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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Comments

[...] the mechanisms through which commensal bacteria regulate host immunity remain unclear and merit future investigation. [...] further investigation is required to determine the repertoire, bio-geographical distribution, and bioactivity of metabolites in the gastrointestinal tract and how it may impact local and systemic inflammatory processes.
Microbiome-Modulated Metabolites at the Interface of Host Immunity Eran Blacher, Maayan Levy, Evgeny Tatirovsky and Eran Elinav DOI: 10.4049/jimmunol.1601247 J Immunol 2017; 198:572-580 http://www.jimmunol.org/content/198/2/572

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The gut microbiome is a microbial ecosystem that has diverse effects on physiological host functions, particularly immune development and activity. The molecular basis of host-microbiome interactions is only just beginning to be unraveled, and is mediated by both cell to cell interactions and the production, modification, and sensing of a large variety of bioactive small molecules, termed metabolites. Some microbiome-associated metabolites are bioactive and affect the host cellular processes [...] A number of metabolites impact mucosal and systemic immune maturation and function [...]
Microbiome-Modulated Metabolites at the Interface of Host Immunity Eran Blacher, Maayan Levy, Evgeny Tatirovsky and Eran Elinav DOI: 10.4049/jimmunol.1601247 J Immunol 2017; 198:572-580 http://www.jimmunol.org/content/198/2/572

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[...] little is known about the genes required for intestinal colonization and exploitation of nutrients by some of the pathogens that colonize the intestinal tract. Further studies in this area are necessary in order to fully clarify how certain pathogens are able to invade the intestinal tract and the mechanisms by which key members of the microbiota outcompete them.
Roles of the intestinal microbiota in pathogen protection Carles Ubeda, Ana Djukovic and Sandrine Isaac Clinical & Translational Immunology (2017) 6, e128; doi:10.1038/cti.2017.2

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[...] the microbiota can confer protection to pathogens through mechanisms that do not require the induction of the immune system. These mechanisms include the production of molecules that inhibit the growth of the pathogen or that interfere with their colonization capabilities. Further analysis of new subsets of metagenomic sequences, in combination with in vitro and in vivo experiments, should therefore expand our knowledge of bacterial derived molecules that can directly influence pathogen colonization capabilities. [...] a greater understanding of the biology of commensals and pathogens is required to identify novel mechanisms of protection.
Roles of the intestinal microbiota in pathogen protection Carles Ubeda, Ana Djukovic and Sandrine Isaac Clinical & Translational Immunology (2017) 6, e128; doi:10.1038/cti.2017.2

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The molecular mechanisms involved in the interaction between commensals and immune responses against pathogens are starting to be understood. [...] the type of diet consumed by the host can play an important role in the defense against infections, a field that requires further investigation.
Roles of the intestinal microbiota in pathogen protection Carles Ubeda, Ana Djukovic and Sandrine Isaac Clinical & Translational Immunology (2017) 6, e128; doi:10.1038/cti.2017.2

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Commensal microbes that colonize the gut can also have systemic effects on immunity, including the activation of neutrophils, induction of IgG responses and enhancement of myelopoiesis. The key commensal bacteria involved in the induction of the different components of the immune system are now starting to be identified, [...] [...] future research using mouse models may elucidate the impact of these novel cultivable bacterial species on the immune system and defense against infections.
Roles of the intestinal microbiota in pathogen protection Carles Ubeda, Ana Djukovic and Sandrine Isaac Clinical & Translational Immunology (2017) 6, e128; doi:10.1038/cti.2017.2

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Commensal microbes that inhabit the gastrointestinal tract are essential for the proper development and functionality of multiple immune cell types. [...] novel subtypes of ILCs have recently been discovered, although their role in defense against infections and how commensal microbes influence their functionality has yet to be defined. It is expected that novel interactions between the intestinal immune system, the microbiota and the pathogen will be discovered in the next few years.
Roles of the intestinal microbiota in pathogen protection Carles Ubeda, Ana Djukovic and Sandrine Isaac Clinical & Translational Immunology (2017) 6, e128; doi:10.1038/cti.2017.2

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Although the host has developed numerous strategies to avoid infections, some pathogens, such as Salmonella, are able to outcompete commensal microbes by exploiting host immune responses. [...] therapies based on the microbiota have started to be applied in the clinical setting with extremely high success. This is the case of fecal transplants utilized for treating C. difficile infections. Although such transplants seem to be very efficient in eliminating certain pathogens, they are not free of risk. Therefore, alternative approaches, including the administration of specific microbes or bacterial-derived molecules, are desirable in order to diminish the appearance of negative side effects. Administration of specific microbes has been proven to confer protection against infections. [...] administration of single or multiple bacteria could be an efficient method for conferring resistance against infections. As an alternative to the ‘probiotic’-based approach, direct administration of bacterial-derived products is proven to be effective in restricting intestinal colonization by pathogens. [...] inoculation of bacterial-derived products that activate certain components of the immune system has also been tested with success. [...] deficits in the immune response caused by antibiotic disruption of the microbiota can be restored by administration of bacterial products.
Roles of the intestinal microbiota in pathogen protection Carles Ubeda, Ana Djukovic and Sandrine Isaac Clinical & Translational Immunology (2017) 6, e128; doi:10.1038/cti.2017.2

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Microbiota induction of the adaptive arm of the immune system, including B cells and T cells, plays a central role in the defense against intestinal pathogens in the gastrointestinal tract. Within the intestinal tract, two major T-cell subsets with very different functions are greatly influenced by commensal microbes [...] [...] the intestinal microbiota influences B-cell development and antibody production.
Roles of the intestinal microbiota in pathogen protection Carles Ubeda, Ana Djukovic and Sandrine Isaac Clinical & Translational Immunology (2017) 6, e128; doi:10.1038/cti.2017.2

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Beneath the epithelium, several specialized innate immune cells are necessary to create an adequate response against intestinal pathogens. Within these cells, ILCs represent the most recently identified arm of the innate immune system, which is crucial for defense against intestinal pathogens. [...] the microbiota has an impact on both the relative abundance of different ILC types and their expression. [...] the three ILC types produce different cytokines and consequently have been implicated in protection against different pathogens. [...] different ILCs confer protection against different pathogens and the microbiota influences ILC functionality. The intestinal microbiota is also required for the proper development and functionality of myeloid cells. [...] contrary microbiota effects through induction of different innate immune cells (i.e. activation of pro-inflammatory neutrophils or regulatory monocytes) are required to counteract infections.
Roles of the intestinal microbiota in pathogen protection Carles Ubeda, Ana Djukovic and Sandrine Isaac Clinical & Translational Immunology (2017) 6, e128; doi:10.1038/cti.2017.2

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Underneath the mucus lies the intestinal epithelium, which is composed of different cell types [...] The intestinal epithelium constitutes the second barrier separating the intestinal microbial ecosystem from the largely sterile underlying tissue. This layer of cells not only constitutes a physical barrier but is also able to synthetize and secrete antimicrobial peptides, which are essential for inhibiting pathogen colonization and for restraining commensal microbes from coming into direct contact with the epithelium. In addition to antimicrobial peptide induction, specific commensal strains can confer resistance to infection by decreasing intestinal permeability to bacterial toxins.
Roles of the intestinal microbiota in pathogen protection Carles Ubeda, Ana Djukovic and Sandrine Isaac Clinical & Translational Immunology (2017) 6, e128; doi:10.1038/cti.2017.2

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The intestinal tract is home to hundreds of bacterial species, referred to collectively as the intestinal microbiota. [...] consumption of dietary nutrients by commensals can confer protection to infections, but certain pathogens exploit products derived from the microbiota metabolism to invade the gut. The layer of mucus that covers the intestinal tract epithelium can be considered the first line of host defense against pathogens.
Roles of the intestinal microbiota in pathogen protection Carles Ubeda, Ana Djukovic and Sandrine Isaac Clinical & Translational Immunology (2017) 6, e128; doi:10.1038/cti.2017.2

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Hundreds of commensal bacterial species inhabit the gastrointestinal tract. This diverse microbial ecosystem plays a crucial role in the prevention and resolution of infectious diseases.
Roles of the intestinal microbiota in pathogen protection Carles Ubeda, Ana Djukovic and Sandrine Isaac Clinical & Translational Immunology (2017) 6, e128; doi:10.1038/cti.2017.2

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[...] proper transcriptional regulation of the ILC- microbiota crosstalk may play critical roles in preservation of a healthy intestinal microenvironment, while preventing auto-inflammatory disorders, some of which involve aberrant ILC3 activity [...] [...] studies of ILC subsets in other tissues from both mice and humans, and in response to various environmental perturbations, have the potential to define new markers, regulatory regions, targets, and pathways perturbed across a wide range of diseases, with prospective for therapeutic intervention.
The Spectrum and Regulatory Landscape of Intestinal Innate Lymphoid Cells Are Shaped by the Microbiome Meital Gury-BenAri, Christoph A. Thaiss, Nicolas Serafini, Deborah R. Winter, Amir Giladi, David Lara-Astiaso, Maayan Levy, Tomer Meir Salame, Assaf Weiner, Eyal David, Hagit Shapiro, Mally Dori-Bachash, Meirav Pevsner-Fischer, Erika Lorenzo-Vivas, Hadas Keren-Shaul, Franziska Paul, Alon Harmelin, Gérard Eberl, Shalev Itzkovitz DOI: 10.1016/j.cell.2016.07.043 Cell, Volume 166, Issue 5, Pages 1231–1246.e13 2016 Elsevier Inc.

Work in progress... stay tuned. Complex complexity.Dionisio_{March 21, 2017
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[...] homeostatic commensal colonization may suppress the regulatory elements involved in ILC3 fate determination and the execution of the associated transcriptional program [...]
The Spectrum and Regulatory Landscape of Intestinal Innate Lymphoid Cells Are Shaped by the Microbiome Meital Gury-BenAri, Christoph A. Thaiss, Nicolas Serafini, Deborah R. Winter, Amir Giladi, David Lara-Astiaso, Maayan Levy, Tomer Meir Salame, Assaf Weiner, Eyal David, Hagit Shapiro, Mally Dori-Bachash, Meirav Pevsner-Fischer, Erika Lorenzo-Vivas, Hadas Keren-Shaul, Franziska Paul, Alon Harmelin, Gérard Eberl, Shalev Itzkovitz DOI: 10.1016/j.cell.2016.07.043 Cell, Volume 166, Issue 5, Pages 1231–1246.e13 2016 Elsevier Inc.

Did somebody say "program"? :) Complex complexity.Dionisio_{March 21, 2017
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[...] temporal and spatial dynamics of marker gene expression not captured by our analysis might constitute another layer of regulation that can be resolved by longitudinal application of the technologies presented here [...] [...] the responsiveness of ILCs to the microbiota is highly heterogeneous, even within the defined subsets. Integration of all three levels of genomic assessment—population transcriptomics, population epigenetics, and single-cell transcriptomics— point toward an unexpected phenomenon, namely, the acquisition of ILC3-like expression profiles across multiple subsets upon depletion of the microbiota.
The Spectrum and Regulatory Landscape of Intestinal Innate Lymphoid Cells Are Shaped by the Microbiome Meital Gury-BenAri, Christoph A. Thaiss, Nicolas Serafini, Deborah R. Winter, Amir Giladi, David Lara-Astiaso, Maayan Levy, Tomer Meir Salame, Assaf Weiner, Eyal David, Hagit Shapiro, Mally Dori-Bachash, Meirav Pevsner-Fischer, Erika Lorenzo-Vivas, Hadas Keren-Shaul, Franziska Paul, Alon Harmelin, Gérard Eberl, Shalev Itzkovitz DOI: 10.1016/j.cell.2016.07.043 Cell, Volume 166, Issue 5, Pages 1231–1246.e13 2016 Elsevier Inc.

Did somebody say "unexpected"? :) Complex complexity.Dionisio_{March 21, 2017
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[...] several fundamental questions of ILC physiology have remained unsolved. The mechanisms by which ILCs perform this integration task are poorly understood. [...] ILCs evaluate the state of microbial colonization by adjusting the enhancer landscape and the accessibility of transcription factor-binding sites within the chromatin architecture [...] [...] the elucidation of functional crosstalk between these pathways and ILC function will present an exciting area of future study. Elucidating the role of within-tissue distribution, cell-cell interactions, exposure to soluble mediators, and response to luminal metabolites on these transcriptional clusters awaits further study.
The Spectrum and Regulatory Landscape of Intestinal Innate Lymphoid Cells Are Shaped by the Microbiome Meital Gury-BenAri, Christoph A. Thaiss, Nicolas Serafini, Deborah R. Winter, Amir Giladi, David Lara-Astiaso, Maayan Levy, Tomer Meir Salame, Assaf Weiner, Eyal David, Hagit Shapiro, Mally Dori-Bachash, Meirav Pevsner-Fischer, Erika Lorenzo-Vivas, Hadas Keren-Shaul, Franziska Paul, Alon Harmelin, Gérard Eberl, Shalev Itzkovitz DOI: 10.1016/j.cell.2016.07.043 Cell, Volume 166, Issue 5, Pages 1231–1246.e13 2016 Elsevier Inc.

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Innate lymphoid cells (ILCs) are the most recently discovered arm of the innate immune system, consisting of cytotoxic cells (NK cells) and ‘‘helper-like’’ ILCs [...] [...] whether these findings represent general plasticity between ILC subsets and whether additional subsets exist that are lacking equivalent T cell counterparts remains unknown.
The Spectrum and Regulatory Landscape of Intestinal Innate Lymphoid Cells Are Shaped by the Microbiome Meital Gury-BenAri, Christoph A. Thaiss, Nicolas Serafini, Deborah R. Winter, Amir Giladi, David Lara-Astiaso, Maayan Levy, Tomer Meir Salame, Assaf Weiner, Eyal David, Hagit Shapiro, Mally Dori-Bachash, Meirav Pevsner-Fischer, Erika Lorenzo-Vivas, Hadas Keren-Shaul, Franziska Paul, Alon Harmelin, Gérard Eberl, Shalev Itzkovitz DOI: 10.1016/j.cell.2016.07.043 Cell, Volume 166, Issue 5, Pages 1231–1246.e13 2016 Elsevier Inc.

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Innate lymphoid cells (ILCs) are critical modulators of mucosal immunity, inflammation, and tissue homeostasis, but their full spectrum of cellular states and regulatory landscapes remains elusive. [...] ILCs differentially integrate signals from the microbial microenvironment to generate phenotypic and functional plasticity.
The Spectrum and Regulatory Landscape of Intestinal Innate Lymphoid Cells Are Shaped by the Microbiome Meital Gury-BenAri, Christoph A. Thaiss, Nicolas Serafini, Deborah R. Winter, Amir Giladi, David Lara-Astiaso, Maayan Levy, Tomer Meir Salame, Assaf Weiner, Eyal David, Hagit Shapiro, Mally Dori-Bachash, Meirav Pevsner-Fischer, Erika Lorenzo-Vivas, Hadas Keren-Shaul, Franziska Paul, Alon Harmelin, Gérard Eberl, Shalev Itzkovitz DOI: 10.1016/j.cell.2016.07.043 Cell, Volume 166, Issue 5, Pages 1231–1246.e13 2016 Elsevier Inc.

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This result reflected earlier findings that ILC and T cell subclasses produce similar sets of cytokines, but also revealed differences in how the two cell types control the activities of these key immune response genes. While the regulatory landscapes of ILCs are primed for a quick defense upon infection, those of T cells are minimally prepared when the pathogen invades. Only following infection are modifications in the landscape made that enable T cells to launch their attack. “ILCs and T cells appear very different, but in the end, the way they control key responses is amazingly similar,” said Han-Yu Shih, Ph.D., a post-doctoral fellow at NIAMS.
Rapid-response immune cells are fully prepared before invasion strikes https://www.nih.gov/news-events/news-releases/rapid-response-immune-cells-are-fully-prepared-before-invasion-strikes Shih et al., Developmental Acquisition of Regulomes Underlies Innate Lymphoid Cell Functionality, Cell (2016), http://dx.doi.org/10.1016/j.cell.2016.04.029

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[...] each subclass of ILCs is associated with a distinct pattern of accessible regions. These patterns can be viewed as a type of barcode for each subclass. [...] ILCs acquire their barcodes in a stepwise manner over the course of cellular development. [...] the barcodes are in place in ILCs before they encounter infection. This open, accessible configuration surrounding the switches that control cytokine genes may be instrumental in enabling ILCs to rapidly launch an assault upon infection. [...] many of the DNA regions controlling cytokine genes in the mice’s T cells are inaccessible and silenced prior to exposure to a pathogen. But upon infection, T cells adopted barcodes similar to those of their ILC counterparts.
Rapid-response immune cells are fully prepared before invasion strikes https://www.nih.gov/news-events/news-releases/rapid-response-immune-cells-are-fully-prepared-before-invasion-strikes Shih et al., Developmental Acquisition of Regulomes Underlies Innate Lymphoid Cell Functionality, Cell (2016), http://dx.doi.org/10.1016/j.cell.2016.04.029

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Part of what makes each cell type unique is its distinctive pattern of DNA structure and regulatory factors. The combination of a stretch of DNA and a set of regulatory factors can be thought of as a switch — it helps determine whether a gene is turned off (inactive) or on (active). Inactive regions of DNA are twisted into tight coils, whereas active regions are open and accessible to the cellular machinery that reads the genetic information. The open portions of the genome include genes themselves, as well as many regions that contribute to the regulation of their activities (the switches). The areas of the genome and the factors that control whether or not the information is read, in total, are referred to as the cell’s regulome.
Rapid-response immune cells are fully prepared before invasion strikes https://www.nih.gov/news-events/news-releases/rapid-response-immune-cells-are-fully-prepared-before-invasion-strikes Shih et al., Developmental Acquisition of Regulomes Underlies Innate Lymphoid Cell Functionality, Cell (2016), http://dx.doi.org/10.1016/j.cell.2016.04.029

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[...] the development of immune cells, called innate lymphoid cells (ILCs), gradually prepares these cells for rapid response to infection. “ILCs are coming into the spotlight because they appear to have a critical role in defending the body’s barrier regions, such as the skin, lungs, and gut, where microbes must first pass to make their way into the body.” - John J. O’Shea, M.D., scientific director of NIAMS.
Rapid-response immune cells are fully prepared before invasion strikes https://www.nih.gov/news-events/news-releases/rapid-response-immune-cells-are-fully-prepared-before-invasion-strikes Shih et al., Developmental Acquisition of Regulomes Underlies Innate Lymphoid Cell Functionality, Cell (2016), http://dx.doi.org/10.1016/j.cell.2016.04.029

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Our immune system has two arms — innate and adaptive. ILCs are innate immune cells that respond quickly against pathogens at the first site of invasion. They release small molecules called cytokines that transmit signals to fight infection. The adaptive immune response kicks in more slowly to build an army of cells that can target specific offending pathogens. T cells, especially helper T cells, are a key part of the adaptive immune system. They produce different cytokines depending upon the type of pathogen they are trying to combat.
Rapid-response immune cells are fully prepared before invasion strikes https://www.nih.gov/news-events/news-releases/rapid-response-immune-cells-are-fully-prepared-before-invasion-strikes Shih et al., Developmental Acquisition of Regulomes Underlies Innate Lymphoid Cell Functionality, Cell (2016), http://dx.doi.org/10.1016/j.cell.2016.04.029

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The human microbiota plays an important role in the wellbeing of the human host, and participates actively in the development of a wide variety of diseases. From the structure to the function of the microbiota, future research should move microbiome investigations toward providing explanations of causality. [...] future advances will help to clarify the interactions between the microbiota and human development, and the potential roles of those microbiota involved in the mechanisms of various diseases [...] The crucial roles of the human microbiota should be investigated at a much deeper level [...]
The Human Microbiota in Health and Disease Baohong Wang, Mingfei Yao, Longxian Lv, Zongxin Ling, Lanjuan Li* Engineering 3 (2017) 71–82 https://www.researchgate.net/publication/314185613

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The metabolic disease is at the dawn of new knowledge. Anyone considering studying metabolic disease should take a deep look at gut microbiota diversity and immune responses. Therapeutic strategies, either pharmacological or nutritional, will most likely emerge over the course of the next decade or so.
Gut microbiota and immune crosstalk in metabolic disease Rémy Burcelin Mol Metab. 5(9): 771–781. doi: 10.1016/j.molmet.2016.05.016

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[...] confirmation of allele-specific binding events is necessary to confirm that a SNP does indeed impact transcription factor function and provides a mechanistic link between genetic variation and disease risk. [...] altered binding of T cell master regulators can predispose individuals to specific autoimmune and inflammatory conditions. This study establishes a scalable method that can be used to explore the impact of genetic variation on the function of other lineage-specifying transcriptional factors. These insights will identify molecular mechanisms that underlie the genetic basis of autoimmune diseases and suggest new therapies for their treatment.
Genetic variants alter T-bet binding and gene expression in mucosal inflammatory disease. Soderquest K, Hertweck A, Giambartolomei C, Henderson S, Mohamed R, Goldberg R, Perucha E, Franke L, Herrero J, Plagnol V, Jenner RG, Lord GM PLoS Genet. 13(2):e1006587. doi: 10.1371/journal.pgen.1006587.

Had we remained in Eden, none of this would have been an issue. Too late now. Work in progress... stay tuned. Complex complexity.Dionisio_{March 21, 2017
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The polarization of CD4+ T cells into distinct T helper cell lineages is essential for protective immunity against infection, but aberrant T cell polarization can cause autoimmunity. The transcription factor T-bet (TBX21) specifies the Th1 lineage and represses alternative T cell fates. Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) that may be causative for autoimmune diseases. [...] genetic polymorphisms may predispose individuals to mucosal autoimmune disease through alterations in T-bet binding. Other disease-associated variants may similarly act by modulating the binding of lineage-specifying transcription factors in a tissue-selective and disease-specific manner.
Genetic variants alter T-bet binding and gene expression in mucosal inflammatory disease. Soderquest K, Hertweck A, Giambartolomei C, Henderson S, Mohamed R, Goldberg R, Perucha E, Franke L, Herrero J, Plagnol V, Jenner RG, Lord GM PLoS Genet. 13(2):e1006587. doi: 10.1371/journal.pgen.1006587.

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[...] our identification of circulating and tissue-resident human ILCPs suggests a concept of ‘‘ILC-poiesis’’ in which ILC differentiation can occur ‘‘on demand’’ in any tissue and at any age. [...] ILCs are long-lived tissue-resident cells that do not recirculate under steady state and some inflammatory conditions [...] The discovery of a circulating ILCPs provides a mechanism to replenish tissue ILCs in response to steady-state losses and in the context of infection and inflammation.
Systemic Human ILC Precursors Provide a Substrate for Tissue ILC Differentiation. Lim AI, Li Y, Lopez-Lastra S, Stadhouders R, Paul F, Casrouge A, Serafini N, Puel A, Bustamante J, Surace L, Masse-Ranson G, David E, Strick-Marchand H, Le Bourhis L, Cocchi R, Topazio D, Graziano P, Muscarella LA, Rogge L, Norel X, Sallenave JM, Allez M, Graf T, Hendriks RW, Casanova JL, Amit I, Yssel H, Di Santo JP. Cell. 168(6):1086-1100.e10. doi: 10.1016/j.cell.2017.02.021.

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Regulation of TF expression dictates ILC fate as well as function. Signature TFs have been identified for ILC subsets that regulate their differentiation at the level of surface phenotype and effector outputs [...]
Systemic Human ILC Precursors Provide a Substrate for Tissue ILC Differentiation. Lim AI, Li Y, Lopez-Lastra S, Stadhouders R, Paul F, Casrouge A, Serafini N, Puel A, Bustamante J, Surace L, Masse-Ranson G, David E, Strick-Marchand H, Le Bourhis L, Cocchi R, Topazio D, Graziano P, Muscarella LA, Rogge L, Norel X, Sallenave JM, Allez M, Graf T, Hendriks RW, Casanova JL, Amit I, Yssel H, Di Santo JP. Cell. 168(6):1086-1100.e10. doi: 10.1016/j.cell.2017.02.021.

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