`This is a very fine text, a powerful piece of work that deserves to be read widely. The analysis is truly panoramic. It ranges across central concerns in the fields of social theory, political ...theory, and science studies and engages with and/or draws upon the ideas of key classical and contemporary thinkers, including Tocqueville, Weber, Schumpeter, Polyani, Habermas, Foucault, Schmitt and Beck' - Barry Smart, Professor of Sociology, University of Portsmouth What are the political implications of 'expert' knowledge and especially scientific knowledge for liberal democracy? If knowledge is not evenly distributed upon what basis can the philosophy of equal rights be sustained? This important book points to the crisis in knowledge in liberal democracies. This crisis, simply put, is that most citizens cannot understand, much less judge, the claims scientists make. One response is the appointment of public commissions to provide conclusions for policy-makers to act upon. There are also `commissions from below', such as grass roots associations that quiz the limits of expert knowledge and power and make rival knowledge claims. Do these commissions represent a new stage in the development of liberal democracy? Or is it merely a pragmatic device of no political consequence. The central argument of the book is that in a `knowledge society' in which specialized knowledge is increasingly important to politics, more has to be delegated because democratic discussion can't handle it. This limitation in the scope of liberal democracy threatens its fundamental character. The book will be required reading in the fields of social theory, political theory and science studies.
Understanding how cell fate decisions are made during cellular differentiation and the mechanisms that drive them is a holy grail of cell biology. In this issue of Immunity, Hu et al. (2018) and ...Johnson et al. (2018) demonstrate that key transcriptional regulators and global changes in nuclear architecture underlie differentiation decisions during T cell development.
Understanding how cell fate decisions are made during cellular differentiation and the mechanisms that drive them is a holy grail of cell biology. In this issue of Immunity, Hu et al. (2018) and Johnson et al. (2018) demonstrate that key transcriptional regulators and global changes in nuclear architecture underlie differentiation decisions during T cell development.
We present a hierarchical genome-assembly process (HGAP) for high-quality de novo microbial genome assemblies using only a single, long-insert shotgun DNA library in conjunction with Single Molecule, ...Real-Time (SMRT) DNA sequencing. Our method uses the longest reads as seeds to recruit all other reads for construction of highly accurate preassembled reads through a directed acyclic graph-based consensus procedure, which we follow with assembly using off-the-shelf long-read assemblers. In contrast to hybrid approaches, HGAP does not require highly accurate raw reads for error correction. We demonstrate efficient genome assembly for several microorganisms using as few as three SMRT Cell zero-mode waveguide arrays of sequencing and for BACs using just one SMRT Cell. Long repeat regions can be successfully resolved with this workflow. We also describe a consensus algorithm that incorporates SMRT sequencing primary quality values to produce de novo genome sequence exceeding 99.999% accuracy.
Petrogenetic models for convergent margins should be consistent with the global systematics of convergent margin volcanic compositions. A newly developed tool for compiling and screening data from ...the GEOROC database was used to generate a global dataset of whole rock chemical analyses from arc front stratovolcano samples. Data from 227 volcanoes within 31 volcanic arc segments were first averaged by volcano and then by arc to explore global systematics. Three different methods of data normalization produce consistent results that persist across a wide range of Mg# Mg#=Mg/(Mg+Fe). Remarkably coherent systematics are present among major and trace element concentrations and ratios, with the exception of three arcs influenced by mantle plumes and Peru/N. Chile, which is built on exceptionally thick crust. Chemical parameters also correlate with the thickness of the overlying arc crust. In addition to previously established correlations of Na6.0 with Ca6.0 and crustal thickness, correlations are observed among major elements, trace elements, and trace element ratios (e.g. La/Yb, Dy/Yb, Zr/Sm, Zr/Ti). Positive correlations include “fluid mobile,” “high field strength,” and “large ion lithophile” element groups, with concentrations that vary by a factor of five in all groups. Incompatible element enrichments also correlate well with crustal thickness, with the greatest enrichment found at arcs with the thickest crust. Intra-crustal processes, however, do not reproduce the global variations. High pressure fractionation produces intermediate magmas enriched in aluminum, but such magmas are rare. Furthermore, differences among magma compositions at various volcanic arcs persist from primitive to evolved compositions, which is inconsistent with the possibility that global variations are produced by crystal fractionation at any pressure. Linear relationships among elements appear to be consistent with mixing between depleted primary magma and an enriched contaminant, but the required composition of the theoretical enriched end-member is not similar to compositions expected in the deep crust or to any known rock composition. The large-scale chemical variations among volcanic arcs are therefore likely to be generated by processes in the subducting slab or mantle wedge, rather than the crust. While crustal processes are important in the differentiation of convergent margin magmas, they do not account for the systematics presented here. Models that attribute the chemical variability of arc magmas to slab or wedge processes are also constrained to be consistent with the global chemical systematics, and are discussed in Turner and Langmuir (2015).
•We present a new carefully filtered global database of arc front volcano chemistry.•Major elements, trace elements, and trace element ratios correlate, varying by up to a factor of 5.•Several chemical parameters correlate with the thickness of the overlying arc crust.•Systematics are not due to high-P fractionation, magma mixing, or buoyancy filtration.
Mutations in MECP2, encoding the epigenetic regulator methyl-CpG-binding protein 2, are the predominant cause of Rett syndrome, a disease characterized by both neurological symptoms and systemic ...abnormalities. Microglial dysfunction is thought to contribute to disease pathogenesis, and here we found microglia become activated and subsequently lost with disease progression in Mecp2-null mice. Mecp2 was found to be expressed in peripheral macrophage and monocyte populations, several of which also became depleted in Mecp2-null mice. RNA-seq revealed increased expression of glucocorticoid- and hypoxia-induced transcripts in Mecp2-deficient microglia and peritoneal macrophages. Furthermore, Mecp2 was found to regulate inflammatory gene transcription in response to TNF stimulation. Postnatal re-expression of Mecp2 using Cx3cr1creER increased the lifespan of otherwise Mecp2-null mice. These data suggest that Mecp2 regulates microglia and macrophage responsiveness to environmental stimuli to promote homeostasis. Dysfunction of tissue-resident macrophages might contribute to the systemic pathologies observed in Rett syndrome.
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•Mecp2 is broadly expressed in macrophages and resident monocytes•Mecp2-null mice exhibit monocyte and resident macrophage deficiencies•Mecp2 expression under Cx3cr1creER extends survival of Mecp2Lox-Stop/y mice•Mecp2 regulates transcriptional responses to inflammatory stimuli
Mutations in the gene encoding Methyl-CpG binding protein 2 (MeCP2) are the primary cause of the neurodevelopmental disease Rett syndrome. Kipnis and colleagues demonstrate that Mecp2 regulates macrophage transcriptional responses to glucocorticoid and inflammatory stimuli, raising the possibility that abnormal macrophage responses contribute to systemic impairments in Rett syndrome.
A través de una serie de casos históricos y análisis cuantitativos, los trabajos presentados en este número de Estudios Sociológicos abordan cuestiones fundamentales sobre las consecuencias políticas ...del financiamiento extranjero de las ciencias sociales. En conjunto, estos trabajos ilustran la paradoja inherente a la financiación de la vida intelectual: el poder de los donantes depende de la legitimidad y, por lo tanto, de la independencia de los donatarios. La cuestión es compleja porque los beneficiarios, que pueden operar como “Estados tapón”, tienen objetivos distintos de los de los donantes. En este marco, los donantes que financiaron proyectos en América Latina tuvieron dificultades para encontrar socios que consideraran fiables, así como para atraer instituciones influyentes. Asimismo, se toparon con variadas resistencias. Los donantes practicaron por ello dos estrategias básicas para adaptarse a las circunstancias locales: el apoyo a instituciones ya existentes preferido por la Fundación Rockefeller, por un lado, y el desarrollo de think tanks elegido por la Fundación Ford, por el otro. Aun cuando los objetivos de los donantes reflejaban, en parte, las preocupaciones de la Guerra Fría, el resultado de su accionar fue un cierto pluralismo intelectual.
Through a series of historical cases and quantitative analysis, the papers presented in this issue of Sociological Studies address fundamental questions about the political consequences of foreign funding of the social sciences. Taken together, these works illustrate the paradox inherent in the financing of intellectual life: the power of donors depends on the legitimacy and therefore the independence of the grantees. The issue is complex because the recipients, who can operate as “buffer states”, have different objectives from those of the donors. Within this framework, donors who financed projects in Latin America had difficulties finding partners they considered reliable, as well as attracting influential institutions. They also met with various resistances. Donors therefore practiced two basic strategies to adapt to local circumstances: the support for existing institutions preferred by the Rockefeller Foundation, on the one hand, and the development of think tanks chosen by the Ford Foundation, on the other. Although the donors’ objectives reflected, in part, Cold War concerns, the result of their actions was a certain intellectual pluralism.
Granzyme B (GzmB) is a protease with a well-characterized intracellular role in targeted destruction of compromised cells by cytotoxic lymphocytes. However, GzmB also cleaves extracellular matrix ...components, suggesting that it influences the interplay between cytotoxic lymphocytes and their environment. Here, we show that GzmB-null effector T cells and natural killer (NK) cells exhibited a cell-autonomous homing deficit in mouse models of inflammation and Ectromelia virus infection. Intravital imaging of effector T cells in inflamed cremaster muscle venules revealed that GzmB-null cells adhered normally to the vessel wall and could extend lamellipodia through it but did not cross it efficiently. In vitro migration assays showed that active GzmB was released from migrating cytotoxic lymphocytes and enabled chemokine-driven movement through basement membranes. Finally, proteomic analysis demonstrated that GzmB cleaved basement membrane constituents. Our results highlight an important role for GzmB in expediting cytotoxic lymphocyte diapedesis via basement membrane remodeling.
•In poxvirus infection, Gzmb−/− NK cell and CTL homing is impaired•In three inflammatory models, Gzmb−/− cytotoxic lymphocyte homing is impaired•Gzmb−/− CTLs extravasate inefficiently but show no defect in interstitial movement•GzmB facilitates chemokine-driven CTL migration in vitro and cleaves ECM proteins
Granzyme B (GzmB) is a secreted leukocyte protease that has a well-documented role in perforin-mediated killing of abnormal or compromised cells. Prakash and colleagues demonstrate that GzmB also expedites migration of leukocytes across the vascular endothelium by remodeling basement membrane.
The
Major Histocompatibility Complex
(MHC) locus encodes classical MHC class I and MHC class II molecules and nonclassical MHC-I molecules. The architecture of these molecules is ideally suited to ...capture and present an array of peptide antigens (Ags). In addition, the CD1 family members and MR1 are MHC class I-like molecules that bind lipid-based Ags and vitamin B precursors, respectively. These Ag-bound molecules are subsequently recognized by T cell antigen receptors (TCRs) expressed on the surface of T lymphocytes. Structural and associated functional studies have been highly informative in providing insight into these interactions, which are crucial to immunity, and how they can lead to aberrant T cell reactivity. Investigators have determined over thirty unique TCR-peptide-MHC-I complex structures and twenty unique TCR-peptide-MHC-II complex structures. These investigations have shown a broad consensus in docking geometry and
provided insight into MHC restriction. Structural studies on TCR-mediated recognition of lipid and metabolite Ags have been mostly confined to TCRs from innate-like natural killer T cells and mucosal-associated invariant T cells, respectively. These studies revealed clear differences between TCR-lipid-CD1, TCR-metabolite-MR1, and TCR-peptide-MHC recognition. Accordingly, TCRs show remarkable structural and biological versatility in engaging different classes of Ag that are presented by polymorphic and monomorphic Ag-presenting molecules of the immune system.
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