Regulation of translation is required for dendritic cell function and survival during activation

In response to inflammatory stimulation, dendritic cells (DCs) have a remarkable pattern of differentiation (maturation) that exhibits specific mechanisms to control antigen processing and presentation. Here, we show that in response to lipopolysaccharides, protein synthesis is rapidly enhanced in DCs. This enhancement occurs via a PI3K-dependent signaling pathway and is key for DC activation. In addition, we show that later on, in a manner similar to viral or apoptotic stress, DC activation leads to the phosphorylation and proteolysis of important translation initiation factors, thus inhibiting cap-dependent translation. This inhibition correlates with major changes in the origin of the peptides presented by MHC class I and the ability of mature DCs to prevent cell death. Our observations have important implications in linking translation regulation with DC function and survival during the immune response.     

Weak base dispiro-1,2,4-trioxolanes: potent antimalarial ozonides

Thirty weak base 1,2,4-dispiro trioxolanes (secondary ozonides) were synthesized. Amino amide trioxolanes had the best combination of antimalarial and biopharmaceutical properties. Guanidine, aminoxy, and amino acid trioxolanes had poor antimalarial activity. Lipophilic trioxolanes were less stable metabolically than their more polar counterparts.     

Acute promyelocytic leukemia: new issues on pathogenesis and treatment response

Pathogenesis of acute promyelocytic leukemia appears to be one of the best understood among human malignancies. The ability of retinoic acid (RA) and arsenic trioxide to directly target the oncogenic promyelocytic leukemia-retinoic receptor A (PML-RARA) fusion protein also made this disease the first model for oncogene-targeted therapies. A set of recent data has significantly increased the complexity of our view of acute promyelocytic leukemia pathogenesis, as well as of therapeutic response. This review summarizes and discusses these findings, which yield novels questions and models.     

Cxcl12 evolution--subfunctionalization of a ligand through altered interaction with the chemokine receptor

The active migration of primordial germ cells (PGCs) from their site of specification towards their target is a valuable model for investigating directed cell migration within the complex environment of the developing embryo. In several vertebrates, PGC migration is guided by Cxcl12, a member of the chemokine superfamily. Interestingly, two distinct Cxcl12 paralogs are expressed in zebrafish embryos and contribute to the chemotattractive landscape. Although this offers versatility in the use of chemokine signals, it also requires a mechanism through which migrating cells prioritize the relevant cues that they encounter. Here, we show that PGCs respond preferentially to one of the paralogs and define the molecular basis for this biased behavior. We find that a single amino acid exchange switches the relative affinity of the Cxcl12 ligands for one of the duplicated Cxcr4 receptors, thereby determining the functional specialization of each chemokine that elicits a distinct function in a distinct process. This scenario represents an example of protein subfunctionalization--the specialization of two gene copies to perform complementary functions following gene duplication--which in this case is based on receptor-ligand interaction. Such specialization increases the complexity and flexibility of chemokine signaling in controlling concurrent developmental processes.     

inSilicoDb: an R/Bioconductor package for accessing human Affymetrix expert-curated datasets from GEO

Microarray technology has become an integral part of biomedical research and increasing amounts of datasets become available through public repositories. However, re-use of these datasets is severely hindered by unstructured, missing or incorrect biological samples information; as well as the wide variety of preprocessing methods in use. The inSilicoDb R/Bioconductor package is a command-line front-end to the InSilico DB, a web-based database currently containing 86 104 expert-curated human Affymetrix expression profiles compiled from 1937 GEO repository series. The use of this package builds on the Bioconductor project's focus on reproducibility by enabling a clear workflow in which not only analysis, but also the retrieval of verified data is supported.     

How many pieces to build a circadian clock?

Biological rhythms represent a fundamental property of various living organisms. In particular, circadian rhythms, i.e. rhythms with a period close to 24 hours, help organisms to adapt to environmental daily rhythms. Although various factors can entrain or reset rhythms, they persist even in the absence of external timing cue, showing that their generation is endogenous. Indeed, the suprachiasmatic nucleus (SCN) of the hypothalamus is considered to be the main circadian clock in mammals. Isolated SCN neurons have been shown to display circadian rhythms, and in each cell, a set of genes, called "clock genes", are devoted to the generation and regulation of rhythms. Recently, it has become obvious that the clock located in the SCN is not homogenous, but is rather composed of multiple functional components somewhat reminiscent of its neurochemical organization. The significance and implications of these findings are still poorly understood but pave the way for future exciting studies. Here, current knowledge concerning these distinct neuronal populations and the ways through which synchronization could be achieved, as well as the potential role of neuropeptides in both photic and non-photic resetting of the clock, are summarized. Finally, we discuss the role of the SCN within the circadian system, which also includes oscillators located in various tissues and cell types.     

Unique Epitopes Recognized by Antibodies Induced in Chikungunya Virus-Infected Non-Human Primates: Implications for the Study of Immunopathology and Vaccine Development

Chikungunya virus (CHIKV) is an Alphavirus that causes chronic and incapacitating arthralgia in humans. Although patient cohort studies have shown the production of CHIKV specific antibodies, the fine specificity of the antibody response against CHIKV is not completely defined. The macaque model of CHIKV infection was established due to limitations of clinical specimens. More importantly, its close relation to humans will allow the study of chronic infection and further identify important CHIKV targets. In this study, serum samples from CHIKV-infected macaques collected at different time-points post infection were used to characterize the antibody production pattern and kinetics. Results revealed that anti-CHIKV antibodies were neutralizing and the E2 glycoprotein, Capsid, nsP1, nsP3 and nsP4 proteins were targets of the anti-CHIKV antibody response in macaques. Furthermore, linear B-cell epitopes recognized by these anti-CHIKV antibodies were identified, and mapped to their structural localization. This characterizes the specificity of anti-CHIKV antibody response in macaques and further demonstrates the importance of the different regions in CHIKV-encoded proteins in the adaptive immune response. Information from this study provides critical knowledge that will aid in the understanding of CHIKV infection and immunity, vaccine design, and pre-clinical efficacy studies.