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ECHOVIRUS Meaning: "orphan" because when discovered they were not known to cause any disease. See definitions of echovirus.

Carl Zimmer's Life's Edge is a departure from his previous work in that it is a book that is as much about what scientists have so far failed to understand as what they have come to understand. As its subtitle suggests, this book is about how life is defined, how life arose, and how we tell life from nonlife. These topics seem as though they would be of great concern to the field of biology—biology being, after all, the study of (“ology”) life (“bio”)—but they have rarely received much formal attention, occupying the scientific margins for hundreds of years and appearing on center stage every so often only to quickly retreat. Zimmer begins with a story from the early 1900s in which a physicist named John Butler Burke synthesized “highly organized bodies” that resembled microbial colonies using radium and sterilized beef broth. Newspapers buzzed with exciting headlines, proclaiming that Burke had discovered the “secret of life.” But the scientist's fame and success were short-lived, his discovery a false start. The book is full of such false starts, including the notable period during which the biologist Thomas Huxley became convinced that life evolved from a kind of primal slime that coats the bottom of the sea. (Spoiler alert: It did not.) Superficially, the question “What is life?” seems resolvable. After all, as Zimmer points out in the book's first chapter, “experiments on animals,” including chickens, “have revealed they can make some of the same distinctions between the living and the nonliving that we do.” If poultry can make sense of the boundary between the living and the nonliving, how difficult could it be? Very difficult, it turns out. At every boundary, life is blurry. When does the life of one generation begin and that of the previous generation end? Is a bacterial spore that is not metabolizing alive or dead or something else? If a human body is partially human cells and partially bacterial cells, and the bacterial cells go on living after the human cells have died, has the organism died? If some of the human cells go on living and dividing, has the human died? Zimmer shows that the more one searches for answers to these questions, the more such answers retreat. Throughout the book, Zimmer illustrates how our behavior and our conceptions of birth, death, and organismal boundaries are very human-centric. For each species, these criteria are different, sometimes substantially so. The “bodies” of slime molds, for instance, can break apart, dry out, and drift in the wind when times are tough, only to reunite again under better circumstances. One has the feeling, while reading this book, of fumbling through the unknown. In a section called “The Quickening,” for example, Zimmer transitions from a careful discussion of the biological details of fertilization, to studies of species such as tardigrades that can enter life stages in which they are quiescent and neither dead nor fully alive, to research on when early human ancestors began to afford the dead special status by burying them. Meanwhile, the poems of Erasmus Darwin are set alongside Mary Shelley's Frankenstein and the chemistry of urea, to fascinating effect. I found myself feeling very grateful that Zimmer had drawn connections among these disparate themes. We biologists are often necessarily narrow in our perspective. “To become an expert on just one kind of life can demand an entire career,” Zimmer acknowledges. His breadth reveals more of the whole, however blurry, than would otherwise be available to the specialist. There were also plenty of sections that made me wish that we were living in a time when dinner parties were possible, so that some of Zimmer's observations might be readily shared: details about the sex lives and intelligence of slime molds, the possibility that tardigrades are currently living on the Moon, and his descriptions of the expandable hearts of some snakes, for example. By the end of this book, I felt challenged as a biologist to pull together my colleagues to talk about the big issues related to the limits of life, the origins of life, and the margins of life. We do not have these conversations often, probably partly because we are all so specialized, but also likely because the beginnings of life and the origins of life have become politicized. To this latter point, Zimmer reminds readers that how we think about the boundaries of life will always depend on what questions we ask. Quoting the biologist Joshua Lederberg, he writes, “The question of when life begins is answered according to the purposes for which we ask it.” By the end of the book, Zimmer had fully convinced me that the question of what it means to be alive is also best answered according to the purposes for which we ask—and that such inquiries will yield different outcomes depending on how we ask them.

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The hologenome concept of evolution is a hypothesis explaining host evolution in the context of the host microbiomes. As a hypothesis, it needs to be evaluated, especially with respect to the extent of fidelity of transgenerational coassociation of host and microbial lineages and the relative fitnes …

Many disease-causing bacteria use a molecular syringe to inject dozens of their proteins, called effectors, into intestinal cells, blocking key immune responses. Ruano-Gallego et al. used the mouse pathogen Citrobacter rodentium to model effector function in vivo. They found that effectors work together as a network, allowing the microbe great flexibility in maintaining pathogenicity. An artificial intelligence platform correctly predicted colonization outcomes of alternative networks from the in vivo data. However, the host was able to bypass the obstacles erected by different effector networks and activate complementary immune responses that cleared the pathogen and induced protective immunity. Science , this issue p. [eabc9531][1] ### INTRODUCTION Infections with many Gram-negative pathogens, including Escherichia coli , Salmonella , Shigella , and Yersinia , rely on the injection of effectors via type III secretion systems (T3SSs). The effectors hijack cellular processes through multiple mechanisms, including molecular mimicry and diverse enzymatic activities. Although in vitro analyses have shown that individual effectors can exhibit complementary, interdependent, or antagonistic relationships, most in vivo studies have focused on the contribution of single effectors to pathogenesis. Citrobacter rodentium is a natural mouse pathogen that shares infection strategies and virulence factors with the human pathogens enteropathogenic and enterohemorrhagic E. coli (EPEC and EHEC). The ability of these pathogens to colonize the gastrointestinal tract is mediated by the injection of effectors via a T3SS. Although C. rodentium infects 31 effectors, the prototype EPEC strain E2348/69 translocates 21 effectors. ### RATIONALE The aim of this study was to test the hypotheses that, rather than operating individually, the T3SS effectors form robust intracellular networks that can sustain large contractions and that expanded effector repertoires play a role in distinct disease phenotypes and host adaption. ### RESULTS We tested the effector-network paradigm by infecting mice with >100 C. rodentium effector mutant combinations. First, using machine learning prediction algorithms, we discovered additional effectors, NleN and NleO. We then sequentially deleted effector genes from two distinct starting points to reach sustainable endpoints, which resulted in strains missing 19 unrelated effectors (CR14) or 10 effectors involved in the modulation of innate immune responses in intestinal epithelial cells (IECs) (CRi9). Moreover, we deleted Map and EspF, which target the mitochondria and disrupt tight junctions. Unexpectedly, all strains colonized the colon and activated conserved metabolic and antimicrobial processes in the IECs while eliciting distinct cytokine and immune cell infiltration responses. In particular, although infection with C. rodentium Δ map /Δ espF failed to induce secretion of interleukin-22 (IL-22), CR14 and CRi9 triggered heightened secretion of IL-6 and granulocyte-macrophage colony-stimulating factor (GM-CSF) and of IL-22, interferon-γ (IFN-γ), and IL-17 from colonic explants, respectively. Nonetheless, infection with CR14 or CRi9 induced protective immunity against secondary infections. Although Tir, EspZ, and NleA are essential, other effectors exhibit context-dependent essentiality in vivo. Moreover, C. rodentium expressing the effector repertoire of EPEC E2348/69 failed to efficiently colonize mice. We used curated functional information and our in vivo data to train a machine learning model that predicted values for colonization efficiency of previously uncharacterized mutant combinations. Notably, a mutant with a low predicted value, lacking only nleF , nleG8 , nleG1 , nleB , and espL , failed to colonize. ### CONCLUSION Our analysis revealed that T3SS effectors form robust networks, which can sustain substantial contractions while maintaining virulence, and that the composition of the effector network contributes to host adaptation. Alternative effector networks within a single pathogen triggered markedly different immune responses yet induced protective immunity. CR14 did not tolerate any further contraction, which suggests that this network reached its robustness limit with only 12 effectors. As the robustness limits of other effector networks depend on the contraction starting point and the order of the deletions, machine learning models could transform our ability to predict alternative network functions. Together, this study demonstrates the robustness of T3SS effector networks and the ability of IECs to withstand drastic perturbations while maintaining antibacterial functions. ![Figure][2] T3SS effectors form robust intracellular networks. T3SS effector networks can sustain substantial contractions while maintaining virulence. Using C. rodentium as a model showed that although triggering the conserved infection signatures in IECs, distinct networks induce divergent immune responses and affect host adaption. Because the robustness limit depends on the contraction sequence, machine learning models could transform our ability to predict the virulence potential of alternative networks. Infections with many Gram-negative pathogens, including Escherichia coli , Salmonella , Shigella , and Yersinia , rely on type III secretion system (T3SS) effectors. We hypothesized that while hijacking processes within mammalian cells, the effectors operate as a robust network that can tolerate substantial contractions. This was tested in vivo using the mouse pathogen Citrobacter rodentium (encoding 31 effectors). Sequential gene deletions showed that effector essentiality for infection was context dependent and that the network could tolerate 60% contraction while maintaining pathogenicity. Despite inducing very different colonic cytokine profiles (e.g., interleukin-22, interleukin-17, interferon-γ, or granulocyte-macrophage colony-stimulating factor), different networks induced protective immunity. Using data from >100 distinct mutant combinations, we built and trained a machine learning model able to predict colonization outcomes, which were confirmed experimentally. Furthermore, reproducing the human-restricted enteropathogenic E. coli effector repertoire in C. rodentium was not sufficient for efficient colonization, which implicates effector networks in host adaptation. These results unveil the extreme robustness of both T3SS effector networks and host responses. [1]: /lookup/doi/10.1126/science.abc9531 [2]: pending:yes

The FindingPheno project will improve how we understand and utilise the functions provided by microbiomes in combating human diseases as well as the way we produce sustainable food for future generations. This newly funded EU Research and Innovation Action awarded to Assoc Prof Shyam Gopalakrishnan and Assoc Prof Morten Limborg, both from Center for Evolutionary Hologenomics and colleagues across Europe, will start on the 1st of March and be placed within the Center for Evolutionary Hologenomics. In this video Coordinator and Assoc Prof Shyam Gopalakrishnan explains about the project

How we think about what it means to be alive will always depend on what questions we ask

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