Anabolism-Associated Mitochondrial Stasis Driving Lymphocyte Differentiation over Self-Renewal

Regeneration requires related cells to diverge in fate. We show that activated lymphocytes yield sibling cells with unequal elimination of aged mitochondria. Disparate mitochondrial clearance impacts cell fate and reflects larger constellations of opposing metabolic states. Differentiation driven by an anabolic constellation of PI3K/mTOR activation, aerobic glycolysis, inhibited autophagy, mitochondrial stasis, and ROS production is balanced with self-renewal maintained by a catabolic constellation of AMPK activation, mitochondrial elimination, oxidative metabolism, and maintenance of FoxO1 activity. Perturbations up and down the metabolic pathways shift the balance of nutritive constellations and cell fate owing to self-reinforcement and reciprocal inhibition between anabolism and catabolism. Cell fate and metabolic state are linked by transcriptional regulators, such as IRF4 and FoxO1, with dual roles in lineage and metabolic choice. Instructing some cells to utilize nutrients for anabolism and differentiation while other cells catabolically self-digest and self-renew may enable growth and repair in metazoa

Bruno Latours Neubestimmung der Differenz von Gesellschaft und Natur

"Ob 'die' Soziologie radikal veränderter theoretischer Grundlagen und insbesondere eines anderen Naturbegriffs bedarf, um zu einem adäquaten Verständnis der 'ökologischen Krise' zu gelangen, ist umstritten. Forderungen nach vielfältig interpretierbaren grundlegenden Kurskorrekturen stehen umweltsoziologischen Normalisierungsstrategien gegenüber. Theoretisch dominieren soziozentrische Ansätze, die die Analyse der natural-stofflichen Dimension der 'ökologischen Krise' den Naturwissenschaften überlassen, ohne deren Charakter als soziale Praxis und damit die Umkämpfheit dieser natural-stofflichen Dimension ernstzunehmen. Latours modernitätskritische 'symmetrische Anthropologie', entwickelt aus wissenschafts- und techniksoziologischen Untersuchungen, beansprucht ein radikal empirisches Programm der 'Ko-Produktion von Gesellschaft und Natur'. Beide Pole sollen demzufolge als kontingente Kristallisierungen - und nicht als gegebene Voraussetzungen - konstruktiver Prozesse aufzufassen sein sollen. In diesen Prozessen spielen Wissenschaft und Technik als 'Politik mit anderen Mitteln' die zentrale Rolle. Jeder Ansatz eines 'spezifisch Sozialen', das die menschliche Form der Vergesellschaftung kennzeichnet, wird als dem Verständnis dieser konstruktiven Prozesse hinderliche Essentialisierung abgewiesen. Latours 'symmetrische Anthropologie' verfolgt vielmehr ein postsoziologisches Programm der Untersuchung soziotechnischer Ensembles. Dieses Konzept soll schließlich auch einer Analyse ökologischer Krisenphänomene als Leitfaden dienen. Dieser Anspruch läßt sich, den produktiven Seiten der Überlegungen Latours zum Trotz, nicht halten. Nicht nur ist unklar, wie eine Erweiterung der semiologischen Wissenschafts- und Technologieanalysen die materiell-stoffliche Dimension der 'ökologischen Krise' sollte thematisieren können, sind doch jene Analysen selbst bereits dem Vorwurf ausgesetzt, die 'Materialität' von Wissenschaft und Technologie zu verfehlen. Latours Frontstellung gegen soziologische Redukdonismen erschwert die Entwicklung eines Konzeptes der 'ökologischen Krise' als ein spezifisch soziales Problem, das gesellschaftliche Ursachen hat und gesellschaftlicher Lösungen bedarf." (Autorenreferat

Influences of forested and grassland vegetation on late Quaternary ecosystem development as recorded in lacustrine sediments

Geosphere-biosphere interactions are ubiquitous features of the Earth surface, yet the development of interactions between newly exposed lithologic surfaces and colonizing plants during primary succession after glaciation are lacking temporal detail. To assess the nature, rate, and magnitude of vegetation influence on parent material and sediment delivery, we analyzed ecosystem and geochemical proxies from lacustrine sediment cores at a grassland site and a forested site in the northern United States. Over time, terrigenous inputs declined at both sites, with increasing amounts of organic inputs toward present. The similarities between sites were striking given that the grassland sequence began in the Early Holocene, and the forested sequence began after the last glacial maximum. Multiple mechanisms of chemical weathering, hydrologic transport, and changes in source material potentially contribute to this pattern. Although there were strong links between vegetation composition and nitrogen cycling at each site, it appears that changes in forest type, or from oak woodland to grassland, did not exert a large influence on elemental (K, Ti, Si, Ca, Fe, Mn, and S) abundance in the sedimentary sequences. Rather, other factors in the catchment-lake system determined the temporal sequence of elemental abundance

EFSA CEF Panel (Panel on Food Contac t Materials, Enzymes, Flavourings and Processing Aids , 2013. Scientific Opinion on Flavouring Group Evaluation 2 07 (FGE.2 07 )

International audienc

Engineering Chimeric Antigen Receptor T-Cells for Racing in Solid Tumors: Don't Forget the Fuel.

T-cells play a critical role in tumor immunity. Indeed, the presence of tumor-infiltrating lymphocytes is a predictor of favorable patient prognosis for many indications and is a requirement for responsiveness to immune checkpoint blockade therapy targeting programmed cell death 1. For tumors lacking immune infiltrate, or for which antigen processing and/or presentation has been downregulated, a promising immunotherapeutic approach is chimeric antigen receptor (CAR) T-cell therapy. CARs are hybrid receptors that link the tumor antigen specificity and affinity of an antibody-derived single-chain variable fragment with signaling endodomains associated with T-cell activation. CAR therapy targeting CD19 has yielded extraordinary clinical responses against some hematological tumors. Solid tumors, however, remain an important challenge to CAR T-cells due to issues of homing, tumor vasculature and stromal barriers, and a range of obstacles in the tumor bed. Protumoral immune infiltrate including T regulatory cells and myeloid-derived suppressor cells have been well characterized for their ability to upregulate inhibitory receptors and molecules that hinder effector T-cells. A critical role for metabolic barriers in the tumor microenvironment (TME) is emerging. High glucose consumption and competition for key amino acids by tumor cells can leave T-cells with insufficient energy and biosynthetic precursors to support activities such as cytokine secretion and lead to a phenotypic state of anergy or exhaustion. CAR T-cell expansion protocols that promote a less differentiated phenotype, combined with optimal receptor design and coengineering strategies, along with immunomodulatory therapies that also promote endogenous immunity, offer great promise in surmounting immunometabolic barriers in the TME and curing solid tumors

Metabolic insufficiency underlies intratumoral cytotoxic T cell dysfunction

T cells have the remarkable ability to recognize and remove abnormal cells with precision, a feature that is very desirable for the treatment of cancer. However, while T cells specific for tumor antigens are primed and can infiltrate tumors, they are quickly rendered dysfunctional, through both cell intrinsic and cell extrinsic mechanisms. One way that tumors cripple T cell function is through the generation of an immunosuppressive microenvironment that is chronically inflamed, hypoxic, and nutrient poor. T cell activation and subsequent generation of effector function is bioenergetically demanding, requiring large amounts of metabolic intermediates to effectively proliferate, produce cytokines, and lyse target cells. We hypothesized that T cell dysfunction in cancer is due, in part, to metabolic insufficiency caused by chronic activation in metabolically dearth conditions. Using single-cell metabolic assays and extracellular flux analysis, we show that CD8+ cytotoxic T cells that infiltrate tumors demonstrate a progressive loss of mitochondrial function and mass, concomitant with upregulation of markers that correlate with T cell exhaustion. This mitochondrial dysfunction occurs independently of coinhibitory molecule signaling and specifically in the tumor microenvironment. This results in a failure to generate an adequate pool of ATP and in inability to effectively translate effector gene transcripts. This in stark contrast to T cells responding to an acute viral infection, where activated effector T cells demonstrate increased mitochondrial mass and ATP reserve. Further, artificial induction of mitochondrial dysfunction in T cells results in upregulation of coinhibitory molecules and an ‘exhausted-like’ phenotype, suggesting that metabolic insufficiency underlies the dysfunctional phenotype in cancer. Taken together, our data support a model in which tumor-infiltrating T cells have metabolic needs that cannot be met, resulting in failed effector function and tumor growth. Our studies also suggest that modulation or reprogramming of the altered metabolism of intratumoral T cells represents a potential strategy to reinvigorate dysfunctional T cells for the immunotherapeutic treatment of cancer

Single Cell Glucose Uptake Assays:A Cautionary Tale

Assays to monitor the metabolic state or nutrient uptake capacity of immune cells at a single cell level are increasingly in demand. One assay, used by many immunologists, employs 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino)-2-Deoxyglucose (2-NBDG), a fluorescent analogue of 2-deoxyglucose (2DG), as a substrate for glucose transporters. This molecule has been validated as a substrate for the glucose transporter Glut2 (Slc2a2) in mammalian cells but 2-NDBG selectivity for the glucose transporters expressed by T cells, Glut1 (Slc2a1) and Glut3 (Slc2a3), has never been explored. Nor has the possibility that 2-NBDG might bind to T cells that do not express glucose transporters been assessed. In this technical commentary we interrogate the specificity of 2-NBBG labelling as a readout for glucose transport in T lymphocytes. We compare flow cytometric 2-NBDG staining against well validated radiolabelled glucose transport assays in murine T cells. Our data show there can be a large discordance between glucose transport capacity and 2-NBDG labelling in T cells. We also find that 2-NBDG uptake into murine T cells is not inhibited by competitive substrates or facilitative glucose transporter inhibitors, nor can 2-NBDG competitively block glucose uptake in T cells. Collectively, these data argue that 2-NBDG uptake alone is not a reliable tool for the assessment of cellular glucose transport capacity.SCOPUS: ar.jDecretOANoAutActifinfo:eu-repo/semantics/publishe