Mystery at the heart of life

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December 21, 2014

Cell biology, Intelligent Design, News

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Cell biology
Intelligent Design
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By Biologic Institute’s Ann Gauger, at Christianity Today’s Behemoth, the secret life of cells:

Our bodies are made up of some 100 trillion cells. We tend to think of cells as static, because that’s how they were presented to us in textbooks. In fact, the cell is like the most antic, madcap, crowded (yet fantastically efficient) city you can picture. And at its heart lies a mystery—or I should say, several mysteries—involving three special kinds of molecules: DNA, RNA, and proteins.

These molecules are assembled into long chains called polymers, and are uniquely suited for the roles they play. More importantly, life absolutely depends upon them. We have to have DNA, RNA, and protein all present and active at the same time for a living organism to live.

How they work together so optimally and efficiently is not merely amazing, but also a great enigma, a mystery that lies at the heart of life itself. More. Paywall soon after. May be worth it.

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[...] ROR? may regulate ILC3 cells [...] [...] ILC2s in different tissues might develop from separate progenitors that have distinct developmental requirements —an important question which requires further investigation. [...] it is still not clear whether Runx proteins are specifically required for the development of ILCs.
Transcriptional regulators dictate innate lymphoid cell fates. Zhong C, Zhu J Protein Cell. doi: 10.1007/s13238-017-0369-7.

[emphasis added] Work in progress… stay tuned. Complex complexity.Dionisio_{March 16, 2017
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Thus as the field continues to explore the functions of ILCs, new and novel functions of various tissue-resident ILC subsets are being reported. At present, the regulatory mechanisms of innate lymphoid cell development have been quite elusive. [...] the precise mechanisms through which Id2 mediates ILC development and the environmental signals that induce Id2 expression in ChILP cells are still elusive. [...] it is intriguing to explore whether the GATA-3 expression levels in innate lymphocyte progenitors can determine their lineage fates towards either helper-like ILCs or cytotoxic cNK cells, in a similar manner to the function of GATA-3 in CD4+ and CD8+ T cell lineage commitment. Interestingly, PLZF is only transiently expressed at the ILC progenitor stage. [...] Notch signaling seems to be dynamically regulated and its functions may be stage specific during ILC development. [...] a decrease in Notch signals, in concert with their downstream target genes, including Tcf7, Hes1, Gata3, and Bcl11b might be responsible for the developmental defect in ChILPs. Although the above transcription factors are essential for the generation of ILCs, the regulatory network among them in ILC progenitors, and the precise mechanism through which ILCs are developed still need further investigation. Our current knowledge about ILC development is still quite limited. The regulation of ILC development is likely to be far more complicated than we have discussed. Additional un-described transcriptional regulators or environment cues may play large roles in governing progenitor cell fates during development. Further studies of ILC progenitors are ultimately necessary to further understand the evolution and lineage specification of the lymphoid system in mice and clinical patients. [...] the detailed mechanism of how GATA-3 maintains mature ILC2s is still unclear. [...] the function of Bcl11b in non-ILC2s is still elusive. The underlying mechanism of ROR?-mediated ILC2 development is still unclear. [...] it is not clear whether ROR? has any function in mature ILC1 or ILC2 cells.
Transcriptional regulators dictate innate lymphoid cell fates. Zhong C, Zhu J Protein Cell. doi: 10.1007/s13238-017-0369-7.

[emphasis added] Just a few outstanding questions left... Work in progress… stay tuned. Complex complexity.Dionisio_{March 16, 2017
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Compared to other cells in the innate immune system, ILCs are unique in that they may produce and secrete cytokines that were classically regarded as CD4+ Th cell products [...] A major feature of innate immunity is the antigen non-specificity. Pattern recongnition (PR) is a well-known manner to initiate an innate response. The innate immune system recognizes pathogen-associated or damage-associated molecular patterns (PAMPs or DAMPs) through pattern recognition receptors (PRRs) in a semi-specific manner [...] Signals transduced downstream of PRRs may promote the production of pro-inflammatory cytokines or chemokines, including IL-1?, TNF?, IFN-?, IL-8, etc.
Transcriptional regulators dictate innate lymphoid cell fates. Zhong C, Zhu J Protein Cell. doi: 10.1007/s13238-017-0369-7.

Complex complexity.Dionisio_{March 16, 2017
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[...] a comprehensive understanding of the interactions and regulatory mechanisms mediated by these transcription factors will help us to further understand how ILCs exert their helper-like functions and bridge the innate and adaptive immunity.
Transcriptional regulators dictate innate lymphoid cell fates. Zhong C, Zhu J Protein Cell. doi: 10.1007/s13238-017-0369-7.

Work in progress… stay tuned. Complex complexity.Dionisio_{March 15, 2017
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Surprisingly, it has been demonstrated that conventional lymphocytes (both B and T cells) can internalize bacteria in an innate-like manner. CD4+ T cells can capture and kill bacteria by transphagocytosis from infected DCs. The precise role of the CD4+ T cell-dependent bacterial clearance during infections in vivo remains to be determined, as the number of bacteria directly cleared by transphagocytosis seems to be low, suggesting other mechanisms for the reduction of bacterial load (i.e., cytokine release or antigen presentation). In agreement with this hypothesis, transphagocytic T cells secrete large amounts of proinflammatory cytokines, mounting a potent Th-1 response.
Close Encounters of Lymphoid Cells and Bacteria. Cruz-Adalia A, Veiga E Front Immunol. 7:405. DOI: 10.3389/fimmu.2016.00405

Surprisingly? Why? Complex complexity.Dionisio_{March 15, 2017
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During infections, the first reaction of the host against microbial pathogens is carried out by innate immune cells, which recognize conserved structures on pathogens, called pathogen-associated molecular patterns. Afterward, some of these innate cells can phagocytose and destroy the pathogens, secreting cytokines that would modulate the immune response to the challenge. This rapid response is normally followed by the adaptive immunity, more specific and essential for a complete pathogen clearance in many cases.
Close Encounters of Lymphoid Cells and Bacteria. Cruz-Adalia A, Veiga E Front Immunol. 7:405. DOI: 10.3389/fimmu.2016.00405

Complex complexity.Dionisio_{March 15, 2017
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Vitamin A (VA) is a lipophilic micronutrient obtained by dietary ingestion of primarily pro-vitamin A carotenoids (such as ?-carotene) and retinyl esters (RE) derived from plant and animal food, respectively. [...] atRA works as a crucial regulator of DC function, which dictates T helper and effector cell function in the mucosal sites and in peripheral tissues. Interestingly, the cytokine milieu can influence DCs to induce pro-inflammatory T helper functions, even in the presence of atRA. [...] atRA exerts a crucial role in DC function in order to maintain tolerance against food and microbial antigens and promote tissue homeostasis.
Retinoic Acid and Its Role in Modulating Intestinal Innate Immunity Paulo Czarnewski, Srustidhar Das, Sara M. Parigi, and Eduardo J. Villablanca Nutrients. 9(1): 68. doi: 10.3390/nu9010068

Complex complexity.Dionisio_{March 15, 2017
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Vitamin A (VA) is amongst the most well characterized food-derived nutrients with diverse immune modulatory roles. Deficiency in dietary VA has not only been associated with immune dysfunctions in the gut, but also with several systemic immune disorders.
Retinoic Acid and Its Role in Modulating Intestinal Innate Immunity Paulo Czarnewski, Srustidhar Das, Sara M. Parigi, and Eduardo J. Villablanca Nutrients. 9(1): 68. doi: 10.3390/nu9010068

Had we stayed in Eden -where we had all we needed- none of this would have been an issue. Oh, well. Too late now. But still there's hope before this age of grace ends. Saving faith in Christ alone can take us back to where we once belonged.Dionisio_{March 15, 2017
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Group 3 ILC play central roles in lymphoid organogenesis, orchestration of adaptive immunity, regulation of peripheral tolerance and as effector cells in the context of immunity and inflammation. [...] challenges remain in resolving the relevance of ILC3 heterogeneity and incorporating recently identified novel transcriptional and metabolic states in the context of current nomenclature. A more nuanced understanding of ILC3 subset?specific roles in intestinal immunity will aid the development of targeted therapeutic interventions aimed at maintaining beneficial homeostatic ILC3 functions, while neutralizing pro?inflammatory ILC3 pathways that contribute to the onset or progression of tissue inflammation.
Functional and phenotypic heterogeneity of group 3 innate lymphoid cells. Melo-Gonzalez F, Hepworth MR Immunology. 150(3):265-275. doi: 10.1111/imm.12697

Work in progress… stay tuned. Complex complexity.Dionisio_{March 15, 2017
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Future studies will elucidate further the mechanisms inducing RET expression in ILC3. Notably, neurotrophic factors are the molecular link between glial cell sensing, innate IL-22 and intestinal epithelial defence. [...] coordination of innate immunity and neuronal function may ensure efficient mucosal homeostasis and a co-regulated neuro-immune response to various environmental challenges, including xenobiotics, intestinal infection, dietary aggressions and cancer.
Glial-cell-derived neuroregulators control type 3 innate lymphoid cells and gut defence. Ibiza S, García-Cassani B, Ribeiro H, Carvalho T, Almeida L, Marques R, Misic AM, Bartow-McKenney C, Larson DM, Pavan WJ, Eberl G, Grice EA, Veiga-Fernandes H. Nature. 535(7612): 440–443. doi: 10.1038/nature18644

Work in progress… stay tuned. Complex complexity.Dionisio_{March 15, 2017
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[...] a better understanding of the regulation of expression of Ret on ILC subsets or other immune cells will be relevant for chronic inflammatory disease pathogenesis and possibly treatment.
A new edge to immune surveillance by the neural system. Bernink JH, Spits H, de Jonge WJ Cell Res. 26(11):1178-1179. doi: 10.1038/cr.2016.107.

Work in progress... stay tuned. Complex complexity.Dionisio_{March 15, 2017
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[...] the role of EGC in immune surveillance may be much more prominent than expected from previous studies.
A new edge to immune surveillance by the neural system. Bernink JH, Spits H, de Jonge WJ Cell Res. 26(11):1178-1179. doi: 10.1038/cr.2016.107.

much more prominent than expected? what else is new? what were those expectations based on? Work in progress... stay tuned. Complex complexity.Dionisio_{March 15, 2017
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It would be of interest to explore whether Ret signaling may also regulate innate type 2 cytokine functions [...]
A new edge to immune surveillance by the neural system. Bernink JH, Spits H, de Jonge WJ Cell Res. 26(11):1178-1179. doi: 10.1038/cr.2016.107.

Work in progress... stay tuned. Complex complexity.Dionisio_{March 15, 2017
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Dissecting the composition of the distinct ILC3 subsets in wild-type mice, Ret-deficient mice, and mice that have a gain-of-function mutation in Ret would further contribute to our understanding of how this kinase is involved in the regulation of IL-22 production in the distinct CCR6? ILC3 subsets.
A new edge to immune surveillance by the neural system. Bernink JH, Spits H, de Jonge WJ Cell Res. 26(11):1178-1179. doi: 10.1038/cr.2016.107.

Work in progress... stay tuned. Complex complexity.Dionisio_{March 14, 2017
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[...] ILC3 can respond to signals from EGCs through Ret, in addition to a variety of previously identified mediators derived from myeloid cells such as IL-1?, IL-23, or dietary products such as retinoic acids and aryl hydrocarbon receptor agonists. It is unclear whether all these signals act on the same cell or on different subsets.
A new edge to immune surveillance by the neural system. Bernink JH, Spits H, de Jonge WJ Cell Res. 26(11):1178-1179. doi: 10.1038/cr.2016.107.

Complex complexity.Dionisio_{March 14, 2017
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The enteric nervous system (ENS) acts largely autonomously to regulate intestinal motility and secretion and is often referred to as our “second brain”, because of its complexity and structure. EGC certainly plays an eminent role in mucosal immune homeostasis although their immune-supportive function is incompletely understood at present. Somewhat surprising, the production of another ILC3 signature cytokine IL-17 is not affected by Ret ablation in ILC3 [...]
A new edge to immune surveillance by the neural system. Bernink JH, Spits H, de Jonge WJ Cell Res. 26(11):1178-1179. doi: 10.1038/cr.2016.107.

Did somebody say "surprising"? :) Complex complexity.Dionisio_{March 14, 2017
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A recent paper published in Nature demonstrates a multifaceted relation between enteric glial cells (EGC), intestinal epithelia, and ILC3, via the EGC release of neurotrophic factors, a structurally related group of ligands within the TGF-? superfamily of signaling molecules and IL-22 produced by ILC3.
A new edge to immune surveillance by the neural system. Bernink JH, Spits H, de Jonge WJ Cell Res. 26(11):1178-1179. doi: 10.1038/cr.2016.107.

Complex complexity.Dionisio_{March 14, 2017
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[...] slithering could be a more widely used mechanism of movement and sorting of epithelial cells that has been overlooked even in well-studied epithelia [...] It will be important to identify the slithering program and indeed the full program of NEB formation including cell selection, migration, differentiation, and innervation [...]
Formation of a neurosensory organ by epithelial cell slithering Christin S. Kuo and Mark A. Krasnow Cell. 163(2): 394–405. doi: 10.1016/j.cell.2015.09.021

Did somebody say "overlooked"? Did somebody say "program"? Complex complexity.Dionisio_{March 5, 2017
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Two prominent features of slithering are its selectivity for NE cells and their specific targeting to diametrically opposed positions at the base of each bronchial branch, raising the questions: what provides the guidance cue and its selectivity for NE cells? Perhaps the cue is a combination of more broadly distributed but overlapping signals [...] A high priority now is to identify the signal(s) and their sources and receptors that control slithering and to determine if the same signals also guide outgrowth of neurites that target NEBs.
Formation of a neurosensory organ by epithelial cell slithering Christin S. Kuo and Mark A. Krasnow Cell. 163(2): 394–405. doi: 10.1016/j.cell.2015.09.021

Complex complexity.Dionisio_{March 5, 2017
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[...] NEBs form by a targeted mode of epithelial cell sorting we call “slithering,” in which the rearranging cells transiently lose epithelial structure and polarity yet remain intimately associated with the epithelial sheet as they traverse neighboring epithelial cells and converge at the target site. This mechanism of cell rearrangement differs dramatically from intercalation, the classical mode of epithelial cell rearrangement [...] [...] slithering occurs without proliferation and is selective, directed, and purposeful.
Formation of a neurosensory organ by epithelial cell slithering Christin S. Kuo and Mark A. Krasnow Cell. 163(2): 394–405. doi: 10.1016/j.cell.2015.09.021

Did somebody say "selective, directed, and purposeful"? Complex complexity.Dionisio_{March 5, 2017
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Epithelia are sheets of cells that line and protect the body and internal organs, and the polarized cells that comprise them play important roles in absorption, secretion, and sensation. Epithelial cells are normally tightly attached to one another through specialized junctions and adhesion proteins along their lateral surface, and anchored to the basement membrane at their basal surface. Although epithelial sheets can grow and change shape, the constituent cells typically maintain their relative positions.
Formation of a neurosensory organ by epithelial cell slithering Christin S. Kuo and Mark A. Krasnow Cell. 163(2): 394–405. doi: 10.1016/j.cell.2015.09.021

Complex complexity.Dionisio_{March 5, 2017
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Cxcr4 is a chemokine receptor regulating cell migration, and N-cadherin is a transmembrane protein regulating cell-cell adhesion. [...] NE cells form NEBs by a novel form of cell migration they named “slithering.” [...] epithelial cell context may influence NEB formation. [...] the majority of migrating NE cells is directed toward distal regions, even when the nearest bifurcation point is found in another direction [...]
Directed Migration of Pulmonary Neuroendocrine Cells toward Airway Branches Organizes the Stereotypic Location of Neuroepithelial Bodies. Noguchi M, Sumiyama K, Morimoto M Cell Rep. 13(12):2679-86. doi: 10.1016/j.celrep.2015.11.058.

Complex complexity.Dionisio_{March 5, 2017
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[...] we shouldn’t take epithelial cells for granted, as they will certainly continue to surprise us with new exciting mechanisms, especially when studied in situ in their many different contexts.
Epithelial Morphogenesis: Stage Diving with Purpose. Gilmour D Dev Cell. 35(1):7-8. doi: 10.1016/j.devcel.2015.09.025.

Complex complexity.Dionisio_{March 4, 2017
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[...] what guides slithering NE progenitors during their coalescence at the branch points [?] [...] how slithering cells physically lift themselves above, or around, neighboring epithelial cells [?] [...] distinct mechanisms may be at work here.
Epithelial Morphogenesis: Stage Diving with Purpose. Gilmour D Dev Cell. 35(1):7-8. doi: 10.1016/j.devcel.2015.09.025.

Complex complexity.Dionisio_{March 4, 2017
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[...] there is the possibility that other, potentially novel guidance mechanisms are involved.
Epithelial Morphogenesis: Stage Diving with Purpose. Gilmour D Dev Cell. 35(1):7-8. doi: 10.1016/j.devcel.2015.09.025.

Complex complexity.Dionisio_{March 4, 2017
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Like many groundbreaking studies, the paper of Kuo and Krasnow gives plenty food for thought and generates a number of fascinating questions that are still to be answered.
Epithelial Morphogenesis: Stage Diving with Purpose. Gilmour D Dev Cell. 35(1):7-8. doi: 10.1016/j.devcel.2015.09.025.

As some outstanding questions get answered, new ones are generated. Complex complexity.Dionisio_{March 4, 2017
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[...] live imaging of slice culture preparations and careful analysis of adhesion and polarity markers reveals a mechanism whereby NE cells first transiently lose epithelial adhesion and polarity, exit the epithelium, extend out, and traverse neighboring cells to converge on the target site before reinserting into the layer. The authors christen this previously undescribed mode of migration “slithering.”
Epithelial Morphogenesis: Stage Diving with Purpose. Gilmour D Dev Cell. 35(1):7-8. doi: 10.1016/j.devcel.2015.09.025.

Complex complexity.Dionisio_{March 4, 2017
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[...] surprisingly, cell division plays no role in NEB formation; rather, these clusters form through the coalescence of individual NE progenitors that can be placed into five different morphological categories [...]
Epithelial Morphogenesis: Stage Diving with Purpose. Gilmour D Dev Cell. 35(1):7-8. doi: 10.1016/j.devcel.2015.09.025.

Did somebody say "surprisingly"? Complex complexity.Dionisio_{March 4, 2017
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Amazingly, when individual NE cells within the epithelium coalesce to form NEB clusters, they do so via the cellular equivalent of “stage diving,” a highly risky maneuver made famous by rock stars.
Epithelial Morphogenesis: Stage Diving with Purpose. Gilmour D Dev Cell. 35(1):7-8. doi: 10.1016/j.devcel.2015.09.025.

Did somebody say "amazingly"? Complex complexity.Dionisio_{March 4, 2017
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Cells can enter into a dormant state when faced with unfavorable conditions. However, how cells enter into and recover from this state is still poorly understood.
A pH-driven transition of the cytoplasm from a fluid- to a solid-like state promotes entry into dormancy Matthias Christoph Munder,1 Daniel Midtvedt,2 Titus Franzmann,1 Elisabeth Nüske,1 Oliver Otto,3 Maik Herbig,3 Elke Ulbricht,3 Paul Müller,3 Anna Taubenberger,3 Shovamayee Maharana,1 Liliana Malinovska,1 Doris Richter,1 Jochen Guck,3 Vasily Zaburdaev,2 and Simon Alberti eLife. 2016; 5: e09347. doi: 10.7554/eLife.09347

Complex complexity.Dionisio_{March 3, 2017
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