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1.  Anthracyclines Induce DNA Damage Response-Mediated Protection against Severe Sepsis 
Immunity  2013;39(5):874-884.
Summary
Severe sepsis remains a poorly understood systemic inflammatory condition with high mortality rates and limited therapeutic options in addition to organ support measures. Here we show that the clinically approved group of anthracyclines acts therapeutically at a low dose regimen to confer robust protection against severe sepsis in mice. This salutary effect is strictly dependent on the activation of DNA damage response and autophagy pathways in the lung, as demonstrated by deletion of the ataxia telangiectasia mutated (Atm) or the autophagy-related protein 7 (Atg7) specifically in this organ. The protective effect of anthracyclines occurs irrespectively of pathogen burden, conferring disease tolerance to severe sepsis. These findings demonstrate that DNA damage responses, including the ATM and Fancony Anemia pathways, are important modulators of immune responses and might be exploited to confer protection to inflammation-driven conditions, including severe sepsis.
doi:10.1016/j.immuni.2013.08.039
PMCID: PMC3968948  PMID: 24184056
Sepsis; ATM; Autophagy; Anthracyclines
2.  Training Experimental Biologists in Bioinformatics 
Advances in Bioinformatics  2012;2012:672749.
Bioinformatics, for its very nature, is devoted to a set of targets that constantly evolve. Training is probably the best response to the constant need for the acquisition of bioinformatics skills. It is interesting to assess the effects of training in the different sets of researchers that make use of it. While training bench experimentalists in the life sciences, we have observed instances of changes in their attitudes in research that, if well exploited, can have beneficial impacts in the dialogue with professional bioinformaticians and influence the conduction of the research itself.
doi:10.1155/2012/672749
PMCID: PMC3286881  PMID: 22400026
3.  Synaptotagmin-mediated vesicle fusion regulates cell migration 
Nature immunology  2010;11(6):495-502.
Chemokines and other chemoattractants direct leukocyte migration and are essential for the development and delivery of immune and inflammatory responses. To probe the molecular mechanisms that underlie chemoattractant-guided migration, we did an RNA-mediated interference screen that identified several members of the synaptotagmin family of calcium-sensing vesicle-fusion proteins as mediators of cell migration: SYT7 and SYTL5 were positive regulators of chemotaxis, whereas SYT2 was a negative regulator of chemotaxis. SYT7-deficient leukocytes showed less migration in vitro and in a gout model in vivo. Chemoattractant-induced calcium-dependent lysosomal fusion was impaired in SYT7-deficient neutrophils. In a chemokine gradient, SYT7-deficient lymphocytes accumulated lysosomes in their uropods and had impaired uropod release. Our data identify a molecular pathway required for chemotaxis that links chemoattractant-induced calcium flux to exocytosis and uropod release.
doi:10.1038/ni.1878
PMCID: PMC2951881  PMID: 20473299
4.  Novel HIV-1 Knockdown Targets Identified by an Enriched Kinases/Phosphatases shRNA Library Using a Long-Term Iterative Screen in Jurkat T-Cells 
PLoS ONE  2010;5(2):e9276.
HIV-1 is a complex retrovirus that uses host machinery to promote its replication. Understanding cellular proteins involved in the multistep process of HIV-1 infection may result in the discovery of more adapted and effective therapeutic targets. Kinases and phosphatases are a druggable class of proteins critically involved in regulation of signal pathways of eukaryotic cells. Here, we focused on the discovery of kinases and phosphatases that are essential for HIV-1 replication but dispensable for cell viability. We performed an iterative screen in Jurkat T-cells with a short-hairpin-RNA (shRNA) library highly enriched for human kinases and phosphatases. We identified 14 new proteins essential for HIV-1 replication that do not affect cell viability. These proteins are described to be involved in MAPK, JNK and ERK pathways, vesicular traffic and DNA repair. Moreover, we show that the proteins under study are important in an early step of HIV-1 infection before viral integration, whereas some of them affect viral transcription/translation. This study brings new insights for the complex interplay of HIV-1/host cell and opens new possibilities for antiviral strategies.
doi:10.1371/journal.pone.0009276
PMCID: PMC2822867  PMID: 20174665
5.  The Cadherin Superfamily in Anopheles gambiae: a Comparative Study With Drosophila melanogaster 
The cadherin superfamily is a diverse and multifunctional group of proteins with extensive representation across genomes of phylogenetically distant species that is involved in cell–cell communication and adhesion. The mosquito Anopheles gambiae is an emerging model organism for the study of innate immunity and host–pathogen interactions, where the malaria parasite induces a profound rearrangement of the actin cytoskeleton at critical stages of infection. We have used bioinformatics tools to retrieve present sequence knowledge about the complete repertoire of cadherins in A. gambiae and compared it to that of the fruit fly, Drosophila melanogaster. In A. gambiae, we have identified 43 genes coding for cadherin extracellular domains that were re-annotated to 38 genes and represent an expansion of this gene family in comparison to other invertebrate organisms. The majority of Drosophila cadherins show a 1 : 1 Anopheles orthologue, but we have observed a remarkable expansion in some groups in A. gambiae, such as N-cadherins, that were recently shown to have a role in the olfactory system of the fruit fly. In vivo dsRNA silencing of overrepresented genes in A. gambiae and other genes showing expression at critical tissues for parasite infection will likely advance our understanding of the problems of host preference and host–pathogen interactions in this mosquito species.
doi:10.1002/cfg.473
PMCID: PMC2447487  PMID: 18629193

Results 1-5 (5)