217), 26–27. https://doi.org/10.1126/science.aaa4567.
Belkaid, Y., & Tamoutounour, S. (2016). “The influence of skin microorganisms on cutaneous immunity.” Nature Reviews Immunology, 16, 353–366. https://doi.org/10.1038/nri.2016.48.
Benias, P. C., Wells, R. G., Sackey-Aboagye, B., Klavan, H., Reidy, J., Buonocore, D., Miranda, M., Kornacki, S., Wayne, M., Carr-Locke, D. L., & Theise, N. D. (2018). “Structure and Distribution of an Unrecognized Interstitium in Human Tissues.” Scientific Reports, 8, 1–8. https://doi.org/10.1038/s41598-018-23062-6.
Burclaff, J., & Mills, J. C. (2017). “Cell biology: Healthy skin rejects cancer.” Nature, 548 (7667), 289–290. https://doi.org/10.1038/nature23534.
Byrd, A. L., Belkaid, Y., & Segre, J. A. (2018). “The human skin microbiome.” Nature Reviews Microbiology, 16, 143–155. https://doi.org/10.1038/nrmicro.2017.157.
Ho, A. W., & Kupper, T. S. (2019). “T cells and the skin: from protective immunity to inflammatory skin disorders.” Nature Reviews Immunology, 19, 490–502. https://doi.org/10.1038/s41577-019-0162-3.
Kabashima, K., Honda, T., Ginhoux, F., & Egawa, G. (2019). “The immunological anatomy of the skin.” Nature Reviews Immunology, 19, 19–30. https://doi.org/10.1038/s41577-018-0084-5.
Naik, S. (2018). “The healing power of painful memories.” Science, 359 (6380), 1113. https://doi.org/10.1126/science.aat0963.
Nakatsuji, T., Chen, T. H., Butcher, A. M., Trzoss, L. L., Nam, S. J., Shirakawa, K. T., Zhou, W., Oh, J., Otto, M., Fenical, W., & Gallo, R. L. (2018). “A commensal strain of Staphylococcus epidermidis protects against skin neoplasia.” Science Advances, 4 (2), eaao4502. https://doi.org/10.1126/sciadv.aao4502.
Oh, J., & Unutmaz, D. (2019). “Immune cells for microbiota surveillance.” Science, 366 (6464), 419–421. https://doi.org/10.1126/science.aaz4014.
Chapter 8: Cancer Cells—the Ultimate Manipulators
From the vast research literature on cancer, these review articles describe some of the salient concepts of cancer signaling—conversations with immune cells, mitochondria, and microbes, as well as new signaling hubs and signaling techniques. In addition, there are research articles about exosomes, nanotubes, obesity, mesenchymal epithelial transitions, electrical synapses in brain cancers, and protection for traveling RNA signals. There is one article about exhausted T cells and one about how local cells become part of the cancer community. Because this field is so enormous, there are slightly more references.
Bommareddy, P. K., Shettigar, M., & Kaufman, H. L. (2018). “Integrating oncolytic viruses in combination cancer immunotherapy.” Nature Reviews Immunology, 18, 498–513. https://doi.org/10.1038/s41577-018-0014-6.
Braicu, C., Tomuleasa, C., Monroig, P., Cucuianu, A., Berindan-Neagoe, I., & Calin, G. A. (2015). “Exosomes as divine messengers: are they the Hermes of modern molecular oncology?” Cell Death and Differentiation, 22 (1), 34–45. https://doi.org/10.1038/cdd.2014.130.
D’Arcangelo, E., Wu, N. C., Cadavid, J. L., & McGuigan, A. P. (2020). “The life cycle of cancer-associated fibroblasts within the tumour stroma and its importance in disease outcome.” British Journal of Cancer. https://doi.org/10.1038/s41416-019-0705-1.
Dejana, E., & Lampugnani, M. G. (2018). “Endothelial cell transitions.” Science, 362 (6416) 746–747. https://doi.org/10.1126/science.aas9432.
DeNardo, D. G., & Ruffell, B. (2019). “Macrophages as regulators of tumor immunity and immunotherapy.” Nature Reviews Immunology, 19, 369–382. https://doi.org/10.1038/s41577-019-0127-6.
Elinav, E., Garrett, W. S., Trinchieri, G., & Wargo, J. (2019). “The cancer microbiome.” Nature Reviews Cancer, 19, 371–376. https://doi.org/10.1038/s41568-019-0155-3.
Font-Burgada, J., Sun, B., & Karin, M. (2016). “Obesity and Cancer: The Oil that Feeds the Flame.” Cell Metabolism, 23 (1), 48–62. https://doi.org/10.1016/j.cmet.2015.12.015.
Garner, H., & de Visser, K.E. (2020). “Immune crosstalk in cancer progression and metastatic spread: a complex conversation.” Nature Reviews Immunology. https://doi.org/10.1038/s41577-019-0271-z.
Huang, Y., Kim, B. Y. S., Chan, C. K., Hahn, S. M., Weissman, I. L., & Jiang, W. (2018). “Improving immune-vascular crosstalk for cancer immunotherapy.” Nature Reviews Immunology, 18, 195–203. https://doi.org/10.1038/nri.2017.145.
Kaiser, J. (2016). “Malignant messengers.” Science, 352 (6282), 164–166. https://doi.org/10.1126/science.352.6282.164.
Lambert, A. W., Pattabiraman, D. R., & Weinberg, R. A. (2017). “Emerging Biological Principles of Metastasis.” Cell, 168 (4), 670–691. https://doi.org/10.1016/j.cell.2016.11.037.
Li, J., & Stanger, B. Z. (2019). “The tumor as organizer model.” Science, 363 (6431), 1038–1039. https://doi.org/10.1126/science.aau9861.
Murillo, O. D., Thistlethwaite, W., Rozowsky, J., Subramanian, S. L., Lucero, R., Shah, N., Jackson, A. R., Srinivasan, S., Chung, A., Laurent, C. D., Kitchen, R. R., Galeev, T., Warrell, J., Diao, J. A., Welsh, J. A., Hanspers, K., Riutta, A., Burgstaller-Muehlbacher, S., Shah, R. V., . . . Milosavljevic, A. (2019). “exRNA Atlas Analysis Reveals Distinct Extracellular RNA Cargo Types and Their Carriers Present across Human Biofluids.” Cell, 177 (2), 463–477. E15. https://doi.org/10.1016/j.cell.2019.02.018.
Shaked, Y. (2019). “The pro-tumorigenic host response to cancer therapies.” Nature Reviews Cancer, 19, 667–685. https://doi.org/10.1038/s41568-019-0209-6.
Venkatesh, H. S. (2019). “The neural regulation of cancer.” Science, 366 (6468), 965. https://doi.org/10.1126/science.aaz7776.
Venkatesh, H. S., Morishita, W., Geraghty, A. C., Silverbush, D., Gillespie, S. M., Arzt, M., Tam, L. T., Espenel, C., Ponnuswami, A., Ni, L., Woo, P. J., Taylor, K. R., Agarwal, A., Regev, A., Brang, D., Vogel, H., Hervey-Jumper, S., Bergles, D. E., Suvà, M. L., . . . Monje, M. (2019). “Electrical and synaptic integration of glioma into neural circuits.” Nature, 573, 539–545. https://doi.org/10.1038/s41586-019-1563-y.
Vyas, S., Zaganjor, E., & Haigis, M. C. (2016). “Mitochondria and Cancer.” Cell, 166, 555–566. https://doi.org/10.1016/j.cell.2016.07.002.
Winkler, F., & Wick, W. (2018). “Harmful networks in the brain and beyond.” Science, 359 (638), 1100–1101. https://doi.org/10.1126/science.aar5555.
Zanconato, F., Cordenonsi, M., & Piccolo, S. (2019). “YAP and TAZ: a signaling hub of the tumour microenvironment.” Nature Reviews Cancer, 19, 454–464. https://doi.org/10.1038/s41568-019-0168-y.
Zhao, Y., Shao, Q., & Peng, G. (2020). “Exhaustion and senescence: two crucial dysfunctional states of T cells in the tumor microenvironment.” Cellular & Molecular Immunology, 17 (1), 27–35. https://doi.org/10.1038/s41423-019-0344-8.
Chapter 9: The World of Neurons
Like cancer, T cells, and microbes, research into neurons is massive. Here there is a smattering of articles related to the limited subjects covered in the chapter. These describe types of signaling that occur beyond neuronal circuits. Review articles describe maintenance of neuronal identity, electrical synapses, and communication with immune cells and cancer cells. Individual research articles include brain waste removal, neurogenesis, and rapid vesicle turnover at synapses. Several articles describe advances in signaling with brain waves in memory regions and the new research into electrical patterns that are not brain waves or axon electrical activity.
Alcamí, P., & Pereda, A. E. (2019). “Beyond plasticity: the dynamic impact of electrical synapses on neural circuits.” Nature Reviews Neuroscience, 20, 253–271. https://doi.org/10.1038/s41583-019-0133-5.
Bentley, M., & Banker, G. (2016). “The cellular mechanisms that maintain neuronal polarity.” Nature Reviews Neuroscience, 17, 611–622. https://doi.org/10.1038/nrn.2016.100.
Boilly, B., Faulkner, S., Jobling, P., & Hondermarck, H. (2017). “Nerve Dependence: From Regeneration to Cancer.” Cancer Cell, 31 (3), 342–354. https://doi.org/10.1016/j.ccell.2017.02.005.
Boldrini, M., Fulmore, C. A., Tartt, A. N., Simeon, L. R., Pavlova, I., Poposka, V., Rosoklija, G. B., Stankov, A., Arango, V., Dwork, A., Hen, R., & Mann, J. J. (2018). “Human Hippocampal Neurogenesis Persists throughout Aging.” Cell Stem Cell, 22 (4), 589–599. https://doi.org/10.1016/j.stem.2018.03.015.
Brincat, S., & Miller, E. K. (2015). “Frequency-specific hippocampal-prefrontal interactions during associative learning.” Nature Neuroscience, 18 (4), 576–581. https://doi.org/10.1038/nn.3954.
Budnik, V., Ruiz-Cañada, C., & Wendler, F. (2016). “Extracellular vesicles round off communication in the nervous system.” Nature Reviews Neuroscience, 17, 160–172. https://doi.org/10.1038/nrn.2015.29.
Colgin, L. L. (2016). “Rhythms of the hippocampal network.” Nature Reviews Neuroscience, 17, 239–249. https://doi.org/10.1038/nrn.2016.21.
Egeland, M., Zunszain, P. A., & Pariante, C. M. (2015). “Molecular mechanisms in the regulation of adult neurogenesis during stress.” Nature Reviews Neuroscience, 16, 189–200. https://doi.org/10.1038/nrn3855.
Grubb, S., & Lauritzen, M. (2019). “Deep sleep drives brain fluid oscillations.” Science, 366 (6465), 572–573. https://doi.org/10.1126/science.aaz5191.
Hanoun, M., Maryanovich, M., Arnal-Estapé, A., & Frenette, P. S. (2015). “Neural Regulation of Hematopoiesis, Inflammation, and Cancer.” Neuron, 86 (2), 360–373. https://doi.org/10.1016/j.neuron.2015.01.026.
Muller, L., Chavane, F., Reynolds, J., & Sejnowski, T. J. (2018). “Cortical travelling waves: mechanisms and computational principles.” Nature Reviews Neuroscience, 19, 255–268. https://doi.org/10.1038/nrn.2018.20.
Pesaran, B., Vinck, M., Einevoll, G. T., Sirota, A., Fries, P., Siegel, M., Truccolo, W., Schroeder, C. E., & Srinivasan, R. (2018). “Investigating large-scale brain dynamics using field potential recordings: analysis and interpretation.” Nature Neuroscience, 21 (7), 903–919. https://doi.org/10.1038/s41593-018-0171-8.
Wohleb, E. S, Franklin, T., Iwata, M., Duman, R. S. (2016). “Integrating neuroimmune systems in the neurobiology of depression.” Nature Reviews Neuroscience, 17, 497–511. https://doi.org/10.1038/nrn.2016.69.
Chapter 10: The Supportive Role of Astrocytes
An increasing amount of research shows how vital astrocytes are to every aspect of neuronal circuits. Five reviews cover the multiple astrocyte functions related to control of synapses and circuits. Research articles include influence on brain clocks, calcium signaling, regulation of myelin structures related to axon velocity, subtypes of astrocytes regulating specific neuronal circuits, and neurons regulating their specific astrocyte types.
Allen, N. J., & Eroglu, C. (2017). “Cell Biology of Astrocyte-Synapse Interactions.” Neuron, 96 (3), 697–708. https://doi.org/10.1016/j.neuron.2017.09.056.
Bazargani, N., & Attwell, D. (2016). “Perspective: Astrocyte calcium signaling: the third wave.” Nature Neuroscience, 19, 182–189. https://doi.org/10.1038/nn.4201.
Ben Haim, L., & Rowitch, D. H. (2017). “Functional diversity of astrocytes in neural circuit regulation.” Nature Reviews Neuroscience, 18, 31–41. https://doi.org/10.1038/nrn.2016.159.
Clarke, L. E., & Liddelow, S. A. (2017). “Neurobiology: Diversity reaches the stars.” Nature, 548 (7668), 396–397. https://doi.org/10.1038/548396a.
Dallérac, G., Zapata, J., Rouach, N. (2018). “Versatile control of synaptic circuits by astrocytes: where, when and how?” Nature Reviews Neuroscience, 19, 729–743. https://doi.org/10.1038/s41583-018-0080-6.
Dutta, D. J., Woo, D. H., Lee, P. R., Pajevic, S., Bukalo, O., Huffman, W. C., Wake, H., Basser, P. J., SheikhBahaei, S., Lazarevic, V., Smith, J. C., & Fields, R. D. (2018). “Regulation of myelin structure and conduction velocity by perinodal astrocytes.” Proceedings of the National Academy of Sciences of the United States, 115 (46), 11832–11837. https://doi.org/10.1073/pnas.1811013115.
Green, C. B. (2019). “Many paths to preserve the body clock.” Science, 363 (6423), 124–125. https://doi.org/10.1126/science.aav9706.
Khakh, B. S., & Sofroniew, M. V. (2015). “Diversity of astrocyte functions and phenotypes in neural circuits.” Nature Reviews Neuroscience, 18, 942–952. https://doi.org/10.1038/nn.4043.
Santello, M., Toni, N., & Volterra, A. (2019). “Astrocyte function from information processing to cognition and cognitive impairment.” Nature Neuroscience, 22 (2), 154–166. https://doi.org/10.1038/s41593-018-0325-8.
Stevens, B., & Muthukumar, A. K. (2016). “Differences among astrocytes.” Science, 351 (6275), 813. https://doi.org/10.1126/science.aaf2849.
Chapter 11: Microglia—Master Regulators of the Brain
Microglia research is rapidly expanding in the fields of neurodegeneration, infections, cancers, and all immune activity. Here are some recent reviews and specific articles on “don’t eat me” signals, an effect on cognition, inclusion in a pain circuit, and recent research showing a mechanism for evaluation of cell function by touching neurons.
Bennett, M. L., & Bennett, F. C. (2020). “The influence of environment and origin on brain resident macrophages and implications for therapy.” Nature Neuroscience, 23, 157–166. https://doi.org/10.1038/s41593-019-0545-6.
Cserép, C., Pósfai, B., Lénárt, N., Fekete, R., László, Z. I., Lele, Z., Orsolits, B., Molnár, G., Heindl, S., Schwarcz, A. D., Ujvári, K., Környei, Z., Tóth, K., Szabadits, E., Sperlágh, B., Baranyi, M., Csiba, L., Hortobágyi, T., Maglóczky, Z., . . . Dénes, Á. (2020). “Microglia monitor and protect neuronal function through specialized somatic purinergic junctions.” Science, 367 (6477), 528–537. https://doi.org/10.1126/science.aax6752.
Deczkowska, A., Keren-Shaul, H., Weiner, A., Colonna, M., Schwartz, M., & Amit, I. (2018). “Disease-Associated Microglia: A Universal Immune Sensor of Neurodegeneration.” Cell, 173 (5), 1073–1081. https://doi.org/10.1016/j.cell.2018.05.003.
Dong, Y., & Yong, V. W. “When encephalitogenic T cells collaborate with microglia in multiple sclerosis.” Nature Reviews Neurology, 15, 704–717. https://doi.org/10.1038/s41582-019-0253-6.
Greenhalgh, A. D., David, S., & Bennett, F. C. (2020). “Immune cell regulation of glia during CNS injury and disease.” Nature Reviews Neuroscience, 21, 139–152. https://doi.org/10.1038/s41583-020-0263-9.
McCarthy, M. M. (2017). “Location, Location, Location: Microglia Are Where They Live.” Neuron, 95 (2), 233–235. https://doi.org/10.1016/j.neuron.2017.07.005.
Neniskyte, U., & Gross, C. T. (2017). “Errant gardeners: glial-cell-dependent synaptic pruning and neurodevelopmental disorders.” Nature Reviews Neuroscience, 18, 658–670. https://doi.org/10.1038/nrn.2017.110.
Nimmerjahn, A. (2020). “Monitoring neuronal health.” Science, 367 (6477), 510–511. https://doi.org/10.1126/science.aba4472.
Niño, D. F., Zhou, Q., Yamaguchi, Y., Martin, L. Y., Wang, S., Fulton, W. B., Jia, H., Lu, P., Prindle Jr., T., Zhang, F., Crawford, J., Hou, Z., Mori, S., Chen, L. L., Guajardo, A., Fatemi, A., Pletnikov, M., Kannan, R. M., Kannan, S., . . . Hackam, D. J. (2018). “Cognitive impairments induced by necrotizing enterocolitis can be prevented by inhibiting microglial activation in mouse brain.” Science Translational Medicine, 10 (471), 1–12. https://doi.org/10.1126/scitranslmed.aan0237.
Rivest, S. (2018). “Pruned to perfection.” Nature, 563, 42–43. https://media.nature.com/original/magazine-assets/d41586-018-07165-8/d41586-018-07165-8.pdf.
Tan, Y., Yuan, Y., & Tian, L. (2020). “Microglial regional heterogeneity and its role in the brain.” Molecular Psychiatry, 25, 351–367. https://doi.org/10.1038/s41380-019-0609-8.
Chapter 12: The Myelin-Producing Oligodendrocytes
The new science of myelin is extremely complex, and myelin is difficult to study. Reviews include the newly discovered signaling between axons and myelin and factors involved in remodeling myelin related to neuroplasticity. Specific articles describe newly discovered subgroups of oligodendrocytes and new research connecting myelin damage in multiple sclerosis with microglia and T cell signaling.
Bonnefil, V., Dietz, K., Amatruda, M., Wentling, M., Aubry, A. V., Dupree, J. L., Temple, G., Park, H. J., Burghardt, N. S., Casaccia, P., & Liu, J. (2019). “Region-specific myelin differences define behavioral consequences of chronic social defeat stress in mice.” eLife, 8, e40855. https://doi.org/10.7554/eLife.40855.
Chang, K. J., Redmond, S. A., & Chan, J. R. (2016). “Remodeling myelination: implications for mechanisms of neural plasticity.” Nature Neuroscience, 19 (2), 190–197. https://doi.org/10.1038/nn.4200.
Dong, Y., & Yong, V. W. (2019). “When encephalitogenic T cells collaborate with microglia in multiple sclerosis.” Nature Reviews Neurology, 15, 704–717. https://doi.org/10.1038/s41582-019-0253-6.
Franklin, R. J. M., & Ffrench-Constant, C. (2017). “Regenerating CNS myelin—from mechanisms to experimental medicines.” Nature Reviews Neuroscience, 18, 753–769. https://doi.org/10.1038/nrn.2017.136.
Lloyd, A. F., & Miron, V. E. (2019). “The pro-remyelination properties of microglia in the central nervous system.” Nature Reviews Neurology, 15, 447–458. https://doi.org/10.1038/s41582-019-0184-2.
Marisca, R., Hoche, T., Agirre, E., Hoodless, L. J., Barkey, W., Auer, F., Castelo-Branco, G., & Czopka, T. (2020). “Functionally distinct subgroups of oligodendrocyte precursor cells integrate neural activity and execute myelin formation.” Nature Neuroscience, 23, 363–374. https://doi.org/10.1038/s41593-019-0581-2.
Micu, I., Plemel, J. R., Capraiello, A. V., Nave, K. A., & Stys, P. K. (2018). “Axo-myelinic neurotransmission: a novel mode of cell signaling in the central nervous system.” Nature Reviews Neuroscience, 19, 49–58. https://doi.org/10.1038/nrn.2017.128.
Mount, C., & Monje, M. (2017). “Wrapped to Adapt: Experience-Dependent Myelination.” Neuron, 95 (4), 743–756. https://doi.org/10.1016/j.neuron.2017.07.009.
Nagy, B., Hovhannisyan, A., Barzan, R., Chen, T. J., & Kukley, M. (2017). “Different patterns of neuronal activity trigger distinct responses of oligodendrocyte precursor cells in the corpus callosum.” PLoS Biology, 15 (8), e2001993. https://doi.org/10.1371/journal.pbio.2001993.
Chapter 13: Guardian Cells of the Brain
The emerging anatomy of the CSF, blood-brain barrier, and meninges is complex and demonstrates multiple new ways immune cells interact with the brain. There is, also, expanded research into functions of choroid cells and pericytes. A large literature is emerging about the unique ways that the brain is “privileged” but also accessible by immune cells and microbes. Several articles describe new avenues for immune cells’ travel into the brain. Other articles describe microbe interactions with brain and immune cells. Research articles describe waste removal and coordinated cilia producing flow in the ventricles. Several articles are about choroid cells and pericytes.
Ahn, J. H., Cho, H., Kim, J. H., Ham, J. S., Park, I., Suh, S. H., Hong, S. P., Song, J. H., Hong, Y. K., Jeong, Y., Park, S. H., & Koh, G. Y. (2019). “Meningeal lymphatic vessels at the skull base drain cerebrospinal fluid.” Nature, 572, 62–66. https://doi.org/10.1038/s41586-019-1419-5.
Alderton, G. (2019). “Immune surveillance of the brain.” Science, 366 (6472), 1467–1469. https://doi.org/10.1126/science.366.6472.1467-r.
Faubel, R., Westendorf, C., Bodenschatz, E., & Eichele, G. (2016). “Cilia-based flow network in the brain ventricles.” Science, 353 (6295), 176–177. https://doi.org/10.1126/science.aae0450.
Forrester, J. V., McMenamin, P. G., & Dando, S. J. (2018). “CNS infection and immune privilege.” Nature Reviews Neuroscience, 19, 655–671. https://doi.org/10.1038/s41583-018-0070-8.
Grubb, S., & Lauritzen, M. (2019). “Deep sleep drives brain fluid oscillations.” Science, 366 (6465), 572–573. https://doi.org/10.1126/science.aaz5191.
Lauer, A. N., Tenenbaum, T., Schroten, H., & Schwerk, C. (2018). “The diverse cellular responses of the choroid plexus during infection of the central nervous system.” American Journal of Physiology Cell Physiology, 314 (2), C152–C165. https://doi.org/10.1152/ajpcell.00137.2017.
Planques, A., Moreira, V. O., Dubreuil, C., Prochiantz, A., & Di Nardo, A. A. (2019). “OTX2 Signals from the Choroid Plexus to Regulate Adult Neurogenesis.” eNeuro, 6 (2), ENEURO.0262-18.2019. https://doi.org/10.1523/ENEURO.0262-18.2019.
Prinz, M., & Priller, J. (2017). “The role of peripheral immune cells in the CNS in steady state and disease.” Nature Neuroscience, 20 (2), 136–144. https://doi.org/10.1038/nn.4475.
Rustenhoven, J., & Kipnis, J. (2019). “Bypassing the blood-brain barrier.” Science, 366 (6472), 1448–1449. https://doi.org/10.1126/science.aay0479.
Sweeney, M. D., Ayyadurai, S., & Zlokovic, B. V. (2016). “Pericytes of the neurovascular unit: key functions and signaling pathways.” Nature Neuroscience, 19 (6), 771–783. https://doi.org/10.1038/nn.4288.
Wardlaw, J. M., Benveniste, H., Nedergaard, M., Zlokovic, B. V., Mestre, H., Lee, H., Doubal, F. N., Brown, R., Ramirez, J., MacIntosh, B. J., Tannenbaum, A., Ballerini, L., Rungta, R. L., Boido, D., Sweeney, M., Montagne, A., Charpak, S., Joutel, A., Smith, K. J., Black, S. E. (2020). “Perivascular spaces in the brain: anatomy, physiology and pathology.” Nature Reviews Neurology, 16, 137–153. https://doi.org/10.1038/s41582-020-0312-z.
Yamazaki, T., & Mukouyama, Y. S. (2018). “Tissue Specific Origin, Development, and Pathological Perspectives of Pericytes.” Frontiers in Cardiovascular Medicine, 5, 78. https://doi.org/10.3389/fcvm.2018.00078.
Chapter 14: Pain and Inflammation
Pain is another area with a vast literature and a large number of unknowns. These articles focus on new signaling concepts such as pain circuits that include cells other than neurons and the general crosstalk that is prevalent between brain cells and immune cells related to pain. Several articles give new insight into possible mechanisms of acupuncture as unusual communication of immune and brain cells.
Baral, P., Udit, S., & Chiu, I. M. (2019). “Pain and immunity: implications for host defense.” Nature Reviews Immunology, 19, 433–447. https://doi.org/10.1038/s41577-019-0147-2.
Bidad, K., Gracey, E., Hemington, K. S., Mapplebeck, J. C. S., Davis, K. D., & Inman, R. D. (2017). “Pain in ankylosing spondylitis: a neuro-immune collaboration.” Nature Reviews Rheumatology, 13, 410–420. https://doi.org/10.1038/nrrheum.2017.92.
Colloca, L., Ludman, T., Bouhassira, D., Baron, R., Dickenson, A. H., Yarnitsky, D., Freeman, R., Truini, A., Attal, N., Finnerup, N. B., Eccleston, C., Kalso, E., Bennett, D. L., Dworkin, R. H., & Raja, S. N. (2017). “Neuropathic pain.” Nature Reviews Disease Primers, 3, 17002. https://doi.org/10.1038/nrdp.2017.2.
Conaghan, P. G., Cook, A. D., Hamilton, J. A., & Tak, P. P. (2019). “Therapeutic options for targeting inflammatory osteoarthritis pain.” Nature Reviews Rheumatology, 15, 355–363. https://doi.org/10.1038/s41584-019-0221-y.
Eom, D. S., & Parichy, D. M. (2017). “A macrophage relay for long-distance signaling during postembryonic tissue remodeling.” Science, 355 (6331), 1317–1320. https://doi.org/10.1126/science.aal2745.
Inoue, K., & Tsuda, M. (2018). “Microglia in neuropathic pain: cellular and molecular mechanisms and therapeutic potential.” Nature Reviews Neuroscience, 19, 138–152. https://doi.org/10.1038/nrn.2018.2.
Ji, R. R., Chamessian, A., & Zhang, Y. Q. (2016). “Pain regulation by non-neuronal cells and inflammation?” Science, 354 (6312), 572–577. https://doi.org/10.1126/science.aaf8924.
Ji, R. R., Donnelly, C. R., & Nedergaard, M. (2019). “Astrocytes in chronic pain and itch.” Nature Reviews Neuroscience, 20, 667–685. https://doi.org/10.1038/s41583-019-0218-1.
Kuner, R., & Flor, H. (2017). “Structural plasticity and reorganization in chronic pain.” Nature Reviews Neuroscience, 18, 21–30. https://doi.org/10.1038/nrn.2016.162.
Mapplebeck, J. C. S., Beggs, S., & Salter, M. W. (2017). “Molecules in pain and sex: a developing story.” Molecular Brain, 10, 9. https://doi.org/10.1186/s13041-017-0289-8.
Peirs, C., Williams, S. P., Zhao, X., Walsh, C. E., Gedeon, J. Y., Cagle, N. E., Goldring, A. C., Hioki, H., Liu, Z., Marell, P. S., & Seal, R. P. (2015). “Dorsal Horn Circuits for Persistent Mechanical Pain.” Neuron, 87 (4), 797–812. https://doi.org/10.1016/j.neuron.2015.07.029.
Torres-Rosas, R., Yehia, G., Peña, G., Mishra, P., del Rocío Thompson-Bonilla, M., Moreno-Eutimio, M. A., Arriaga-Pizano, L. A., Isibasi, A., & Ulloa, L. (2014). “Dopamine mediates vagal modulation of the immune system by electroacupuncture.” Nature Medicine, 20, 291–295. https://doi.org/10.1038/nm.3479.
Tracey, K. J. (2009). “Reflex control of immunity.” Nature Reviews Immunology, 9, 418–428. https://doi.org/10.1038/nri2566.
>Chapter 15: Microbial Behavior and Conversations
The literature on microbe behavior is possibly the largest of all. It is difficult to filter the most relevant review and research articles. The review by Chubukov, et al., is important because it gives a clue as to how microbes make internal decisions. Two articles describe quorum sensing; one article describes efflux pumps and secretion systems; three describe varied biofilms; and two are about behavior that leads to forms of multicellular behaviors. Individual research articles include a possible explanation of the microbe receptor system, a primitive form of microbe memory, and the microbe ability to solve mazes. Last are five articles about exotic forms of communication, including electrical wires, nanotubes, and vesicles.
Aschtgen, M. S., Brennan, C. A., Nikolakakis, K., Cohen, S., McFall-Ngai, M., & Ruby, E. G. (2019). “Insights into flagellar function and mechanism from the squid–vibrio symbiosis.” npj Biofilms and Microbiomes, 5, 32. https://doi.org/10.1038/s41522-019-0106-5.
Brown, L., Wolf, J. M., Prados-Rosales, R., & Casadevall, A. (2015). “Through the wall: extracellular vesicles in Gram-positive bacteria, mycobacteria and fungi.” Nature Reviews Microbiology, 13, 620–630. https://doi.org/10.1038/nrmicro3480.
Chubukov, V., Gerosa, L., Kochanowski, K., & Sauer, U. (2014). “Coordination of microbial metabolism.” Nature Reviews Microbiology, 12, 327–339. https://doi.org/10.1038/nrmicro3238.
Claessen, D., Rozen, D. E., Kuipers, O. P., Søgaard-Andersen, L., & van Wezel, G. P. (2014). “Bacterial solutions to multicellularity: a tale of bio-films, filaments and fruiting bodies.” Nature Reviews Microbiology, 12, 115–124. https://doi.org/10.1038/nrmicro3178.
Du, D., Wang-Kan, X., Neuberger, A., van Veen, H. W., Pos, K. M., Piddock, L. J. V., & Luisi, B. F. (2018). “Multidrug efflux pumps: structure, function and regulation.” Nature Reviews Microbiology, 16, 523–539. https://doi.org/10.1038/s41579-018-0048-6.
Duan, J., Navarro-Dorado, J., Clark, J. H., Kinnear, N. P., Meinke, P., Schirmer, E. C., & Evans, A. M. (2019). “The cell-wide web coordinates cellular processes by directing site-specific Ca2+ flux across cytoplasmic nanocourses.” Nature Communications, 10, 229. https://doi.org/10.1038/s41467-019-10055-w.
Humphries, J., Xiong, L., Liu, J., Prindle, A., Yuan, F., Arjes, H. A., Tsimring, L., & Süel, G. M. (2017). “Species-Independent Attraction to Biofilms through Electrical Signaling Electrical Signaling.” Cell, 168, 200–209. https://doi.org/10.1016/j.cell.2016.12.014.
Lee, C. K., de Anda, J., Baker, A. E., Bennett, R. R., Luo, Y., Lee, E. Y., Keefe, J. A., Helali, J. S., Ma, J., Zhao, K., Golestanian, R., O’Toole, G. A., & Wong, G. C. L. (2018). “Multigenerational memory and adaptive adhesion in early bacterial biofilm communities.” Proceedings of the National Academy of Sciences of the United States of America, 115 (17), 4471–4476. https://doi.org/10.1073/pnas.1720071115.
Lohse, M. B., Gulati, M., Johnson, A. D., & Nobile, C. J. (2018). “Development and regulation of single- and multi-species Candida albicans Bio-films.” Nature Reviews Microbiology, 16, 19–31. https://doi.org/10.1038/nrmicro.2017.107.
Meysman, F. J. R., Cornelissen, R., Trashin, S., Bonné, R., Hidalgo Martinez, S., van der Veen, J., Blom, C. J., Karman, C., Hou, J. L., Thiruvallur Eachambadi, R., Geelhoed, J. S., De Wael, K., Beaumont, H. J. E., Cleuren, B., Valcke, R., van der Zant, H. S. J., Boschker, H. T. S., & Manca, J. V. (2019). “A highly conductive fibre network enables centimetre-scale electron transport in multicellular cable bacteria.” Nature Communications, 10, 4120. https://doi.org/10.1038/s41467-019-12115-7.
Moura-Alves, P., Puyskens, A., Stinn, A., Klemm, M., Guhlich-Bornhof, U., Dorhoi, A., Furkert, J., Kreuchwig, A., Protze, J., Lozza, L., Pei, G., Saikali, P., Perdomo, C., Mollenkopf, H. J., Hurwitz, R., Kirschhoefer, F., Brenner-Weiss, G., Weiner J. 3rd, Oschkinat, H., . . . Kaufmann, S. H. E. (2019). “Host monitoring of quorum sensing during Pseudomonas aeruginosa infection.” Science, 366 (6472), eaaw1629. https://doi.org/10.1126/science.aaw1629.
Nadell, C. D., Drescher, K., & Foster, K. R. (2016). “Spatial structure, cooperation and competition in biofilms.” Nature Reviews Microbiology, 14, 589–600. https://doi.org/10.1038/nrmicro.2016.84.
Pennisi, E. (2018). “The power of many.” Science, 360 (6396), 1388–1391. https://doi.org/10.1126/science.360.6396.1388.
Salek, M. M., Carrara, F., Fernandez, V., Guasto, J. S., & Stocker, R. (2019). “Bacterial chemotaxis in a microfluidic T-maze reveals strong phenotypic heterogeneity in chemotactic sensitivity.” Nature Communications, 10, 1877. https://doi.org/10.1038/s41467-019-09521-2.
Shi, L., Dong, H., Reguera, G., Beyenal, H., Lu, A., Liu, J., Yu, H. Q., & Fredrickson, J. K. (2016). “Extracellular electron transfer mechanisms between microorganisms and minerals.” Nature Reviews Microbiology, 14, 651–662. https://doi.org/10.1038/nrmicro.2016.93.
Szempruch, A. J., Dennison, L., Kieft, R., Harrington, J. M., & Hajduk, S. L. (2016). “Sending a message: extracellular vesicles of pathogenic protozoan parasites.” Nature Reviews Microbiology, 14, 669–675. https://doi.org/10.1038/nrmicro.2016.110.
Teschler, J. K., Zamorano-Sánchez, D., Utada, A. S., Warner, C. J. A., Wong, G. C. L., Linington, R. G., & Yildiz, F. H. (2015). “Living in the matrix: assembly and control of Vibrio cholerae biofilms.” Nature Reviews Microbiology, 13, 255–268. https://doi.org/10.1038/nrmicro3433.
Whiteley, M., Diggle, S., & Greenberg, E. (2017). “Progress in and promise of bacterial quorum sensing research.” Nature, 551, 313–320. https://doi.org/10.1038/nature24624.
Chapter 16: Battles Between Microbes and Human Cells
The research literature into the interactions of microbes and human cells is vast. Articles listed here include varied immune responses and microbe counter-responses, the regulation of receptors used in these battles, and the use of programmed cell suicide to eliminate cellular infection. Three articles describe tagging systems used by both sides. Several articles refer to the use of vesicles by cells to capture and destroy microbes and also the ability of microbes to live inside these vesicles. One article describes the unique lifestyle of the bacteria causing leprosy.
Ashida, H., Kim, M., & Sasakawa, C. (2014). “Exploitation of the host ubiquitin system by human bacterial pathogens.” Nature Reviews Microbiology, 12, 399–413. https://doi.org/10.1038/nrmicro3259.
Cao, X. (2016). “Self-regulation and cross-regulation of pattern-recognition receptor signaling in health and disease.” Nature Reviews Immunology, 16, 35–50. https://doi.org/10.1038/nri.2015.8.
Chan, Y. K., & Gack, M. U. (2016). “Viral evasion of intracellular DNA and RNA sensing.” Nature Reviews Microbiology, 14, 360–373. https://doi.org/10.1038/nrmicro.2016.45.
Erwig, L. P., & Gow, N. A. (2016). “Interactions of fungal pathogens with phagocytes.” Nature Reviews Microbiology, 14, 163–176. https://doi.org/10.1038/nrmicro.2015.21.
Everett, R. D., Boutell, C., & Hale, B. G. (2013). “Interplay between viruses and host SUMOylation pathways.” Nature Reviews Microbiology, 11, 400–411. https://doi.org/10.1038/nrmicro3015.
Fung, T., Olson, C., & Hsiao, E. “Interactions between the microbiota, immune and nervous systems in health and disease.” Nature Neuroscience, 20, 145–155. htttps://doi.org/10.1038/nn.4476.
Huang, J., & Brumell, J. H. (2014). “Bacteria-autophagy interplay: a battle for survival.” Nature Reviews Microbiology, 12, 101–114. https://doi.org/10.1038/nrmicro3160.
Jorgensen, I., Rayamajhi, M., & Miao, E. A. (2017). “Programmed cell death as a defense against infection.” Nature Reviews Immunology, 17, 151–164. https://doi.org/10.1038/nri.2016.147.
Masaki, T., Qu, J., Cholewa-Waclaw, J., Burr, K., Raaum, R., & Rambukkana, A. (2013). “Reprogramming adult Schwann cells to stem cell-like cells by leprosy bacilli promotes dissemination of infection.” Cell, 152, 51–67. https://doi.org/10.1016/j.cell.2012.12.014.
Matz, J. M., Beck, J. R., & Blackman, M. J. (2020). “The parasitophorous vacuole of the blood-stage malaria parasite.” Nature Reviews Microbiology. https://doi.org/10.1038/s41579-019-0321-3.
Nothelfer, K., Sansonetti, P. J., & Phalipon, A. (2015). “Pathogen manipulation of B cells: the best defence is a good offence.” Nature Reviews Microbiology, 13, 173–184. https://doi.org/10.1038/nrmicro3415.
Stewart, M. K., & Cookson, B. T. (2016). “Evasion and interference: intracellular pathogens modulate caspase-dependent inflammatory responses.” Nature Reviews Microbiology, 14, 346–359. https://doi.org/10.1038/nrmicro.2016.50.
Thammavongsa, V., Kim, H. K., Missiakas, D., & Schneewind, O. (2015). “Staphylococcal manipulation of host immune responses.” Nature Reviews Microbiology, 13, 529–543. https://doi.org/10.1038/nrmicro3521.
Venugopal, K., Hentzschel, F., Valkiūnas, G., & Marti, M. (2020). “Plasmodium asexual growth and sexual development in the haematopoietic niche of the host.” Nature Reviews Microbiology, 18, 177–189. https://doi.org/10.1038/s41579-019-0306-2.
Wimmer, P., Schreiner, S., & Dobner, T. (2011). “Human Pathogens and the Host Cell SUMOylation System.” Journal of Virology, 86 (2), 642–654. https://doi.org/10.1128/JVI.06227-11.
Chapter 17: Microbe Politics in the Gut
Of all microbe fields, the idea that microbes in the gut can affect all other organs has captured the public imagination. These articles focus on how microbe and immune signaling in the gut produces health and disease. One article shows how dangerousness does not necessarily come from the number of microbes present but from conversations with other microbes, immune cells, and gut lining cells. Several articles highlight the importance of virus interactions with bacteria and human cells. Others highlight the variability of the environment through the entire gut. One article describes how environmental factors such as exercise can influence microbes and their ultimate effects. Another article describes a new mechanism whereby microbes regulate gut cells via epigenetics.
Allen, J. M., Mailing, L. J., Cohrs, J., Salmonson, C., Fryer, J. D., Nehra, V., Hale, V. L., Kashyap, P., White, B. A., & Woods, J. A. (2018). “Exercise training-induced modification of the gut microbiota persists after microbiota colonization and attenuates the response to chemically-induced colitis in gnotobiotic mice.” Gut Microbes, 9 (2), 115–130. https://doi.org/10.1080/19490976.2017.1372077.
Ansari, I., Raddatz, G., Gutekunst, J., Ridnik, M., Cohen, D., Abu-Remaileh, M., Tuganbaev, T., Shapiro, H., Pikarsky, E., Elinav, E., Lyko, F., & Bergman, Y. (2020). “The microbiota programs DNA methylation to control intestinal homeostasis and inflammation.” Nature Microbiology. https://doi.org/10.1038/s41564-019-0659-3.
Bäumler, A. J., & Sperandio, V. (2016). “Interactions between the microbiota and pathogenic bacteria in the gut.” Nature, 535, 85–93. https://doi.org/10.1038/nature18849.
Brown, J. M., & Hazen, S. L. (2018). “Microbial modulation of cardiovascular Disease.” Nature Reviews Microbiology, 16, 171–181. https://doi.org/10.1038/nrmicro.2017.149.
Cani, P. D., Van Hul, M., Lefort, C., Depommier, C., Rastelli, M., & Everard, A. (2019). “Microbial regulation of organismal energy homeostasis.” Nature Metabolism, 1, 34–46. https://doi.org/10.1038/s42255-018-0017-4.
Donaldson, G. P, Lee, S. M., & Mazmanian, S. K. (2016). “Gut biogeography of the bacterial microbiota.” Nature Reviews Microbiology, 14, 20–32. https://doi.org/10.1038/nrmicro3552.
Frank, M. G., Fonken, L. K., Dolzani, S. D., Annis, J. L., Siebler, P. H., Schmidt, D., Watkins, L. R., Maier, S. F., & Lowry, C. A. (2018). “Immunization with Mycobacterium vaccae induces an anti-inflammatory milieu in the CNS: Attenuation of stress-induced microglial priming, alarm-ins and anxiety-like behavior.” Brain, Behavior, and Immunity, 73, 352–363. https://doi.org/10.1016/j.bbi.2018.05.020.
Karst, S. M. (2016). “The influence of commensal bacteria on infection with enteric viruses.” Nature Reviews Microbiology, 14, 197–204. https://doi.org/10.1038/nrmicro.2015.25.
Khan Mirzaei, M., & Maurice, C. F. (2017). “Ménage à trois in the human gut: interactions between host, bacteria and phages.” Nature Reviews Microbiology, 15, 397–408. https://doi.org/10.1038/nrmicro.2017.30.
Martens, E. C., Neumann, M., & Desai, M. S. (2018). “Interactions of commensal and pathogenic microorganisms with the intestinal mucosal barrier.” Nature Reviews Microbiology, 16, 457–470. https://doi.org/10.1038/s41579-018-0036-x.
Schroeder, B. O, & Bäckhed, F. (2016). “Signals from the gut microbiota to distant organs in physiology and disease.” Nature Medicine, 22 (10), 1079–1089. https://doi.org/10.1038/nm.4185.
Sommer, F., Moltzau Anderson, J., Bharti, R., Raes, J., & Rosenstiel, P. (2017). “The resilience of the intestinal microbiota influences health and disease.” Nature Reviews Microbiology, 15, 630–638. https://doi.org/10.1038/nrmicro.2017.58.
Sonnenburg, J. L., & Bäckhed, F. (2016). “Diet-microbiota interactions as moderators of human metabolism.” Nature, 535, 56–64. https://doi.org/10.1038/nature18846.
Stacy, A., McNally, L., Darch, S. E., Brown, S. P., & Whiteley, M. (2016). “The biogeography of polymicrobial infection.” Nature Reviews Microbiology, 14, 93–105. https://doi.org/10.1038/nrmicro.2015.8.
Wekerle, H. (2018). “Brain inflammatory cascade controlled by gut-derived molecules.” Nature, 557, 642–643. https://doi.org/10.1038/d41586-018-05113-0.
Chapter 18: Microbe Influences on the Brain
There is increasing evidence that microbes influence the brain and behavior, and this is reflected in four articles. Other articles describe microbe travels into the brain. Two articles reflect the increasing evidence that gut microbe signals in particular affect the brain.
Coureuil, M., Lécuyer, H., Bourdoulous, S., & Nassif, X. “A journey into the brain: insight into how bacterial pathogens cross blood–brain barriers.” Nature Reviews Microbiology, 15, 149–159. https://doi.org/10.1038/nrmicro.2016.178.
Dalile, B., Van Oudenhove, L., Vervliet, B., & Verbeke, K. (2019). “The role of short-chain fatty acids in microbiota–gut–brain communication.” Nature Reviews Gastroenterology and Hepatology, 16, 461–478. https://doi.org/10.1038/s41575-019-0157-3.
Fung, T. C., Olson, C. A., & Hsiao, E. Y. (2017). “Interactions between the microbiota, immune and nervous systems in health and disease.” Nature Neuroscience, 20 (2), 145–155. https://doi.org/10.1038/nn.4476.
Kiraly, D. D. (2019). “Gut microbes help mice forget their fear.” Nature, 574, 488–489. https://doi.org/10.1038/d41586-019-03114-1.
Miller, K. D., Schnell, M. J., & Rall, G. F. (2016). “Keeping it in check: chronic viral infection and antiviral immunity in the brain.” Nature Reviews Neuroscience, 17, 766–776. https://doi.org/10.1038/nrn.2016.140.
Sharon, G., Sampson, T. R., Geschwind, D. H., & Mazmanian, S. K. (2016). “The Central Nervous System and the Gut Microbiome.” Cell, 167 (4), 915–932. https://doi.org/10.1016/j.cell.2016.10.027.
Sherwin, E., Bordenstein, S. R., Quinn, J. L., Dinan, T. G., & Cryan, J. F. (2019). “Microbiota and the social brain.” Science, 366 (6465), eaar2016. https://doi.org/10.1126/science.aar2016.
Warner, B. B. (2019). “The contribution of the gut microbiome to neurodevelopment and neuropsychiatric disorders.” Pediatric Research, 85, 216–224. https://doi.org/10.1038/s41390-018-0191-9.
Chapter 19: The Complex World of Viruses
Articles reflect the increasing evidence that viruses, like other microbes, use signals as a community to coordinate their actions. Two articles highlight this communication against bacteria, including the discoveries of actual virus signals. Other articles represent the ways bacteria and viruses fight and cooperate. Several describe the abilities of viruses to evade attacks while inside the human cell. Specific articles highlight the remarkable lifestyles of four viruses discussed in the chapter—Ebola, HIV, varicella, and bacteriophage. Several articles reflect the unusual abilities of viruses to rewire human cell activity and manipulate cell scaffolding and information vesicles.
Bernheim, A., & Sorek, R. (2018). “Viruses cooperate to defeat bacteria.” Nature, 559, 482–485. https://doi.org/10.1038/d41586-018-05762-1.
Berry, R., Watson, G. M., Jonjic, S., Degli-Esposti, M. A., & Rossjohn, J. (2020). “Modulation of innate and adaptive immunity by cytomegaloviruses.” Nature Reviews Immunology, 20, 113–127. https://doi.org/10.1038/s41577-019-0225-5.
Dolgin, E. (2019). “The Secret Social Lives of Viruses.” Nature, 570, 290–292. https://doi.org/10.1038/d41586-019-01880-6.
Erez, Z., Steinberger-Levy, I., Shamir, M., Doron, S., Stokar-Avihail, A., Peleg, Y., Melamed, S., Leavitt, A., Savidor, A., Albeck, S., Amitai, G., & Sorek, R. (2017). “Communication between viruses guides lysis–lysogeny decisions.” Nature, 541, 488–493. https://doi.org/10.1038/nature21049.
Felix, J., & Savvides, S. N. (2017). “Mechanisms of immunomodulation by mammalian and viral decoy receptors: insights from structures.” Nature Reviews Immunology, 17, 112–129. https://doi.org/10.1038/nri.2016.134.
Kim, J. S. (2018). “Microbial warfare against viruses.” Science, 359 (6379), 993. https://doi.org/10.1126/science.aas9430.
Lee, H., Chathuranga, K., & Lee, J. (2019). “Intracellular sensing of viral genomes and viral evasion.” Experimental & Molecular Medicine, 51, 1–13. https://doi.org/10.1038/s12276-019-0299-y.
Lusic, M., & Siliciano, R. F. (2017). “Nuclear landscape of HIV-1 infection and integration.” Nature Reviews Microbiology, 15, 69–81. https://doi.org/10.1038/nrmicro.2016.162.
Misasi, J., & Sullivan, N. J. (2014). “Camouflage and Misdirection: The Full-On Assault of Ebola Virus Disease.” Cell, 159 (3), 477–486. https://doi.org/10.1016/j.cell.2014.10.006.
Neufeldt, C. J., Cortese, M., Acosta, E. G., Bartenschlager, R. (2018). “Rewiring cellular networks by members of the Flaviviridae family.” Nature Reviews Microbiology, 16, 125–142. https://doi.org/10.1038/nrmicro.2017.170.
Nobrega, F. L., Vlot, M., de Jonge, P. A., Dreesens, L. L., Beaumont, H. J. E., Lavigne, R., Dutilh, B. E., & Brouns, S. J. J. (2018). “Target mechanisms of tailed bacteriophages.” Nature Reviews Microbiology, 16, 760–773. https://doi.org/10.1038/s41579-018-0070-8.
Seo, G. Y., Giles, D. A., & Kronenberg, M. (2020). “The role of innate lymphoid cells in response to microbes at mucosal surfaces.” Mucosal Immunology. https://doi.org/10.1038/s41385-020-0265-y.
Standfuss, J. (2015). “Viral chemokine mimicry.” Science, 347 (6226), 1071–1072. https://doi.org/10.1126/science.aaa7998.
Zerboni, L., Sen, N., Oliver, S. L., & Arvin, A. M. (2014). “Molecular mechanisms of varicella zoster virus pathogenesis.” Nature Reviews Microbiology, 12, 197–210. https://doi.org/10.1038/nrmicro3215.
Chapter 20: Microbe-Plant Interactions
Articles highlight two types of plant-microbe conversations—cooperation and battle. Six articles describe the elaborate back-andforth communication related to building nitrogen factories inside plants. Three articles describe plant microbe battles and immune responses.
Couto, D., & Zipfel, C. (2016). “Regulation of pattern recognition receptor signaling in plants.” Nature Reviews Immunology, 16, 537–551. https://doi.org/10.1038/nri.2016.77.
Ivanov, S., Austin, J., Berg, R. H., & Harrison, M. J. (2019). “Extensive membrane systems at the host–arbuscular mycorrhizal fungus interface.” Nature Plants, 5, 194–203. https://doi.org/10.1038/s41477-019-0364-5.
Kuypers, M. M. M., Marchant, H. K., & Kartal, B. (2018). “The microbial nitrogen-cycling network.” Nature Reviews Microbiology, 16, 263–276. https://doi.org/10.1038/nrmicro.2018.9.
Oldroyd, G. E. D. (2013). “Speak, friend, and enter: signaling systems that promote beneficial symbiotic associations in plants.” Nature Reviews Microbiology, 11, 252–263. https://doi.org/10.1038/nrmicro2990.
Poole, P., Ramachandran, V., & Terpolilli, J. (2018). “Rizhobia: from saprophytes to endosymbionts.” Nature Reviews Microbiology, 16, 291–303. https://doi.org/10.1038/nrmicro.2017.171.
Pumplin, N., & Voinnet, O. (2013). “RNA silencing suppression by plant pathogens: defense, counter-defense and counter-counter-defense.” Nature Reviews Microbiology, 11, 745–760. https://doi.org/10.1038/nrmicro3120.
Tsikou, D., Yan, Z., Holt, D. B., Abel, N. B., Reid, D. E., Madsen, L. H., Bhasin, H., Sexauer, M., Stougaard, J., & Markmann, K. (2018). “Systemic control of legume susceptibility to rhizobial infection by a mobile microRNA.” Science, 362 (6411), 233–236. https://doi.org/10.1126/science.aat6907.
Wang, M., Schäfer, M., Li, D., Halitschke, R., Dong, C., McGale, E., Paetz, C., Song, Y., Li, S., Dong, J., Heiling, S., Groten, K., Franken, P., Bitterlich, M., Harrison, M. J., Paszkowski, U., & Baldwin, I. T. (2018). “Blumenols as shoot markers of root symbiosis with arbuscular mycorrhizal fungi.” eLife, 7, e37093. https://doi.org/10.7554/eLife.37093.
Wu, C. H., Derevnina, L., & Kamoun, S. (2018). “Receptor networks underpin plant immunity.” Science, 60 (6395), 1300–1301. https://doi.org/10.1126/science.aat2623.
Chapter 21: Microbes’ Love-Hate Relationship with Cancer
Increasing research shows the positive and negative impacts of microbes on cancers. Also, the natural signaling between them is harnessed for new treatments. One article describes what is known about infections and cancers globally. Several articles demonstrate examples of microbes manipulating immune response to help cancers. Other articles show anticancer effects of microbe products. Several articles highlight treatment effects related to microbes.
de Martel, C., Georges, D., Bray, F., Ferlay, J., & Clifford, G. M. (2020). “Global burden of cancer attributable to infections in 2018: a worldwide incidence analysis.” Lancet, 8 (2), e180–c190. https://doi.org/10.1016/S2214-109X(19)30488-7.
Guglielmi, G. (2018). “How Gut Microbes Are Joining the Fight Against Cancer.” Nature, 557, 482–484. https://doi.org/10.1038/d41586-018-05208-8.
Hartmann, N., & Kronenberg, M. (2018). “Cancer immunity thwarted by the microbiome.” Science, 360 (6391), 858–859. https://doi.org/10.1126/science.aat8289.
Helmink, B. A., Khan, M. A. W., Hermann, A., Gopalakrishnan, V., & Wargo, J. A. (2019). “The microbiome, cancer, and cancer therapy.” Nature Medicine, 25, 377–388. https://doi.org/10.1038/s41591-019-0377-7.
Krump, N. A., & You, J. (2018). “Molecular mechanisms of viral oncogenesis in humans.” Nature Reviews Microbiology, 16, 684–698. https://doi.org/10.1038/s41579-018-0064-6.
Łaniewski, P., Ilhan, Z. E., & Herbst-Kralovetz, M. M. (2020). “The microbiome and gynaecological cancer development, prevention and therapy.” Nature Reviews Urology. https://doi.org/10.1038/s41585-020-0286-z.
Wong, S. H., & Yu, J. (2019). “Gut microbiota in colorectal cancer: mechanisms of action and clinical applications.” Nature Reviews Gastroenterology & Hepatology, 16 (11), 690–704. https://doi.org/10.1038/s41575-019-0209-8.
Zhang, Z., Tang, H., Chen, P., Xie, H., & Tao, Y. (2019). “Demystifying the manipulation of host immunity, metabolism, and extraintestinal tumors by the gut microbiome.” Signal Transduction and Targeted Therapy, 4, 41. https://doi.org/10.1038/s41392-019-0074-5.
Zitvogel, L., Daillère, R., Roberti, M. P., Routy, B., & Kroemer, G. (2017). “Anticancer effects of the microbiome and its products.” Nature Reviews Microbiology, 15, 465–478. https://doi.org/10.1038/nrmicro.2017.44.
Chapter 22: Microbial Conversations with Organelles
Microbes must interact with membranes to enter cells and must manipulate organelles to reproduce and evade cell defenses. Several articles survey microbe attacks on organelles. Two articles describe the multifaceted interactions with the endoplasmic reticulum. Several articles describe microbes’ love-hate relationship with vacuoles. Other articles describe virus manipulation of cell scaffolding and vesicles.
Celli, J., & Tsolis, R. M. (2015). “Bacteria, the endoplasmic reticulum and the unfolded protein response: friends or foes?” Nature Reviews Microbiology, 13, 71–82. https://doi.org/10.1038/nrmicro3393.
Escoll, P., Mondino, S., Rolando, M., & Buchrieser, C. (2016). “Targeting of host organelles by pathogenic bacteria: a sophisticated subversion strategy.” Nature Reviews Microbiology, 14, 5–19. https://doi.org/10.1038/nrmicro.2015.1.
Hicks, S. W., & Galán, J. E. (2013). “Exploitation of eukaryotic subcellular targeting mechanisms by bacterial effectors.” Nature Reviews Microbiology, 11, 316–325. https://doi.org/10.1038/nrmicro3009.
Liehl, P., Zuzarte-Luis, V., & Mota, M. M. (2015). “Unveiling the pathogen behind the vacuole.” Nature Reviews Microbiology, 13, 589–598. https://doi.org/10.1038/nrmicro3504.
Matz, J. M., Beck, J. R., & Blackman, M. J. (2020). “The parasitophorous vacuole of the blood-stage malaria parasite.” Nature Reviews Microbiology. https://doi.org/10.1038/s41579-019-0321-3.
Raab-Traub, N., & Dittmer, D. P. (2017). “Viral effects on the content and function of extracellular vesicles.” Nature Reviews Microbiology, 15, 559–572. https://doi.org/10.1038/nrmicro.2017.60.
Ravindran, M. S., Bagchi, P., Cunningham, C. N., & Tsai, B. (2016). “Opportunistic intruders: how viruses orchestrate ER functions to infect cells.” Nature Reviews Microbiology, 14, 407–420. https://doi.org/10.1038/nrmicro.2016.60.
Taylor, M. P., Koyuncu, O. O., & Enquist, L. W. (2011). “Subversion of the actin cytoskeleton during viral infection.” Nature Reviews Microbiology, 9, 427–439. https://doi.org/10.1038/nrmicro2574.
Chapter 23: Communication Among Organelles
These articles reflect the new science of intracellular organelle signaling. One article describes positive and negative effects of these conversations. Four articles describe widespread signaling—two related to response to unfolded proteins, one related to importing material into the cell, and one to cell division. Five articles describe newly discovered contact sites. One article describes the central importance of signaling with the lysosome, further described in the chapter on mTOR.
Carlton, J. G., Jones, H., & Eggert, U. S. (2020). “Membrane and organelle dynamics during cell division.” Nature Reviews Molecular Cell Biology, 21, 151–166. https://doi.org/10.1038/s41580-019-0208-1.
Gottschling, D. E., & Nyström, T. (2017). “The Upsides and Downsides of Organelle Interconnectivity.” Cell, 169 (1), 24–34. https://doi.org/10.1016/j.cell.2017.02.030.
Grootjans, J., Kaser, A., Kaufman, R. J., & Blumberg, R. S. (2016). “The unfolded protein response in immunity and inflammation.” Nature Reviews Immunology, 16, 469–484. https://doi.org/10.1038/nri.2016.62.
Haynes, C. M. (2015). “Surviving import failure.” Nature, 524, 419–420. https://doi.org/10.1038/nature14644.
Kornmann, B., & Weis, K. (2020). “Liquid but not contactless.” Science, 367 (6477), 507–508. https://doi.org/10.1126/science.aba3771.
Lawrence, R. E., & Zoncu, R. (2019). “The lysosome as a cellular centre for signalling, metabolism and quality control.” Nature Cell Biology, 21, 133–142. https://doi.org/10.1038/s41556-018-0244-7.
Olzmann, J. A., & Carvalho, P. (2019). “Dynamics and functions of lipid droplets.” Nature Reviews Molecular Cell Biology, 20, 137–155. https://doi.org/10.1038/s41580-018-0085-z.
Scorrano, L., De Matteis, M. A., Emr, S., Giordano, F., Hajnóczky, G., Kornmann, B., Lackner, L. L., Levine, T. P., Pellegrini, L., Reinisch, K., Rizzuto, R., Simmen, T., Stenmark, H., Ungermann, C., & Schuldiner, M. (2019). “Coming together to define membrane contact sites.” Nature Communications, 10, 1287. https://doi.org/10.1038/s41467-019-09253-3.
Shpilka, T., & Haynes, C. M. (2018). “The mitochondrial UPR: mechanisms, physiological functions and implications in ageing.” Nature Reviews Molecular Cell Biology, 19, 109–120. https://doi.org/10.1038/nrm.2017.110.
Wu, H., Carvalho, P., Voeltz, G. K. (2018). “Here, there, and everywhere: The importance of ER membrane contact sites.” Science, 361 (6401), eaan5835. https://doi.org/10.1126/science.aan5835.
Yoboue, E. D., Sitia, R., & Simmen, T. (2018). “Redox crosstalk at endoplasmic reticulum (ER) membrane contact sites (MCS) uses toxic waste to deliver messages.” Cell Death & Disease, 9, 331. https://doi.org/10.1038/s41419-017-0033-4.
Chapter 24: Mitochondrial Conversations
There is extensive research on mitochondria in many aspects of cellular biology. Mitochondria in cancer are described in chapter eight, about cancer. Here, articles describe findings related to membrane dynamics, special mitochondrial proteins, mitochondria at the neuron synapse, communication with the nucleus, and transport along microtubules. The most is known about mitochondria signals with the endoplasmic reticulum; here, there are four articles on this subject. The first article is a unique new finding of large numbers of free mitochondria in the blood. This finding will need to be replicated, but it could be significant.
Amir Dache, A., Otandault, A., Tanos, R., Pastor, B., Meddeb, R., Sanchez, C., Arena, G., Lasorsa, L., Bennett, A., Grange, T., El Messaoudi, S., Mazard, T., Prevostel, C., & Thierry, A. R. (2020). “Blood contains circulating cell-free respiratory competent mitochondria.” The FASEB Journal, 34 (3), 3616–3630. https://doi.org/10.1096/fj.201901917RR.
Bernard-Marissal, N., Chrast, R., & Schneider, B. L. (2018). “Endoplasmic reticulum and mitochondria in diseases of motor and sensory neurons: a broken relationship?” Cell Death & Disease, 9, 333. https://doi.org/10.1038/s41419-017-0125-1.
Devine, M., &Kittler, J. (2018). “Mitochondria at the neuronal presynapse in health and disease.” Nature Reviews Neuroscience, 19, 63–80. https://doi.org/10.1038/nrn.2017.170.
Eisner, V., Picard, M., & Hajnóczky, G. (2018). “Mitochondrial dynamics in adaptive and maladaptive cellular stress responses.” Nature Cell Biology, 20, 755–765. https://doi.org/10.1038/s41556-018-0133-0.
Giacomello, M., Pyakurel, A., Glytsou, C., & Scorrano, L. (2020). “The cell biology of mitochondrial membrane dynamics.” Nature Reviews Molecular Cell Biology. https://doi.org/10.1038/s41580-020-0210-7.
Gómez-Suaga, P., Bravo-San Pedro, J. M., González-Polo, R. A, Fuentes, J. M., & Niso-Santano, M. (2018). “ER–mitochondria signaling in Parkinson’s disease.” Cell Death & Disease, 9, 337. https://doi.org/10.1038/s41419-017-0079-3.
Mehta, M. M., Weinberg, S. E., & Chandel, N. S. (2017). “Mitochondrial control of immunity: beyond ATP.” Nature Reviews Immunology, 17, 608–620. https://doi.org/10.1038/nri.2017.66.
Mottis, A., Herzig, S., & Auwerx, J. (2019). “Mitocellular communication: Shaping health and disease.” Science, 366 (6467), 827–832. https://doi.org/10.1126/science.aax3768.
Pfanner, N., Warscheid, B., & Wiedemann, N. (2019). “Mitochondrial proteins: from biogenesis to functional networks.” Nature Reviews Molecular Cell Biology, 20, 267–284. https://doi.org/10.1038/s41580-018-0092-0.
Rieusset, J. (2018). “The role of endoplasmic reticulum-mitochondria contact sites in the control of glucose homeostasis: an update.” Cell Death & Disease, 9, 388. https://doi.org/10.1038/s41419-018-0416-1.
Sheng, Z. H., & Cai, Q. (2012). “Mitochondrial transport in neurons: impact on synaptic homeostasis and neurodegeneration.” Nature Reviews Neuroscience, 13, 77–93. https://doi.org/10.1038/nrn3156.
Wang, M., & Kaufman, R. (2016). “Protein misfolding in the endoplasmic reticulum as a conduit to human disease.” Nature, 529, 326–335. https://doi.org/10.1038/nature17041.
Chapter 25: Membrane Production
This is a difficult field to research, and some of the important papers are still from a number of years ago. There are several general articles about membrane functions, contact sites, and unique lipid ingredients. Three articles describe transport in the secretory, protein, and endocytic pathways. One article each is about membranes in T cell signaling and cell division.
Anitei, M., & Hoflack, B. (2012). “Bridging membrane and cytoskeleton dynamics in the secretory and endocytic pathways.” Nature Cell Biology, 14, 11–19. https://doi.org/10.1038/ncb2409.
Carlton, J. G., Jones, H., & Eggert, U. S. (2020). “Membrane and organelle dynamics during cell division.” Nature Reviews Molecular Cell Biology, 21, 151–166. https://doi.org/10.1038/s41580-019-0208-1.
Holthuis, J., & Menon, A. (2014). “Lipid landscapes and pipelines in membrane homeostasis.” Nature, 510, 48–57. https://doi.org/10.1038/nature13474.
Kononenko, N. L., & Haucke, V. (2015). “Molecular Mechanisms of Presynaptic Membrane Retrieval and Synaptic Vesicle Reformation.” Neuron, 85 (3), 484–496. https://doi.org/10.1016/j.neuron.2014.12.016.
Lev, S. (2010). “Non-vesicular lipid transport by lipid-transfer proteins and beyond.” Nature Reviews Molecular Cell Biology, 11, 739–750. https://doi.org/10.1038/nrm2971.
Prinz, W. A., Toulmay, A., & Balla, T. (2020). “The functional universe of membrane contact sites.” Nature Reviews Molecular Cell Biology, 21, 7–24. https://doi.org/10.1038/s41580-019-0180-9.
Tsirigotaki, A., De Geyter, J., Šoštarić, N., Economou, A., & Karamanou, S. (2017). “Protein export through the bacterial Sec pathway.” Nature Reviews Microbiology, 15, 21–36. https://doi.org/10.1038/nrmicro.2016.161.
Turpin-Nolan, S. M., & Brüning, J. C. (2020). “The role of ceramides in metabolic disorders: when size and localization matters.” Nature Reviews Endocrinology. https://doi.org/10.1038/s41574-020-0320-5.
Watanabe, S. (2015). “Slow or fast? A tale of synaptic vesicle recycling: A new model accounts for synaptic transmission speed.” Science, 350 (6256), 46–47. https://doi.org/10.1126/science.aad2996.
Wu, W., Shi, X., & Xu, C. (2016). “Regulation of T cell signaling by membrane lipids.” Nature Reviews Immunology, 16, 689–701. https://doi.org/10.1038/nri.2016.103.
Chapter 26: Transporting Materials on Scaffolding Highways
The enormous complexity of axonal transport of materials and organelles via motors and attachments is just now being worked out. Several articles about the structures of the highways include the tubulin code, interactions of actin and microtubules, and nano architecture of microtubule axon highways. Several articles describe the rapidly changing cytoskeleton to accommodate particular types of transport and the precise types of attachments and motors that are necessary for varied types of cargo. One article describes axon transport breakdown causing disease, another describes special retrograde rapid transit of important molecules, and a third, transport of mitochondria for energy.
Devine, M. J., & Kittler, J. T. (2018). “Mitochondria at the neuronal presynapse in health and disease.” Nature Reviews Neuroscience, 19, 63–80. https://doi.org/10.1038/nrn.2017.170.
Dogterom, M., & Koenderink, G. H. (2019). “Actin–microtubule crosstalk in cell biology.” Nature Reviews Molecular Cell Biology, 20, 38–54. https://doi.org/10.1038/s41580-018-0067-1.
Harrington, A. W., & Ginty, D. D. (2013). “Long-distance retrograde neurotrophic factor signalling in neurons.” Nature Reviews Neuroscience, 14, 177–187. https://doi.org/10.1016/j.neuron.2014.10.019.
Janke, C., & Magiera, M. M. (2020). “The tubulin code and its role in controlling microtubule properties and functions.” Nature Reviews Molecular Cell Biology. https://doi.org/10.1038/s41580-020-0214-3.
Leterrier, C., Dubey, P., & Roy, S. (2017). “The nano-architecture of the axonal cytoskeleton.” Nature Reviews Neuroscience, 18, 713–726. https://doi.org/10.1038/nrn.2017.129.
Maday, S., Twelvetrees, A. E., Moughamian, A. J., & Holzbaur, E. L. (2014). “Axonal Transport: Cargo-Specific Mechanisms of Motility and Regulation.” Neuron, 84 (2), 292–309. https://doi.org/10.1016/j.neuron.2014.10.019.
Nirschl, J., Ghiretti, A., & Holzbaur, E. (2017). “The impact of cytoskeletal organization on the local regulation of neuronal transport.” Nature Reviews Neuroscience, 18, 585–597. https://doi.org/10.1038/nrn.2017.100.
Reck-Peterson, S. L., Redwine, W. B., Vale, R. D., & Carter, A. P. (2018). “The cytoplasmic dynein transport machinery and its many cargoes.” Nature Reviews Molecular Cell Biology, 19, 382–398. https://doi.org/10.1038/s41580-018-0004-3.
Sleigh, J. N., Rossor, A. M., Fellows, A. D., Tosolini, A. P., & Schiavo, G. (2019). “Axonal transport and neurological disease.” Nature Reviews Neurology, 15, 691–703. https://doi.org/10.1038/s41582-019-0257-2.
Chapter 27: Dendritic Highways
The vast signaling among large numbers of compartments in dendrites is just now coming into focus. Examples are being learned about specific types of computations based on signals among dendritic compartments. But there is much more to be learned, and it is incredibly difficult research. One article is a sixty-year historic retrospective about how dendrites calculate signals. Two articles detail rapidly changing spines related to neuroplasticity. One article is about spine changes related to neuropsychiatric illness. One article is about dendritic calculation complexity, and a recent article shows a particular type of dendrite calculation in the cortex.
Bartol, T. M., Bromer, C., Kinney, J., Chirillo, M. A., Bourne, J. N., Harris, K. M., & Sejnowski, T. J. (2015). “Nanoconnectomic upper bound on the variability of synaptic plasticity.” eLife, 4, e10778. https://doi.org/10.7554/eLife.10778.
Forrest, M. P., Parnell, E., & Penzes, P. (2018). “Dendritic structural plasticity and neuropsychiatric disease.” Nature Reviews Neuroscience, 19, 215–234. https://doi.org/10.1038/nrn.2018.16.
Gidon, A., Zolnik, T. A., Fidzinski, P., Bolduan, F., Papoutsi, A., Poirazi, P., Holtkamp, M., Vida, I., & Larkum, M. E. (2020). “Dendritic action potentials and computation in human layer 2/3 cortical neurons.” Science, 367 (6473), 83–87. https://doi.org/10.1126/science.aax6239.
Hanus, C., & Schuman, E. M. (2013). “Proteostasis in complex dendrites.” Nature Reviews Neuroscience, 14, 638–648. https://doi.org/10.1038/nrn3546.
Koleske, A. J. (2013). “Molecular mechanisms of dendrite stability.” Nature Reviews Neuroscience, 14, 536–550. https://doi.org/10.1038/nrn3486.
Nishiyama, J., & Yasuda, R. “Biochemical Computation for Spine Structural Plasticity.” Neuron, 87 (1), 63–75. https://doi.org/10.1016/j.neuron.2015.05.043.
Stuart, G. J., & Spruston, N. (2015). “Dendritic integration: 60 years of progress.” Nature Neuroscience, 18, 1713–1721. https://doi.org/10.1038/nn.4157.
Chapter 28: The Significance of Cilia
The wide-ranging functions of primary cilia are described in two articles. Another two articles describe particular cilia functions in cancer and the developing brain. One article is about transport in the cilium. Two others are about building the cilium.
Anvarian, Z., Mykytyn, K., Mukhopadhyay, S., Pedersen, L. B., Christensen, S. T. (2019). “Cellular signaling by primary cilia in development, organ function and disease.” Nature Reviews Nephrology, 15, 199–219. https://doi.org/10.1038/s41581-019-0116-9.
Bhogaraju, S., Cajanek, L., Fort, C., Blisnick, T., Weber, K., Taschner, M., Mizuno, N., Lamla, S., Bastin, P., Nigg, E. A., & Lorentzen, E. (2013). “Molecular Basis of Tubulin Transport Within the Cilium by IFT74 and IFT81.” Science, 341 (6149), 1009–1012. https://doi.org/10.1126/science.1240985.
Goetz, S. C., & Anderson, K. V. (2010). “The primary cilium: a signaling centre during vertebrate development.” Nature Reviews Genetics, 11, 331–344. https://doi.org/10.1038/nrg2774.
Guemez-Gamboa, A., Coufal, N. G., & Gleeson, J. G. (2014). “Primary Cilia in the Developing and Mature Brain.” Neuron, 82 (3), 511–521. https://doi.org/10.1016/j.neuron.2014.04.024.
Ishikawa, H., & Marshall, W. F. (2011). “Ciliogenesis: building the cell’s antenna.” Nature Reviews Molecular Cell Biology, 12, 222–234. https://doi.org/10.1038/nrm3085.
Liu, H., Kiseleva, A. A., & Golemis, E. A. (2018). “Ciliary signaling in cancer.” Nature Reviews Cancer, 18, 511–524. https://doi.org/10.1038/s41568-018-0023-6.
Nachury, M. V., & Mick, D. U. (2019). “Establishing and regulating the composition of cilia for signal transduction.” Nature Reviews Molecular Cell Biology, 20, 389–405. https://doi.org/10.1038/s41580-019-0116-4.
Chapter 29: Talking Molecules? The Case for mTOR
Three articles describe the incredible number of functions related to the molecule mTOR. One article describes mTOR’s amino acid sensing for protein building and another mTOR’s significance in neurology. Another article describes the central role of the lysosome, which works closely with mTOR in signaling and cell quality control.
Abraham, R. T. (2015). “Making sense of amino acid sensing.” Science, 347 (6218), 128–129. https://doi.org/10.1126/science.aaa4570.
Jones, R. G., & Pearce, E. J. (2017). “MenTORing Immunity: mTOR Signaling in the Development and Function of Tissue-Resident Immune Cells.” Immunity, 46 (5), 730–742. https://doi.org/10.1016/j.immuni.2017.04.028.
Lawrence, R. E., & Zoncu, R. (2019). “The lysosome as a cellular centre for signalling, metabolism and quality control.” Nature Cell Biology, 21, 133–142. https://doi.org/10.1038/s41556-018-0244-7.
Lipton, J. O., & Sahin, M. (2014). “The Neurology of mTOR.” Neuron, 84 (2), 275–291. https://doi.org/10.1016/j.neuron.2014.09.034.
Liu, G. Y., & Sabatini, D. M. (2020). “mTOR at the nexus of nutrition, growth, ageing and disease.” Nature Reviews Molecular Cell Biology. https://doi.org/10.1038/s41580-019-0199-y.
Saxton, R. A., & Sabatini, D. M. (2017). “mTOR Signaling in Growth, Metabolism, and Disease.” Cell, 168 (6), 960–976. https://doi.org/10.1016/j.cell.2017.02.004.