Functional characterization of ARID1A mutations in follicular lymphoma

Background: Follicular lymphoma (FL) is one of the most common malignant lymphomas worldwide and the most common form of indolent lymphoma. FL is highly heterogeneous from both the clinical and molecular point of view. It remains a clinical challenge since advanced-stage disease is still considered incurable, and patients ultimately present with relapsed or re-fractory disease. Molecularly, FL is characterized by highly recurrent genetic mutations in genes coding for epigenetic modifiers. ARID1A mutations are among the most frequent mutations in FL (~10-20 % at the time of diagnosis). ARID1A mutations are a component of the prognostic clinic-genetic risk model m7-FLIPI (Pastore, Jurinovic et al. 2015). These mutations are primari-ly disruptive and result in protein haplodeficiency. Functionally, ARID1A is part of a SWI/SNF complex, which controls chromatin accessibility and is involved in numerous processes, includ-ing gene expression. Aim: Functionally characterize ARID1A mutations in representative human FL model systems. Methods: I used established and primary FL-like cell lines that harbor the hallmark t(14;18) translocation with or without heterozygous or homozygous ARID1A mutations (introduced by CRISPR/Cas9) or knock-down (by shRNA). I applied complementary omics approaches (RNA-Seq and ATAC-Seq) and functional assays to untangle the consequences of ARID1A loss in these FL model systems. Results: ARID1A loss profoundly altered gene expression. Across three cell lines, we observed consistent down-regulation of genes involved in cell cycle regulation and apoptosis pathways upon ARID1A loss. In functional experiments, I could show that ARID1A mutant clones are characterized by significantly slower cell proliferation and increased formation of anaphase bridges. Next, I demonstrated that ARID1A loss results in decreased FAS levels and lower sensitivity to FASLG-induced apoptosis. We discovered the underlying molecular mechanism through ad-vanced bioinformatics analyses and functional experiments. Briefly, ARID1A loss does not di-rectly affect FAS expression. Still, it results in reduced DNA accessibility and expression of the co-transcription factor RUNX3, thereby hindering RUNX3-ETS1 cooperativity and ETS1-induced FAS expression, which promotes a functionally and clinically relevant immune-evasive pheno-type. Finally, RNA-Seq analysis indicated that ARID1A loss alters the plasma membrane and cyto-skeleton functions, as well as the overall abundance of ligands and receptors. Ex vivo co-cultures of FL-like cells with T cells suggested impaired immune synapse formation with CD4 T lymphocytes upon ARID1A loss. Discussion and conclusion: Overall, our analyses provide novel insights into the functional consequences of ARID1A mutations in FL, most notably promoting immune evasion. A better understanding of mutation-specific biology, including its impact on interactions within the tumor microenvironment, holds promise for improved patient stratification and the development of personalized treatment approaches

Taking Legal Pluralism Seriously: The Alien Tort Claims Act and the Role of International Law Before U.S. Federal Courts

Back to Government?: The Pluralistic Deficit in the Decisionmaking Processes and Before the Courts, Symposium. University of Trento, Italy, June 11-12, 2004

Taking Legal Pluralism Seriously: The Alien Tort Claims Act and the Role of International Law Before U.S. Federal Courts

Back to Government?: The Pluralistic Deficit in the Decisionmaking Processes and Before the Courts, Symposium. University of Trento, Italy, June 11-12, 2004

Ocorrência de dano mecânico por impacto nas operações de colheita e pós-colheita de maçãs.

Esta Circular Técnica tem como objetivo disponibilizar informações relativas à magnitude dos impactos que ocorrem nas operações de colheita e em linhas de beneficiamento e classificação de maçãs, identificando os pontos de ocorrência e propondo medidas de redução dos danos mecânicos. Traz ainda informações referentes à manifestação do dano em maçãs 'Royal Gala' em decorrência dos níveis de impacto observados.bitstream/item/73906/1/Circular-Tecnica-94-online.pd

Legal Integration of Private Law in Europe and in the United States of America – Comparative Remarks

The increasing convergence of law, particularly private and commercial law in the Western legal systems is among the most debated issues in comparative law studies. This paper analyzes legal integration of private (and commercial) law in the U.S. and in the EU legal systems, and aims at comparing – in a nutshell – actors, methods, strategies and outcomes of this phenomenon in the two different institutional settings. Legal integration initiatives are part of a coherent plan to support economic transactions with a legal structure that encourages enterprise and reduces costs. The motivation for these changes is economic, but the engine driving legal integration is essentially political and cultural, and therefore is closely linked to the institutional setting and the legal tradition(s) in which legal integration takes place

Sistema de avaliação de dano mecânico por impacto em linhas de beneficiamento de maçãs.

O objetivo deste comunicado técnico é descrever o sistema de avaliação da ocorrência dos danos mecânicos por impacto com a utilização da esfera instrumentada (Impact Recording Device, IRD - Techmark, Inc., Lansing, USA), como forma de subsidiar e orientar os ajustes necessários para eliminação ou redução dos mesmos nas linhas de beneficiamento e classificação de maçãs.bitstream/item/48512/1/Comunicado-Tecnico-105.pd

[i]Conidames[/i], a new oriental genus of Sycophaginae (Hymenoptera, Agaonidae) associated with [i]Ficus[/i] section Conosycea (Moraceae)

The sycophagines are strictly associated with two subgenera of Fit to L. (Moraceae), namely,Slycomo77/S and Urostignza. They mostly oviposit through the fig wall and lay their eggs within the fig flowers, being either gall-makers or parasitoids of other fig wasps. In this contribution, a new genus of Sycophaginae, [i]Conidarnes[/i] Earache & Rasplus, gen. n., is described with seven new species: [i]Conidarnes achterbergi[/i] Earache & Rasplus, sp. n.; [i]Conidarwes beryl'[/i] Farache & Rasplus, sp. n.; [i]Conidarnes laevis[/i] Earache & Rasplus, sp. n.;[i] Conidames santineloi[/i] Earache & Rasplus, sp. n.; [i]Conidarnes subtectae[/i] Earache & Rasplus, sp. n.; [i]Conidarnes sidcata[/i] Farache & Rasplus, sp. n.; and [i]Conidarnes sumatranae[/i] Farache & Rasplus, sp. n. Illustrations, morphological diagnoses, dichotomous keys and multi-entry online keys to species are provided. [i]Conidarnes[/i] species strictly occur in the oriental region, and their distribution does not oVerlap with the distribution of the two other genera belonging to the same clade. Due to their relative rarity, we encourage extensive sampling of Conosycea figs to improve our knowledge of the genus