Fibroblasts regulate tissue homeostasis, coordinate inflammatory responses, and mediate tissue damage. In rheumatoid arthritis (RA), synovial fibroblasts maintain chronic inflammation which leads to ...joint destruction. Little is known about fibroblast heterogeneity or if aberrations in fibroblast subsets relate to pathology. Here, we show functional and transcriptional differences between fibroblast subsets from human synovial tissues using bulk transcriptomics of targeted subpopulations and single-cell transcriptomics. We identify seven fibroblast subsets with distinct surface protein phenotypes, and collapse them into three subsets by integrating transcriptomic data. One fibroblast subset, characterized by the expression of proteins podoplanin, THY1 membrane glycoprotein and cadherin-11, but lacking CD34, is threefold expanded in patients with RA relative to patients with osteoarthritis. These fibroblasts localize to the perivascular zone in inflamed synovium, secrete proinflammatory cytokines, are proliferative, and have an in vitro phenotype characteristic of invasive cells. Our strategy may be used as a template to identify pathogenic stromal cellular subsets in other complex diseases.
Invariant natural killer T cells (iNKT cells) are lipid-sensing innate T cells that are restricted by the antigen-presenting molecule CD1d and express the transcription factor PLZF. iNKT cells ...accumulate in adipose tissue, where they are anti-inflammatory, but the factors that contribute to their anti-inflammatory nature, as well as their targets in adipose tissue, are unknown. Here we found that iNKT cells in adipose tissue had a unique transcriptional program and produced interleukin 2 (IL-2) and IL-10. Unlike other iNKT cells, they lacked PLZF but expressed the transcription factor E4BP4, which controlled their IL-10 production. The adipose iNKT cells were a tissue-resident population that induced an anti-inflammatory phenotype in macrophages and, through the production of IL-2, controlled the number, proliferation and suppressor function of regulatory T cells (Treg cells) in adipose tissue. Thus, iNKT cells in adipose tissue are unique regulators of immunological homeostasis in this tissue.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Fibroblasts are major contributors to and regulators of inflammation and dominant producers of interleukin-6 (IL-6) in inflammatory diseases like rheumatoid arthritis. Yet, compared to leukocytes, ...the regulation of inflammatory pathways in fibroblasts is largely unknown. Here, we report that analyses of genes coordinately upregulated with IL-6 pointed to STAT4 and leukemia inhibitory factor (LIF) as potentially linked. Gene silencing revealed that STAT4 was required for IL-6 transcription. STAT4 was recruited to the IL-6 promoter after fibroblast activation, and LIF receptor (LIFR) and STAT4 formed a molecular complex that, together with JAK1 and TYK2 kinases, controlled STAT4 activation. Importantly, a positive feedback loop involving autocrine LIF, LIFR, and STAT4 drove sustained IL-6 transcription. Besides IL-6, this autorine loop also drove the production of other key inflammatory factors including IL-8, granulocyte-colony stimulating factor (G-CSF), IL-33, IL-11, IL-1α, and IL-1β. These findings define the transcriptional regulation of fibroblast-mediated inflammation as distinct from leukocytes.
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•During inflammation, human fibroblasts upregulate LIF and STAT4•LIF acts in an autocrine manner via LIF receptor to promote STAT4 activation•Activated STAT4 together with NF-κB/p65-p52 and C/EBPβ enhances IL-6 transcription•LIFR/STAT4 circuit also regulates IL-8, G-CSF, IL-33, IL-11, IL-1α, and IL-1β
Growing evidence implicates fibroblasts as inflammatory cells in sites of peripheral inflammation. Nguyen and colleagues demonstrate that regulation of IL-6 along with a set of other inflammatory cytokines and chemokines is regulated by a positive feedback loop involving LIF, LIF receptor, and STAT4 that selectively operates in fibroblasts.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
RNA molecules aggregate under certain conditions. The resulting condensates are implicated in human neurological disorders, and can potentially be designed towards specified bulk properties in vitro. ...However, the mechanism for aggregation-including how aggregation properties change with sequence and environmental conditions-remains poorly understood. To address this challenge, we introduce an analytical framework based on multimer enumeration. Our approach reveals the driving force for aggregation to be the increased configurational entropy associated with the multiplicity of ways to form bonds in the aggregate. Our model uncovers rich phase behavior, including a sequence-dependent reentrant phase transition, and repeat parity-dependent aggregation. We validate our results by comparison to a complete computational enumeration of the landscape, and to previously published molecular dynamics simulations. Our work unifies and extends published results, both explaining the behavior of CAG-repeat RNA aggregates implicated in Huntington's disease, and enabling the rational design of programmable RNA condensates.
A high-velocity (≈1 ms−1) impact between a liquid droplet (≈1 mm) and a solid surface produces a splash. Classical observations traced the origin of this splash to a thin sheet of fluid ejected near ...the impact point, though the fluid mechanical mechanism leading to the sheet is not known. Mechanisms of sheet formation have heretofore relied on initial contact of the droplet and the surface. In this paper, we theoretically and numerically study the events within the time scale of about 1 μs over which the coupled dynamics between the gas and the droplet becomes important. The droplet initially tries to contact the substrate by either draining gas out of a thin layer or compressing it, with the local behaviour described by a self-similar solution of the governing equations. This similarity solution is not asymptotically consistent: forces that were initially negligible become relevant and dramatically change the behaviour. Depending on the radius and impact velocity of the droplet, we show that the solution is overtaken by initially subdominant physical effects such as the surface tension of the liquid–gas interface or viscous forces in the liquid. At low impact velocities surface tension stops the droplet from impacting the surface, whereas at higher velocities viscous forces become important before surface tension. The ultimate dynamics of the interface once droplet viscosity cannot be neglected is not yet known.
The essence of turbulent flow is the conveyance of energy through the formation, interaction, and destruction of eddies over a wide range of spatial scales-from the largest scales where energy is ...injected down to the smallest scales where it is dissipated through viscosity. Currently, there is no mechanistic framework that captures how the interactions of vortices drive this cascade. We show that iterations of the elliptical instability, arising from the interactions between counter-rotating vortices, lead to the emergence of turbulence. We demonstrate how the nonlinear development of the elliptical instability generates an ordered array of antiparallel secondary filaments. The secondary filaments mutually interact, leading to the formation of even smaller tertiary filaments. In experiments and simulations, we observe two and three iterations of this cascade, respectively. Our observations indicate that the elliptical instability could be one of the fundamental mechanisms by which the turbulent cascade develops.
Natural odors typically consist of many molecules at different concentrations. It is unclear how the numerous odorant molecules and their possible mixtures are discriminated by relatively few ...olfactory receptors. Using an information theoretic model, we show that a receptor array is optimal for this task if it achieves two possibly conflicting goals: (i) Each receptor should respond to half of all odors and (ii) the response of different receptors should be uncorrelated when averaged over odors presented with natural statistics. We use these design principles to predict statistics of the affinities between receptors and odorant molecules for a broad class of odor statistics. We also show that optimal receptor arrays can be tuned to either resolve concentrations well or distinguish mixtures reliably. Finally, we use our results to predict properties of experimentally measured receptor arrays. Our work can thus be used to better understand natural olfaction, and it also suggests ways to improve artificial sensor arrays.
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This landmark book is the first comprehensive account of the
lives of the Jews who remained in Germany immediately following the
war. Gathering never-before-published eyewitness accounts from
...Holocaust survivors, Michael Brenner presents a remarkable history
of this period. While much has been written on the Holocaust
itself, until now little has been known about the fate of those
survivors who remained in Germany. Jews emerging from concentration
camps would learn that most of their families had been murdered and
their communities destroyed. Furthermore, all Jews in the country
would face the stigma of living, as a 1948 resolution of the World
Jewish Congress termed it, on "bloodsoaked German soil." Brenner
brings to life the psychological, spiritual, and material obstacles
they surmounted as they rebuilt their lives in Germany. At the
heart of his narrative is a series of fifteen interviews Brenner
conducted with some of the most important witnesses who played an
active role in the reconstruction--including presidents of Jewish
communities, rabbis, and journalists. Based on the Yiddish and
German press and unpublished archival material, the first part of
this book provides a historical introduction to this fascinating
topic. Here the author analyzes such diverse aspects as liberation
from concentration camps, cultural and religious life among the
Jewish Displaced Persons, antisemitism and philosemitism in
post-war Germany, and the complex relationship between East
European and German Jews. A second part consists of the fifteen
interviews, conducted by Brenner, with witnesses representing the
diverse background of the postwar Jewish community. While most of
them were camp survivors, others returned from exile or came to
Germany as soldiers of the Jewish Brigade or with international
Jewish aid organizations. A third part, which covers the
development of the Jewish community in Germany from the 1950s until
today, concludes the book.
Adipose tissue invariant natural killer T (iNKT) cells are phenotypically different from other iNKT cells because they produce IL-10 and control metabolic homeostasis. Why that is the case is ...unclear. Here, using single-cell RNA sequencing, we found several adipose iNKT clusters, which we grouped into two functional populations based on NK1.1 expression. NK1.1NEG cells almost exclusively produced IL-10 and other regulatory cytokines, while NK1.1POS iNKT cells predominantly produced IFNγ. Mechanistically, biochemical fractionation revealed that free fatty acids drive IL-10 production primarily in NK1.1NEG iNKT cells via the IRE1α-XBP1s arm of the unfolded protein response. Correspondingly, adoptive transfer of adipose tissue NK1.1NEG iNKT cells selectively restored metabolic function in obese mice. Further, we found an unexpected role for NK1.1POS iNKT cells in lean adipose tissue, as IFNγ licenses natural killer cell-mediated macrophage killing to limit pathological macrophage expansion. Together, these two iNKT cell populations utilize non-redundant pathways to preserve metabolic integrity.
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•scRNA-seq reveals distinct populations of adipose tissue iNKT cells•FFAs drive IL-10 production via IRE1α-XBP1s signaling, primarily in NK1.1NEG iNKT cells•NK1.1NEG regulatory iNKT cells selectively restore metabolic function during obesity•In lean adipose, NK1.1POS iNKT cells license NK cell killing of macrophages via IFNγ
LaMarche et al. reveal two pathways by which iNKT cell subsets control adipose tissue inflammation. NK1.1NEG iNKT cells dominantly produce anti-inflammatory IL-10, driven by intracellular lipid accumulation and IRE1α-XBP1s signaling. In contrast, NK1.1POS cells produce IFNγ, which, in lean adipose tissue, drives NK cell-mediated macrophage killing to limit pathogenic macrophage expansion.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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