Integrated perspective on translating biophysical to economic impacts of climate change

Estimates of climate change’s economic impacts vary widely, depending on the applied methodology. This uncertainty is a barrier for policymakers seeking to quantify the benefits of mitigation. In this Perspective, we provide a comprehensive overview and categorization of the pathways and methods translating biophysical impacts into economic damages. We highlight the open question of the persistence of impacts as well as key methodological gaps, in particular the effect of including inequality and adaptation in the assessments. We discuss the need for intensifying interdisciplinary research, focusing on the uncertainty of econometric estimates of damages as well as identification of the most socioeconomically relevant types of impact. A structured model intercomparison related to economic impacts is noted as a crucial next step

Multiple Changes in Peptide and Lipid Expression Associated with Regeneration in the Nervous System of the Medicinal Leech

peer reviewe

CRTAM receptor engagement by Necl-2 on tumor cells triggers cell death of activated Vγ9Vδ2 T cells.

International audienceHuman Vγ9Vδ2 T cells exert potent in vitro and in vivo antitumor activities, making them promising candidates for immunotherapy strategies. Recognition of tumor cells by Vγ9Vδ2 T cells requires engagement of the TCR and/or NK receptors. Recently, one of the novel NK receptors, the class I-restricted T cell-associated molecule (CRTAM), has been described to promote cytotoxic function of NK cells and to lead to IFN-γ secretion by CD8(+) T cells through interaction with its ligand, Necl-2. A better understanding of the role of CRTAM in Vγ9Vδ2 T cell functions is highly relevant to optimize innate-like T cell-based cancer immunotherapy. In this article, we report that CRTAM is transiently expressed on activated Vγ9Vδ2 T lymphocytes following TCR engagement. However, CRTAM-Necl-2 interaction does not modify the cytotoxic function or IFN-γ secretion of Vγ9Vδ2 T cells. The expression of CRTAM in activated Vγ9Vδ2 T cells is quickly downregulated following interaction with Necl-2 on tumor cells. Of interest, CRTAM is concurrently acquired at the cell surface of Necl-2(+) tumor cells through Vγ9Vδ2 T cell membrane capture. Finally, we highlight that coculture experiments with tumor cells expressing Necl-2 result in significant cell death of CRTAM(+) Vγ9Vδ2 T cells. CRTAM-mediated cell death is dependent on an autophagic process, but not on apoptosis or necroptosis, as attested by the expression of characteristic markers and blocking experiments with specific inhibitors. On the basis of these findings, we propose that Necl-2 on tumor cells represents a new tumor counterattack mechanism and a potential target to improve efficiency of γδ T cell-based immunotherapy

Exonic Splicing Mutations Are More Prevalent than Currently Estimated and Can Be Predicted by Using In Silico Tools

International audienceThe identification of a causal mutation is essential for molecular diagnosis and clinical management of many genetic disorders. However, even if next-generation exome sequencing has greatly improved the detection of nucleotide changes, the biological interpretation of most exonic variants remains challenging. Moreover, particular attention is typically given to protein-coding changes often neglecting the potential impact of exonic variants on RNA splicing. Here, we used the exon 10 of MLH1, a gene implicated in hereditary cancer, as a model system to assess the prevalence of RNA splicing mutations among all single-nucleotide variants identified in a given exon. We performed comprehensive minigene assays and analyzed patient's RNA when available. Our study revealed a staggering number of splicing mutations in MLH1 exon 10 (77% of the 22 analyzed variants), including mutations directly affecting splice sites and, particularly, mutations altering potential splicing regulatory elements (ESRs). We then used this thoroughly characterized dataset, together with experimental data derived from previous studies on BRCA1, BRCA2, CFTR and NF1, to evaluate the predictive power of 3 in silico approaches recently described as promising tools for pinpointing ESR-mutations. Our results indicate that ΔtESRseq and ΔHZEI-based approaches not only discriminate which variants affect splicing, but also predict the direction and severity of the induced splicing defects. In contrast, the ΔΨ-based approach did not show a compelling predictive power. Our data indicates that exonic splicing mutations are more prevalent than currently appreciated and that they can now be predicted by using bioinformatics methods. These findings have implications for all genetically-caused diseases

Direct Toll-Like Receptor 8 signaling increases the functional avidity of human CD8+ T lymphocytes generated for adoptive T cell therapy strategies

International audienceAdoptive transfer of in vitro activated and expanded antigen-specific cytotoxic T lymphocytes (CTLs) is a promising therapeutic strategy for infectious diseases and cancers. Obtaining in vitro a sufficient amount of highly specific cytotoxic cells and capable of retaining cytotoxic activity in vivo remains problematic. We studied the role of Toll-Like Receptor-8 (TLR8) engagement on peripheral CTLs activated with melanoma antigen MART-1-expressing artificial antigen-presenting cells (AAPCs). After a 3-week co-culture, 3–27% of specific CTLs were consistently obtained. CTLs expressed TLR8 in the intracellular compartment and at the cell surface. Specific CTLs activated with a TLR8 agonist (CL075) 24 h before the end of the culture displayed neither any change in their production levels of molecules involved in cytotoxicity (IFN-γ, Granzyme B, and TNF-α) nor major significant change in their cell surface phenotype. However, these TLR8-stimulated lymphocytes displayed increased cytotoxic activity against specific peptide-pulsed target cells related to an increase in specific anti-melanoma CTL functional avidity. TLR8 engagement on CTLs could, therefore, be useful in different immunotherapy strategies

Disequilibrium between <i>BRCA1</i> and <i>BRCA2</i> Circular and Messenger RNAs Plays a Role in Breast Cancer

Breast cancer is a frequent disease for which the discovery of markers that enable early detection or prognostic assessment remains challenging. Circular RNAs (circRNAs) are single-stranded structures in closed loops that are produced by backsplicing. CircRNA and messenger RNA (mRNA) are generated co-transcriptionally, and backsplicing and linear splicing compete against each other. As mRNAs are key players in tumorigenesis, we hypothesize that a disruption of the balance between circRNAs and mRNAs could promote breast cancer. Hence, we developed an assay for a simultaneous study of circRNAs and mRNAs, which we have called splice and expression analyses by exon ligation and high-throughput sequencing (SEALigHTS). Following SEALigHTS validation for BRCA1 and BRCA2, our hypothesis was tested using an independent research set of 95 pairs from tumor and adjacent normal breast tissues. In this research set, ratios of BRCA1 and BRCA2 circRNAs/mRNAs were significantly lower in the tumor breast tissue compared to normal tissue (p = 1.6 × 10−9 and p = 4.4 × 10−5 for BRCA1 and BRCA2, respectively). Overall, we developed an innovative method to study linear splicing and backsplicing, described the repertoire of BRCA1 and BRCA2 circRNAs, including 15 novel ones, and showed for the first time that a disequilibrium between BRCA1 and BRCA2 circRNAs and mRNAs plays a role in breast cancer