Acyl-Imidazoles A Privileged Ester Surrogate for Enantioselective Synthesis

International audienceSince the first report by Evans in asymmetric Friedel‐Crafts reactions, the use of acyl‐imidazoles has blossomed as powerful ester/amide surrogates. The imidazole scaffold indeed displays stability and special activation features allowing both better reactivity and selectivity in traditional ester/amide functionalizations: α‐(enolate chemistry), β‐(conjugate additions), α,β‐(cycloadditions) or γ/δ‐(vinylogous). An overview of the contemporary and growing interest in acyl‐imidazoles in metal‐ and organo‐catalyzed transformations (bio‐hybrid catalytic systems will be fully described in a back‐to‐back Minireview) will be highlighted. Moreover, post‐functionalization expediencies are also going to be discussed in this Minireview

Protective CD8+ T lymphocytes in Primates Immunized with Malaria Sporozoites

Live attenuated malaria vaccines are more potent than the recombinant protein, bacterial or viral platform vaccines that have been tested, and an attenuated sporozoite vaccine against falciparum malaria is being developed for humans. In mice, attenuated malaria sporozoite vaccines induce CD8+ T cells that kill parasites developing in the liver. We were curious to know if CD8+ T cells were also important in protecting primates against malaria. We immunized 9 rhesus monkeys with radiation attenuated Plasmodium knowlesi sporozoites, and found that 5 did not develop blood stage infections after challenge with live sporozoites. We then injected 4 of these protected monkeys with cM-T807, a monoclonal antibody to the CD8 molecule which depletes T cells. The fifth monkey received equivalent doses of normal IgG. In 3 of the 4 monkeys receiving cM-T807 circulating CD8+ T cells were profoundly depleted. When re-challenged with live sporozoites all 3 of these depleted animals developed blood stage malaria. The fourth monkey receiving cM-T807 retained many circulating CD8+ T cells. This monkey, and the vaccinated monkey receiving normal IgG, did not develop blood stage malaria at re-challenge with live sporozoites. Animals were treated with antimalarial drugs and rested for 4 months. During this interval CD8+ T cells re-appeared in the circulation of the depleted monkeys. When all vaccinated animals received a third challenge with live sporozoites, all 5 monkeys were once again protected and did not develop blood stage malaria infections. These data indicate that CD8+ T cells are important effector cells protecting monkeys against malaria sporozoite infection. We believe that malaria vaccines which induce effector CD8+ T cells in humans will have the best chance of protecting against malaria

The Spitzer Extragalactic Representative Volume Survey (SERVS): Survey Definition and Goals

We present the Spitzer Extragalactic Representative Volume Survey (SERVS), an 18 deg^2 medium-deep survey at 3.6 and 4.5 μm with the postcryogenic Spitzer Space Telescope to ≈2 μJy (AB = 23.1) depth of five highly observed astronomical fields (ELAIS-N1, ELAIS-S1, Lockman Hole, Chandra Deep Field South, and XMM-LSS). SERVS is designed to enable the study of galaxy evolution as a function of environment from z ∼ 5 to the present day and is the first extragalactic survey that is both large enough and deep enough to put rare objects such as luminous quasars and galaxy clusters at z ≳ 1 into their cosmological context. SERVS is designed to overlap with several key surveys at optical, near- through far-infrared, submillimeter, and radio wavelengths to provide an unprecedented view of the formation and evolution of massive galaxies. In this article, we discuss the SERVS survey design, the data processing flow from image reduction and mosaicking to catalogs, and coverage of ancillary data from other surveys in the SERVS fields. We also highlight a variety of early science results from the survey

A Role for Immune Responses against Non-CS Components in the Cross-Species Protection Induced by Immunization with Irradiated Malaria Sporozoites

Immunization with irradiated Plasmodium sporozoites induces sterile immunity in rodents, monkeys and humans. The major surface component of the sporozoite the circumsporozoite protein (CS) long considered as the antigen predominantly responsible for this immunity, thus remains the leading candidate antigen for vaccines targeting the parasite's pre-erythrocytic (PE) stages. However, this role for CS was questioned when we recently showed that immunization with irradiated sporozoites (IrrSpz) of a P. berghei line whose endogenous CS was replaced by that of P. falciparum still conferred sterile protection against challenge with wild type P. berghei sporozoites. In order to investigate the involvement of CS in the cross-species protection recently observed between the two rodent parasites P. berghei and P. yoelii, we adopted our gene replacement approach for the P. yoelii CS and exploited the ability to conduct reciprocal challenges. Overall, we found that immunization led to sterile immunity irrespective of the origin of the CS in the immunizing or challenge sporozoites. However, for some combinations, immune responses to CS contributed to the acquisition of protective immunity and were dependent on the immunizing IrrSpz dose. Nonetheless, when data from all the cross-species immunization/challenges were considered, the immune responses directed against non-CS parasite antigens shared by the two parasite species played a major role in the sterile protection induced by immunization with IrrSpz. This opens the perspective to develop a single vaccine formulation that could protect against multiple parasite species

On Tightly Secure Primitives in the Multi-Instance Setting

We initiate the study of general tight reductions in cryptography. There already exist a variety of works that offer tight reductions for a number of cryptographic tasks, ranging from encryption and signature schemes to proof systems. However, our work is the first to provide a universal definition of a tight reduction (for arbitrary primitives), along with several observations and results concerning primitives for which tight reductions have not been known. Technically, we start from the general notion of reductions due to Reingold, Trevisan, and Vadhan (TCC 2004), and equip it with a quantification of the respective reduction loss, and a canonical multi-instance extension to primitives. We then revisit several standard reductions whose tight security has not yet been considered. For instance, we revisit a generic construction of signature schemes from one-way functions, and show how to tighten the corresponding reduction by assuming collision-resistance from the used one-way function. We also obtain tightly secure pseudorandom generators (by using suitable rerandomisable hard-core predicates), and tightly secure lossy trapdoor functions

Inhibitory Effect of TNF-α on Malaria Pre-Erythrocytic Stage Development: Influence of Host Hepatocyte/Parasite Combinations

BACKGROUND: The liver stages of malaria parasites are inhibited by cytokines such as interferon-gamma or Interleukin (IL)-6. Binding of these cytokines to their receptors at the surface of the infected hepatocytes leads to the production of nitric oxide (NO) and radical oxygen intermediates (ROI), which kill hepatic parasites. However, conflicting results were obtained with TNF-alpha possibly because of differences in the models used. We have reassessed the role of TNF-alpha in the different cellular systems used to study the Plasmodium pre-erythrocytic stages. METHODS AND FINDINGS: Human or mouse TNF-alpha were tested against human and rodent malaria parasites grown in vitro in human or rodent primary hepatocytes, or in hepatoma cell lines. Our data demonstrated that TNF-alpha treatment prevents the development of malaria pre-erythrocytic stages. This inhibitory effect however varies with the infecting parasite species and with the nature and origin of the cytokine and hepatocytes. Inhibition was only observed for all parasite species tested when hepatocytes were pre-incubated 24 or 48 hrs before infection and activity was directed only against early hepatic parasite. We further showed that TNF-alpha inhibition was mediated by a soluble factor present in the supernatant of TNF-alpha stimulated hepatocytes but it was not related to NO or ROI. Treatment TNF-alpha prevents the development of human and rodent malaria pre-erythrocytic stages through the activity of a mediator that remains to be identified. CONCLUSIONS: Treatment TNF-alpha prevents the development of human and rodent malaria pre-erythrocytic stages through the activity of a mediator that remains to be identified. However, the nature of the cytokine-host cell-parasite combination must be carefully considered for extrapolation to the human infection

The evolution of the star formation activity per halo mass up to redshift ~ 1.6 as seen by Herschel

Star formation in massive galaxies is quenched at some point during hierarchical mass assembly. To understand where and when the quenching processes takes place, we study the evolution of the total star formation rate per unit total halo mass (\Sigma(SFR/M)) in three different mass scales: low mass halos (field galaxies), groups, and clusters, up to a redshift ~1.6. We use deep far-infrared PACS data at 100 and 160 um to accurately estimate the total star formation rate of the Luminous Infrared Galaxy population of 9 clusters with mass ~10^{15} M_{\odot}, and 9 groups/poor clusters with mass ~ 5 x 10^{13} M_{\odot}. Estimates of the field \Sigma(SFR/M) are derived from the literature, by dividing the star formation rate density by the mean comoving matter density of the universe. The field \Sigma(SFR/M) increases with redshift up to z~1 and it is constant thereafter. The evolution of the \Sigma(SFR/M)-z relation in galaxy systems is much faster than in the field. Up to redshift z~0.2, the field has a higher \Sigma(SFR/M) than galaxy groups and galaxy clusters. At higher redshifts, galaxy groups and the field have similar \Sigma(SFR/M), while massive clusters have significantly lower \Sigma(SFR/M) than both groups and the field. There is a hint of a reversal of the SFR activity vs. environment at z~1.6, where the group \Sigma(SFR/M) lies above the field \Sigma(SFR/M)-z relation. We discuss possible interpretations of our results in terms of the processes of downsizing, and star-formation quenching.Comment: 8 pages, 3 figures, accepted for publication on A&

Why Functional Pre-Erythrocytic and Bloodstage Malaria Vaccines Fail: A Meta-Analysis of Fully Protective Immunizations and Novel Immunological Model

Background: Clinically protective malaria vaccines consistently fail to protect adults and children in endemic settings, and at best only partially protect infants. Methodology/Principal Findings: We identify and evaluate 1916 immunization studies between 1965-February 2010, and exclude partially or nonprotective results to find 177 completely protective immunization experiments. Detailed reexamination reveals an unexpectedly mundane basis for selective vaccine failure: live malaria parasites in the skin inhibit vaccine function. We next show published molecular and cellular data support a testable, novel model where parasite-host interactions in the skin induce malaria-specific regulatory T cells, and subvert early antigen-specific immunity to parasite-specific immunotolerance. This ensures infection and tolerance to reinfection. Exposure to Plasmodium-infected mosquito bites therefore systematically triggers immunosuppression of endemic vaccine-elicited responses. The extensive vaccine trial data solidly substantiate this model experimentally. Conclusions/Significance: We conclude skinstage-initiated immunosuppression, unassociated with bloodstage parasites, systematically blocks vaccine function in the field. Our model exposes novel molecular and procedural strategies to significantly and quickly increase protective efficacy in both pipeline and currently ineffective malaria vaccines, and forces fundamental reassessment of central precepts determining vaccine development. This has major implications fo