Borreliella burgdorferi Antimicrobial-Tolerant Persistence in Lyme Disease and Posttreatment Lyme Disease Syndromes.

The annual incidence of Lyme disease, caused by tick-transmitted Borreliella burgdorferi, is estimated to be at least 476,000 cases in the United States and many more worldwide. Ten to 20% of antimicrobial-treated Lyme disease patients display posttreatment Lyme disease syndrome (PTLDS), a clinical complication whose etiology and pathogenesis remain uncertain. Autoimmunity, cross-reactivity, molecular mimicry, coinfections, and borrelial tolerance to antimicrobials/persistence have been hypothesized and studied as potential causes of PTLDS. Studies of borrelial tolerance/persistence in vitro in response to antimicrobials and experimental studies in mice and nonhuman primates, taken together with clinical reports, have revealed that B. burgdorferi becomes tolerant to antimicrobials and may sometimes persist in animals and humans after the currently recommended antimicrobial treatment. Moreover, B. burgdorferi is pleomorphic and can generate viable-but-nonculturable bacteria, states also involved in antimicrobial tolerance. The multiple regulatory pathways and structural genes involved in mediating this tolerance to antimicrobials and environmental stressors by persistence might include the stringent (rel and dksA) and host adaptation (rpoS) responses, sugar metabolism (glpD), and polypeptide transporters (opp). Application of this recently reported knowledge to clinical studies can be expected to clarify the potential role of bacterial antibacterial tolerance/persistence in Lyme disease and PTLDS.

Spatial waves and temporal oscillations in vertebrate limb development.

The mesenchymal tissue of the developing vertebrate limb bud is an excitable medium that sustains both spatial and temporal periodic phenomena. The first of these is the outcome of general Turing-type reaction-diffusion dynamics that generate spatial standing waves of cell condensations. These condensations are transformed into the nodules and rods of the cartilaginous, and eventually (in most species) the bony, endoskeleton. In the second, temporal periodicity results from intracellular regulatory dynamics that generate oscillations in the expression of one or more gene whose products modulate the spatial patterning system. Here we review experimental evidence from the chicken embryo, interpreted by a set of mathematical and computational models, that the spatial wave-forming system is based on two glycan-binding proteins, galectin-1A and galectin-8 in interaction with each other and the cells that produce them, and that the temporal oscillation occurs in the expression of the transcriptional coregulator Hes1. The multicellular synchronization of the Hes1 oscillation across the limb bud serves to coordinate the biochemical states of the mesenchymal cells globally, thereby refining and sharpening the spatial pattern. Significantly, the wave-forming reaction-diffusion-based mechanism itself, unlike most Turing-type systems, does not contain an oscillatory core, and may have evolved to this condition as it came to incorporate the cell-matrix adhesion module that enabled its pattern-forming capability.

Interplay of mesoscale physics and agent-like behaviors in the parallel evolution of aggregative multicellularity.

Myxobacteria and dictyostelids are prokaryotic and eukaryotic multicellular lineages, respectively, that after nutrient depletion aggregate and develop into structures called fruiting bodies. The developmental processes and resulting morphological outcomes resemble one another to a remarkable extent despite their independent origins, the evolutionary distance between them and the lack of traceable homology in molecular mechanisms. We hypothesize that the morphological parallelism between the two lineages arises as the consequence of the interplay within multicellular aggregates between generic processes, physical and physicochemical processes operating similarly in living and non-living matter at the mesoscale (~10-3-10-1 m) and agent-like behaviors, unique to living systems and characteristic of the constituent cells, considered as autonomous entities acting according to internal rules in a shared environment. Here, we analyze the contributions of generic and agent-like determinants in myxobacteria and dictyostelid development and their roles in the generation of their common traits. Consequent to aggregation, collective cell-cell contacts mediate the emergence of liquid-like properties, making nascent multicellular masses subject to novel patterning and morphogenetic processes. In both lineages, this leads to behaviors such as streaming, rippling, and rounding-up, as seen in non-living fluids. Later the aggregates solidify, leading them to exhibit additional generic properties and motifs. Computational models suggest that the morphological phenotypes of the multicellular masses deviate from the predictions of generic physics due to the contribution of agent-like behaviors of cells such as directed migration, quiescence, and oscillatory signal transduction mediated by responses to external cues. These employ signaling mechanisms that reflect the evolutionary histories of the respective organisms. We propose that the similar developmental trajectories of myxobacteria and dictyostelids are more due to shared generic physical processes in coordination with analogous agent-type behaviors than to convergent evolution under parallel selection regimes. Insights from the biology of these aggregative forms may enable a unified understanding of developmental evolution, including that of animals and plants.

Multiscale modeling of vertebrate limb development.

We review the current state of mathematical modeling of cartilage pattern formation in vertebrate limbs. We place emphasis on several reaction-diffusion type models that have been proposed in the last few years. These models are grounded in more detailed knowledge of the relevant regulatory processes than previous ones but generally refer to different molecular aspects of these processes. Considering these models in light of comparative phylogenomics permits framing of hypotheses on the evolutionary order of appearance of the respective mechanisms and their roles in the fin-to-limb transition. This article is categorized under: Analytical and Computational Methods > Computational Methods Models of Systems Properties and Processes > Mechanistic Models Developmental Biology > Developmental Processes in Health and Disease Analytical and Computational Methods > Analytical Methods.

The experience of transition from nursing students to newly graduated registered nurses in Singapore.

OBJECTIVES: To investigate the experience of newly graduated registered nurses (NGRNs) in Singapore following their initial 6-12 months of transition from nursing student to registered nurse. METHODS: This mixed-methods study consisted of two phases. In the first phase, data were collected via the administration of the online survey to 30 NGRNs. The questionnaire contained 42 items of the four-point Likert scale survey. In the second phase, a focus group interview was conducted with 5 NGRNs to gather complementary information regarding the major findings from the first phase. RESULTS: The survey revealed despite most NGRNs (80%) in this study expressed overall satisfied with their transition, the item score was (2.97±0.61) out of 4, the majority (83.3%) also perceived their transition to professional practice being stressful, the item score was (3.07±0.74) out of 4.Three themes emerged from the interview, 'personal transition experience', 'professional transition experience', and 'organizational transition experience', which are entwined to construct overall NGRNs' transition experiences. CONCLUSIONS: This study reaffirms the theory-practice gap phenomenon. This signifies the need for closer collaboration between educational, healthcare industry and regulatory stakeholders to examine and address factors that influence their transition experience to better support them for workforce readiness.

Cell differentiation: What have we learned in 50 years?

I revisit two theories of cell differentiation in multicellular organisms published a half-century ago, Stuart Kauffman's global genome regulatory dynamics (GGRD) model and Roy Britten's and Eric Davidson's modular gene regulatory network (MGRN) model, in light of newer knowledge of mechanisms of gene regulation in the metazoans (animals). The two models continue to inform hypotheses and computational studies of differentiation of lineage-adjacent cell types. However, their shared notion (based on bacterial regulatory systems) of gene switches and networks built from them have constrained progress in understanding the dynamics and evolution of differentiation. Recent work has described unique write-read-rewrite chromatin-based expression encoding in eukaryotes, as well metazoan-specific processes of gene activation and silencing in condensed-phase, enhancer-recruiting regulatory hubs, employing disordered proteins, including transcription factors, with context-dependent identities. These findings suggest an evolutionary scenario in which the origination of differentiation in animals, rather than depending exclusively on adaptive natural selection, emerged as a consequence of a type of multicellularity in which the novel metazoan gene regulatory apparatus was readily mobilized to amplify and exaggerate inherent cell functions of unicellular ancestors. The plausibility of this hypothesis is illustrated by the evolution of the developmental role of Grainyhead-like in the formation of epithelium.

The many roads to and from multicellularity.

The multiple origins of multicellularity had far-reaching consequences ranging from the appearance of phenotypically complex life-forms to their effects on Earth's aquatic and terrestrial ecosystems. Yet, many important questions remain. For example, do all lineages and clades share an ancestral developmental predisposition for multicellularity emerging from genomic and biophysical motifs shared from a last common ancestor, or are the multiple origins of multicellularity truly independent evolutionary events? In this review, we highlight recent developments and pitfalls in understanding the evolution of multicellularity with an emphasis on plants (here defined broadly to include the polyphyletic algae), but also draw upon insights from animals and their holozoan relatives, fungi and amoebozoans. Based on our review, we conclude that the evolution of multicellular organisms requires three phases (origination by disparate cell-cell attachment modalities, followed by integration by lineage-specific physiological mechanisms, and autonomization by natural selection) that have been achieved differently in different lineages.

Corrigendum: Inherency of Form and Function in Animal Development and Evolution.

[This corrects the article DOI: 10.3389/fphys.2019.00702.].

John Tyler Bonner: Remembering a scientific pioneer.

Throughout his life, John Tyler Bonner contributed to major transformations in the fields of developmental and evolutionary biology. He pondered the evolution of complexity and the significance of randomness in evolution, and was instrumental in the formation of evolutionary developmental biology. His contributions were vast, ranging from highly technical scientific articles to numerous books written for a broad audience. This historical vignette gathers reflections by several prominent researchers on the greatness of John Bonner and the implications of his work.

Inherent forms and the evolution of evolution.

John Bonner presented a provocative conjecture that the means by which organisms evolve has itself evolved. The elements of his postulated nonuniformitarianism in the essay under discussion-the emergence of sex, the enhanced selection pressures on larger multicellular forms-center on a presumed close mapping of genotypic to phenotypic change. A different view emerges from delving into earlier work of Bonner's in which he proposed the concept of "neutral phenotypes" and "neutral morphologies" allied to D'Arcy Thompson's analysis of physical determinants of form and studied the conditional elicitation of intrinsic organizational properties of cell aggregates in social amoebae. By comparing the shared and disparate mechanistic bases of morphogenesis and developmental outcomes in the embryos of metazoans (animals), closely related nonmetazoan holozoans, more distantly related dictyostelids, and very distantly related volvocine algae, I conclude, in agreement with Bonner's earlier proposals, that understanding the evolution of multicellular evolution requires knowledge of the inherent forms of diversifying lineages, and that the relevant causative factors extend beyond genes and adaptation to the physics of materials.

Inherency and homomorphy in the evolution of development.

Organismal development occurs when expression of certain genes leads to the mobilization of physical forces and effects that shape and pattern multicellular clusters. All materials exhibit preferred forms, but the inherent morphological motifs of some, such as liquids and crystalline solids are well-characterized. Recent work has shown that the origin of the animals (Metazoa) was accompanied by the acquisition by their developing tissues of liquid-like and liquid-crystalline properties. This and the novel capacity to produce stiff internal substrata (basal laminae) set these organisms apart from their closest relatives by the propensity (predictable from their material nature) to form complex bodies and organs. Once functional forms became established, however, they were susceptible to further genetic change as well as partial or full supplanting of original physical determinants by different ones. This results in the increasingly recognized phenomenon of homomorphy, the presence of the same structure in descendent organisms, brought about by transformed developmental mechanisms.

Inherency of Form and Function in Animal Development and Evolution.

I discuss recent work on the origins of morphology and cell-type diversification in Metazoa - collectively the animals - and propose a scenario for how these two properties became integrated, with the help of a third set of processes, cellular pattern formation, into the developmental programs seen in present-day metazoans. Inherent propensities to generate familiar forms and cell types, in essence a parts kit for the animals, are exhibited by present-day organisms and were likely more prominent in primitive ones. The structural motifs of animal bodies and organs, e.g., multilayered, hollow, elongated and segmented tissues, internal and external appendages, branched tubes, and modular endoskeletons, can be accounted for by the properties of mesoscale masses of metazoan cells. These material properties, in turn, resulted from the recruitment of "generic" physical forces and mechanisms - adhesion, contraction, polarity, chemical oscillation, diffusion - by toolkit molecules that were partly conserved from unicellular holozoan antecedents and partly novel, distributed in the different metazoan phyla in a fashion correlated with morphological complexity. The specialized functions of the terminally differentiated cell types in animals, e.g., contraction, excitability, barrier function, detoxification, excretion, were already present in ancestral unicellular organisms. These functions were implemented in metazoan differentiation in some cases using the same transcription factors as in single-celled ancestors, although controlled by regulatory mechanisms that were hybrids between earlier-evolved processes and regulatory innovations, such as enhancers. Cellular pattern formation, mediated by released morphogens interacting with biochemically responsive and excitable tissues, drew on inherent self-organizing processes in proto-metazoans to transform clusters of holozoan cells into animal embryos and organs.

Synchronization of Hes1 oscillations coordinates and refines condensation formation and patterning of the avian limb skeleton.

The tetrapod appendicular skeleton is initiated as spatially patterned mesenchymal condensations. The size and spacing of these condensations in avian limb buds are mediated by a reaction-diffusion-adhesion network consisting of galectins Gal-1A, Gal-8 and their cell surface receptors. In cell cultures, the appearance of condensations is synchronized across distances greater than the characteristic wavelength of their spatial pattern. We explored the possible role of observed oscillations of the transcriptional co-regulator Hes1 in this phenomenon. Treatment of micromass cultures with DAPT, a γ-secretase inhibitor, damped Hes1 oscillations, elevated Gal-1A and -8 mRNA levels, and led to irregularly-sized proto-condensations that subsequently fused. In developing limb buds, DAPT led to spatially non-uniform Hes1 expression and fused, truncated and misshapen digits. Periodicity in adhesive response to Gal-1A, a plausible Hes1-dependent function, was added to a previously tested mathematical model for condensation patterning by the two-galectin network. The enhanced model predicted regularization of patterning due to synchronization of Hes1 oscillations and resulting spatiotemporal coordination of its expression. The model also predicted changes in galectin expression and patterning in response to suppression of Hes1 expression, which were confirmed in in vitro experiments. Our results indicate that the two-galectin patterning network is regulated by Hes1 dynamics, the synchronization of which refines and regularizes limb skeletogenesis.

Does resource availability help determine the evolutionary route to multicellularity?

Genetic heterogeneity and homogeneity are associated with distinct sets of adaptive advantages and bottlenecks, both in developmental biology and population genetics. Whereas populations of individuals are usually genetically heterogeneous, most multicellular metazoans are genetically homogeneous. Observing that resource scarcity fuels genetic heterogeneity in populations, we propose that monoclonal development is compatible with the resource-rich and stable internal environments that complex multicellular bodies offer. In turn, polyclonal development persists in tumors and in certain metazoans, both exhibiting a closer dependence on external resources. This eco-evo-devo approach also suggests that multicellularity may originally have emerged through polyclonal development in early metazoans, because of their reduced shielding from environmental fluctuations.

Polarity, planes of cell division, and the evolution of plant multicellularity.

Organisms as diverse as bacteria, fungi, plants, and animals manifest a property called "polarity." The literature shows that polarity emerges as a consequence of different mechanisms in different lineages. However, across all unicellular and multicellular organisms, polarity is evident when cells, organs, or organisms manifest one or more of the following: orientation, axiation, and asymmetry. Here, we review the relationships among these three features in the context of cell division and the evolution of multicellular polarity primarily in plants (defined here to include the algae). Data from unicellular and unbranched filamentous organisms (e.g., Chlamydomonas and Ulothrix) show that cell orientation and axiation are marked by cytoplasmic asymmetries. Branched filamentous organisms (e.g., Cladophora and moss protonema) require an orthogonal reorientation of axiation, or a localized cell asymmetry (e.g., "tip" growth in pollen tubes and fungal hyphae). The evolution of complex multicellular meristematic polarity required a third reorientation of axiation. These transitions show that polarity and the orientation of the future plane(s) of cell division are dyadic dynamical patterning modules that were critical for multicellular eukaryotic organisms.