Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy

Conventional cancer treatments rely on radiotherapy and chemotherapy. Such treatments supposedly mediate their effects via the direct elimination of tumor cells. Here we show that the success of some protocols for anticancer therapy depends on innate and adaptive antitumor immune responses. We describe in both mice and humans a previously unrecognized pathway for the activation of tumor antigen-specific T-cell immunity that involves secretion of the high-mobility-group box 1 (HMGB1) alarmin protein by dying tumor cells and the action of HMGB1 on Toll-like receptor 4 (TLR4) expressed by dendritic cells (DCs). During chemotherapy or radiotherapy, DCs require signaling through TLR4 and its adaptor MyD88 for efficient processing and cross-presentation of antigen from dying tumor cells. Patients with breast cancer who carry a TLR4 loss-of-function allele relapse more quickly after radiotherapy and chemotherapy than those carrying the normal TLR4 allele. These results delineate a clinically relevant immunoadjuvant pathway triggered by tumor cell death.     

Food for all: designing sustainable and secure future seafood systems

Reviews in Fish Biology and Fisheries - Food from the sea can make a larger contribution to healthy and sustainable diets, and to addressing hunger and malnutrition, through improvements in...     

Preliminary insights into the population characteristics and distribution of reef (Mobula alfredi) and oceanic (M. birostris) manta rays in French Polynesia

Coral Reefs - In French Polynesia, both currently recognized manta ray species, Mobula alfredi and M. birostris, are observed. Despite being an important cultural asset and generating significant...     

Radical trapping properties of imidazolyl nitrones

The ability of ten imidazolyl nitrones to directly scavenge free radicals (R(*)) generated in polar ((*)OH, O(*)(2)(-), SO(*)(3)(-) cysteinyl, (*)CH(3)) or in apolar (CH(3)-(*)CH-CH(3)) media has been studied. When oxygen or sulfur-centered radicals are generated in polar media, EPR spectra are not or weakly observed with simple spectral features. Strong line intensities and more complicated spectra are observed with the isopropyl radical generated in an apolar medium. Intermediate results are obtained with (*)CH(3) generated in a polar medium. EPR demonstrates the ability of these nitrones to trap radicals to the nitrone C(alpha) atom (alpha radical adduct) and to the imidazol C(5) atom (5-radical adduct). Beside the nucleophilic addition of the radical to the C(alpha) atom, the EPR studies suggest a two-step mechanism for the overall reaction of R(*) attacking the imidazol core. The two steps seem to occur very fast with the (*)OH radical obtained in a polar medium and slower with the isopropyl radical prepared in benzene. In conclusion, imidazolyl nitrones present a high capacity to trap and stabilize carbon-centered radicals.     

Kinetic characterization of vero cell metabolism in a serum‐free batch culture process

A global kinetic study of the central metabolism of Vero cells cultivated in a serum‐free medium is proposed in the present work. Central metabolism including glycolysis, glutaminolysis, and tricarboxylic acid cycle (TCA) was demonstrated to be saturated by high flow rates of consumption of the two major substrates, glucose, and glutamine. Saturation was reavealed by an accumulation of metabolic intermediates and amino acids, by a high production of lactate needed to balance the redox pathway, and by a low participation of the carbon flow to the TCA cycle supply. Different culture conditions were set up to reduce the central metabolism saturation and to better balance the metabolic flow rates between lactate production and energetic pathways. From these culture conditions, substitutions of glutamine by other carbon sources, which have lower transport rates such as asparagine, or pyruvate in order to shunt the glycolysis pathway, were successful to better balance the central metabolism. As a result, an increase of the cell growth with a concomitant decrease of cell death and a better distribution of the carbon flow between TCA cycle and lactate production occurred. We also demonstrated that glutamine was a major carbon source to supply the TCA cycle in Vero cells and that a reduction of lactate production did not necessary improve the efficiency of the Vero cell metabolism. Thus, to adapt the formulation of the medium to the Vero cell needs, it is important to provide carbon substrates inducing a regulated supply of carbon in the TCA cycle either through the glycolysis or through other pathways such as glutaminolysis. Finally, this study allowed to better understand the Vero cell behavior in serum‐free medium which is a valuable help for the implementation of this cell line in serum‐free industrial production processes. Biotechnol. Bioeng. 2010;107: 143–153. © 2010 Wiley Periodicals, Inc.     

Different Tempo and Anatomic Location of Dual-Tropic and X4 Virus Emergence in a Model of R5 Simian-Human Immunodeficiency Virus Infection

We previously reported coreceptor switch in rhesus macaques inoculated intravenously with R5 simian-human immunodeficiency virus SF162P3N (SHIV_SF162P3N). Whether R5-to-X4 virus evolution occurs in mucosally infected animals and in which anatomic site the switch occurs, however, were not addressed. We herein report a change in coreceptor preference in macaques infected intrarectally with SHIV_SF162P3N. The switch occurred in infected animals with high levels of virus replication and undetectable antiviral antibody response and required sequence changes in the V3 loop of the gp120 envelope protein. X4 virus emergence was associated with an accelerated drop in peripheral CD4⁺ T-cell count but followed rather than preceded the onset of CD4⁺ T-cell loss. The conditions, genotypic requirements, and patterns of coreceptor switch in intrarectally infected animals were thus remarkably consistent with those found in macaques infected intravenously. They also overlapped with those reported for humans, suggestive of a common mechanism for coreceptor switch in the two hosts. Furthermore, two independent R5-to-X4 evolutionary pathways were identified in one infected animal, giving rise to dual-tropic and X4 viruses which differed in switch kinetics and tissue localization. The dual-tropic switch event predominated early, and the virus established infection in multiple tissues sites. In contrast, the switch to X4 virus occurred later, initiating and expanding mainly in peripheral lymph nodes. These findings help define R5 SHIV_SF162P3N infection of rhesus macaques as a model to study the mechanistic basis, dynamics, and sites of HIV-1 coreceptor switch.The human immunodeficiency virus (HIV) enters target cells via binding of the viral envelope glycoprotein to the CD4 receptor, triggering envelope conformational changes that allow for interaction with either the CCR5 or CXCR4 chemokine receptor (1, 3, 8, 15, 16, 18). Most HIV type 1 (HIV-1) transmissions are initiated with CCR5-using (R5) viruses (58, 68). With time, CXCR4-tropic (X4) viruses emerge and coexist with R5 viruses in close to 50% of subtype B-infected individuals, and this is accompanied by a rise in viremia, rapid CD4⁺ T-cell loss, and progression to disease (4, 7, 11, 34, 57, 65). The mechanistic basis and reasons for HIV-1 coreceptor switch, however, are still not well understood. Several factors including high viral load, low CD4⁺ T-cell numbers, reduced availability of CCR5⁺ cells, and progressive immune dysfunction have been proposed as playing important roles (48, 54). Since X4 virus emergence is associated with a faster rate of disease progression, insights into the determinants of HIV-1 coreceptor switch are of interest in understanding viral pathogenesis. Furthermore, with the introduction of CCR5 entry inhibitors as anti-HIV therapeutics (19, 23, 24, 38), there is a need not only to identify the presence of X4 variants in patients when treatment options are considered but also to understand the factors that influence X4 virus evolution. Although the majority of individuals failing on short-term CCR5 antagonist monotherapy harbor preexisting minor X4 variants (71), it is conceivable that given the right conditions and selective forces, inhibiting HIV-1 entry via CCR5 may drive the virus to evolve to CXCR4 usage and exacerbate disease. An animal model that faithfully recapitulates the process of coreceptor switch will be highly useful to study and identify the determinants and conditions that facilitate the change in coreceptor preference. In addition, an animal model provides the opportunity to track the kinetics of coreceptor switching at different anatomical sites, which may inform on the mechanisms of X4 virus emergence.In this regard, we recently reported coreceptor switch in two of nine rhesus macaques (RM) inoculated intravenously with simian-human immunodeficiency virus SF162P3N (SHIV_SF162P3N) that bears an HIV-1 CCR5-tropic Env (28, 29). In order to establish a reproducible model for coreceptor switch, however, it was crucial to document additional switching events. Furthermore, since the majority of HIV transmission occurs via mucosal surfaces, it was important to demonstrate coreceptor switch in macaques infected with R5 SHIV_SF162P3N by the mucosal route to validate this animal model in studying the in vivo evolution of HIV-1 coreceptor usage. Additionally, the tissue compartment(s) where CXCR4-using viruses evolve and expand is not well characterized. A recent study indicates that the thymus may play an important role in the evolution and/or amplification of coreceptor variants in pediatric HIV infection (56). Since the thymus is the primary source of T lymphopoiesis during early life (45) and since CXCR4 is the predominant coreceptor expressed on thymocytes (33, 64), this organ would seem to provide the ideal milieu for X4 amplification in infants and children. Indeed, we previously showed that whereas X4 SHIV infection of newborn RM resulted in severe thymic involution, R5 SHIV infection induced only a minor disruption in thymic morphology (55), lending support to the idea that the thymus is a preferred site for X4 replication in pediatric HIV infections. Nevertheless, thymopoietic function declines with age (17, 42, 60), and naïve T cells that express high levels of CXCR4 are also enriched in peripheral lymph nodes (5, 27, 36, 66). Thus, the role of the thymus and other lymphoid tissues in HIV-1 coreceptor switch in older individuals remains to be determined. To address these issues, we inoculated adult RM intrarectally (i.r.) with R5 SHIV_SF162P3N and performed frequent longitudinal blood and tissue samplings. Our goal was to document changes in coreceptor preference in mucosally infected macaques, as well as to obtain a more detailed picture of the kinetics and site of X4 virus evolution and amplification in vivo.     

Plant resource-use strategies: the importance of phenotypic plasticity in response to a productivity gradient for two subalpine species

Background and Aims

Functional traits are indicators of plant interactions with their environment and the resource-use strategies of species can be defined through some key functional traits. The importance of genetic variability and phenotypic plasticity in trait variations in response to a common environmental change was investigated in two subalpine species.

Methods

Two species with contrasted resource-use strategies, Dactylis glomerata and Festuca paniculata, were grown along a productivity gradient in a greenhouse experiment. Functional traits of different genotypes were measured to estimate the relative roles of phenotypic plasticity and genetic variability, and to compare their levels of phenotypic plasticity.

Key Results

Trait variability in the field for the two species is more likely to be the result of phenotypic plasticity rather than of genetic differentiation between populations. The exploitative species D. glomerata expressed an overall higher level of phenotypic plasticity compared with the conservative species F. paniculata. In addition to different amplitudes of phenotypic plasticity, the two species differed in their pattern of response for three functional traits relevant to resource use (specific leaf area, leaf dry matter content and leaf nitrogen content).

Conclusions

Functional trait variability was mainly the result of phenotypic plasticity, with the exploitative species showing greater variability. In addition to average trait values, two species with different resource-use strategies differed in their plastic responses to productivity.     

Insecticide-Driven Patterns of Genetic Variation in the Dengue Vector Aedes aegypti in Martinique Island

Effective vector control is currently challenged worldwide by the evolution of resistance to all classes of chemical insecticides in mosquitoes. In Martinique, populations of the dengue vector Aedes aegypti have been intensively treated with temephos and deltamethrin insecticides over the last fifty years, resulting in heterogeneous levels of resistance across the island. Resistance spreading depends on standing genetic variation, selection intensity and gene flow among populations. To determine gene flow intensity, we first investigated neutral patterns of genetic variability in sixteen populations representative of the many environments found in Martinique and experiencing various levels of insecticide pressure, using 6 microsatellites. Allelic richness was lower in populations resistant to deltamethrin, and consanguinity was higher in populations resistant to temephos, consistent with a negative effect of insecticide pressure on neutral genetic diversity. The global genetic differentiation was low, suggesting high gene flow among populations, but significant structure was found, with a pattern of isolation-by-distance at the global scale. Then, we investigated adaptive patterns of divergence in six out of the 16 populations using 319 single nucleotide polymorphisms (SNPs). Five SNP outliers displaying levels of genetic differentiation out of neutral expectations were detected, including the kdr-V1016I mutation in the voltage-gated sodium channel gene. Association tests revealed a total of seven SNPs associated with deltamethrin resistance. Six other SNPs were associated with temephos resistance, including two non-synonymous substitutions in an alkaline phosphatase and in a sulfotransferase respectively. Altogether, both neutral and adaptive patterns of genetic variation in mosquito populations appear to be largely driven by insecticide pressure in Martinique.