Funktionelle Untersuchung aktivierender NK-Zell Rezeptoren durch die Expression chimärer Rezeptoren in verschiedenen T-Zellpopulationen

Durch die Modifikation von T-Zellen mit tumorspezifischen chimären Rezeptoren kann das Immunsystem des Menschen auch zur Bekämpfung von Tumorerkrankungen genutzt werden. Die Ursache für die rasche Inaktivierung der modifizierten Zellen in vivo könnte das Fehlen von Kostimulation sein. In dieser Arbeit wurde die kostimulatorische Bedeutung von NK-Zell Rezeptoren untersucht. Die konstruierten chimären Rezeptoren enthielten entweder nur die Rezeptoranteile von 2B4 und NKG2D/DAP10 oder wiesen zusätzlich den signaltransduzierenden Anteil der z-Kette des T-Zell Rezeptors auf. Während sich die chimären Rezeptoren ohne z-Kette als nicht funktionell erwiesen, zeigte 14.G2a-DAP10-z eine hohe Unspezifität. Hingegen konnten 14.G2a-2B4-z transduzierte polyklonale T-Zellen Antigen-positive Tumorzellen spezifisch lysieren und von diesen zur klonalen Proliferation angeregt werden. Damit konnte gezeigt werden, dass der NK-Zell Rezeptor 2B4 in polyklonalen T-Zellen kostimulatorisch wirken kann

Band gap renormalization, carrier mobilities, and the electron-phonon self-energy in crystalline naphthalene

Organic molecular crystals are expected to feature appreciable electron-phonon interactions that influence their electronic properties at zero and finite temperature. In this work, we report first-principles calculations and an analysis of the electron-phonon self-energy in naphthalene crystals. We compute the zero-point renormalization and temperature dependence of the fundamental band gap, and the resulting scattering lifetimes of electronic states near the valence- and conduction-band edges employing density functional theory. Further, our calculated phonon renormalization of the $GW$-corrected quasiparticle band structure predicts a fundamental band gap of 5 eV for naphthalene at room temperature, in good agreement with experiments. From our calculated phonon-induced electron lifetimes, we obtain the temperature-dependent mobilities of electrons and holes in good agreement with experimental measurements at room temperatures. Finally, we show that an approximate energy self-consistent computational scheme for the electron-phonon self-energy leads to the prediction of strong satellite bands in the electronic band structure. We find that a single calculation of the self-energy can reproduce the self-consistent results of the band gap renormalization and electrical mobilities for naphthalene, provided that the on-the-mass-shell approximation is used, i.e., if the self-energy is evaluated at the bare eigenvalues.Comment: 12 pages, 7 figures, 3 table

Dual Function of the NK Cell Receptor 2B4 (CD244) in the Regulation of HCV-Specific CD8+ T Cells

The outcome of viral infections is dependent on the function of CD8+ T cells which are tightly regulated by costimulatory molecules. The NK cell receptor 2B4 (CD244) is a transmembrane protein belonging to the Ig superfamily which can also be expressed by CD8+ T cells. The aim of this study was to analyze the role of 2B4 as an additional costimulatory receptor regulating CD8+ T cell function and in particular to investigate its implication for exhaustion of hepatitis C virus (HCV)-specific CD8+ T cells during persistent infection. We demonstrate that (i) 2B4 is expressed on virus-specific CD8+ T cells during acute and chronic hepatitis C, (ii) that 2B4 cross-linking can lead to both inhibition and activation of HCV-specific CD8+ T cell function, depending on expression levels of 2B4 and the intracellular adaptor molecule SAP and (iii) that 2B4 stimulation may counteract enhanced proliferation of HCV-specific CD8+ T cells induced by PD1 blockade. We suggest that 2B4 is another important molecule within the network of costimulatory/inhibitory receptors regulating CD8+ T cell function in acute and chronic hepatitis C and that 2B4 expression levels could also be a marker of CD8+ T cell dysfunction. Understanding in more detail how 2B4 exerts its differential effects could have implications for the development of novel immunotherapies of HCV infection aiming to achieve immune control

A inserção do Brasil no mercado mundial de alumínio: incorporando contribuições da Ecologia Política para a Saúde Coletiva

O presente artigo discute a inserção do Brasil no mercado mundial de alumínio a partir dos referenciais teóricos da ecologia política, da economia política do território e da saúde coletiva. A conjuntura contemporânea da economia mundial tem sido pautada pela desregulamentação e liberalização, característicos do ideário neoliberal propalado pelas nações centrais. A maior participação do Brasil nesse mercado tem sido realizada a partir do aumento da produção e exportação de commodities agrárias e metálicas, como o alumínio. Nesse sentido, a partir dos paradigmas da ecologia política, o texto propõe uma análise das consequências socioambientais, assim como sobre novas territorialidades que se produzem e reproduzem dentro de uma lógica econômica que privilegia as nações centrais. Do mesmo modo, procura-se compreender os dilemas da saúde coletiva sob uma perspectiva holística e integradora na qual se articula aos modelos de desenvolvimento econômico. Percebe-se que a produção e exportação de alumínio primário, apesar de apresentar um valor agregado maior, esconde um conjunto difuso de impactos que afetam o ambiente e a saúde coletiva

Vaccination to improve the persistence of CD19CAR gene-modified T cells in relapsed pediatric acute lymphoblastic leukemia

Trials with 2nd generation CD19 chimeric antigen receptors (CAR) T-cells report unprecedented responses but associated with risk of Cytokine Release Syndrome (CRS). Instead, we studied use of donor Epstein Barr virus-specific T-cells (EBV CTL) transduced with a 1st generation CD19CAR, relying on the endogenous T-cell receptor for proliferation. We conducted a multi- center phase I/II study of donor CD19CAR transduced EBV CTL in pediatric ALL. Patients were eligible pre-emptively if they developed molecular relapse (>5 × 10-4) post-1st SCT, or prophylactically post-2nd SCT. An initial cohort showed poor expansion/persistence. We next investigated EBV-directed vaccination to enhance expansion/persistence. 11 patients were treated. No CRS, neurotoxicity or GVHD was observed. At 1 month, 5 patients were in CR (4 continuing, 1 de-novo), 1 PR, 3 had stable disease and 3 no response. At a median follow-up of 12 months, 10 of 11 have relapsed, 2 are alive with disease and 1 alive in CR 3 years. Whilst CD19CAR CTL expansion was poor, persistence was enhanced by vaccination. Median persistence was 0 (range 0-28) days without vaccination compared to 56 (range 0-221) days with vaccination (P=0.06). This study demonstrates feasibility of such multi-center studies and the potential for enhancing persistence with vaccination.Leukemia accepted article preview online, 27 January 2017. doi:10.1038/leu.2017.39

Human Rights and the Pink Tide in Latin America : Which Rights Matter?

Latin America witnessed the election of ‘new Left’ governments in the early 21 st century that, in different ways, sought to open a debate about alternatives to paradigms of neoliberal development. What has this meant for the way that human rights are understood and for patterns of human rights compliance? Using qualitative and quantitative evidence, this article discusses how human rights are imagined and the compliance records of new Left governments through the lens of the three ‘generations’ of human rights — political and civil, social and economic, and cultural and environmental rights. The authors draw in particular on evidence from Andean countries and the Southern Cone. While basic civil and individual liberties are still far from guaranteed, especially in the Andean region, new Left countries show better overall performances in relation to socio-economic rights compared to the past and to other Latin American countries. All new Left governments also demonstrate an increasing interest in ‘third generation’ (cultural and environmental) rights, though this is especially marked in the Andean Left. The authors discuss the tensions around interpretations and categories of human rights, reflect on the stagnation of first generation rights and note the difficulties associated with translating second and third generation rights into policy

Metabolic Rift or Metabolic Shift? Dialectics, Nature, and the World-Historical Method

Abstract In the flowering of Red-Green Thought over the past two decades, metabolic rift thinking is surely one of its most colorful varieties. The metabolic rift has captured the imagination of critical environmental scholars, becoming a shorthand for capitalism’s troubled relations in the web of life. This article pursues an entwined critique and reconstruction: of metabolic rift thinking and the possibilities for a post-Cartesian perspective on historical change, the world-ecology conversation. Far from dismissing metabolic rift thinking, my intention is to affirm its dialectical core. At stake is not merely the mode of explanation within environmental sociology. The impasse of metabolic rift thinking is suggestive of wider problems across the environmental social sciences, now confronted by a double challenge. One of course is the widespread—and reasonable—sense of urgency to evolve modes of thought appropriate to an era of deepening biospheric instability. The second is the widely recognized—but inadequately internalized—understanding that humans are part of nature

Language experience impacts brain activation for spoken and signed language in infancy: Insights from unimodal and bimodal bilinguals

Recent neuroimaging studies suggest that monolingual infants activate a left lateralised fronto-temporal brain network in response to spoken language, which is similar to the network involved in processing spoken and signed language in adulthood. However, it is unclear how brain activation to language is influenced by early experience in infancy. To address this question, we present functional near infrared spectroscopy (fNIRS) data from 60 hearing infants (4-to-8 months): 19 monolingual infants exposed to English, 20 unimodal bilingual infants exposed to two spoken languages, and 21 bimodal bilingual infants exposed to English and British Sign Language (BSL). Across all infants, spoken language elicited activation in a bilateral brain network including the inferior frontal and posterior temporal areas, while sign language elicited activation in the right temporo-parietal area. A significant difference in brain lateralisation was observed between groups. Activation in the posterior temporal region was not lateralised in monolinguals and bimodal bilinguals, but right lateralised in response to both language modalities in unimodal bilinguals. This suggests that experience of two spoken languages influences brain activation for sign language when experienced for the first time. Multivariate pattern analyses (MVPA) could classify distributed patterns of activation within the left hemisphere for spoken and signed language in monolinguals (proportion correct = 0.68; p = 0.039) but not in unimodal or bimodal bilinguals. These results suggest that bilingual experience in infancy influences brain activation for language, and that unimodal bilingual experience has greater impact on early brain lateralisation than bimodal bilingual experience