Reduced naïve CD8+ T‐cell priming efficacy in elderly adults

Aging is associated with impaired vaccine efficacy and increased susceptibility to infectious and malignant diseases. CD8⁺ T‐cells are key players in the immune response against pathogens and tumors. In aged mice, the dwindling naïve CD8⁺ T‐cell compartment is thought to compromise the induction of de novo immune responses, but no experimental evidence is yet available in humans. Here, we used an original in vitro assay based on an accelerated dendritic cell coculture system in unfractioned peripheral blood mononuclear cells to examine CD8⁺ T‐cell priming efficacy in human volunteers. Using this approach, we report that old individuals consistently mount quantitatively and qualitatively impaired de novo CD8⁺ T‐cell responses specific for a model antigen. Reduced CD8⁺ T‐cell priming capacity in vitro was further associated with poor primary immune responsiveness in vivo. This immune deficit likely arises as a consequence of intrinsic cellular defects and a reduction in the size of the naïve CD8⁺ T‐cell pool. Collectively, these findings provide new insights into the cellular immune insufficiencies that accompany human aging.     

Functional cross-modulation between SOCS proteins can stimulate cytokine signaling

SOCS (suppressors of cytokine signaling) proteins are negative regulators of cytokine signaling that function primarily at the receptor level. Remarkably, in vitro and in vivo observations revealed both inhibitory and stimulatory effects of SOCS2 on growth hormone signaling, suggesting an additional regulatory level. In this study, we examined the possibility of direct cross-modulation between SOCS proteins and found that SOCS2 could interfere with the inhibitory actions of other SOCS proteins in growth hormone, interferon, and leptin signaling. This SOCS2 effect was SOCS box-dependent, required recruitment of the elongin BC complex, and coincided with degradation of target SOCS proteins. Detailed mammalian protein-protein interaction trap (MAPPIT) analysis indicated that SOCS2 can interact with all members of the SOCS family. SOCS2 may thus function as a molecular bridge between a ubiquitin-protein isopeptide ligase complex and SOCS proteins, targeting them for proteasomal turnover. We furthermore extended these observations to SOCS6 and SOCS7. Our findings point to a unique regulatory role for SOCS2, SOCS6, and SOCS7 within the SOCS family and provide an explanation for the unexpected phenotypes observed in SOCS2 and SOCS6 transgenic mice.     

Simple di- and trivanillates exhibit cytostatic properties toward cancer cells resistant to pro-apoptotic stimuli

A series of 33 novel divanillates and trivanillates were synthesized and found to possess promising cytostatic rather than cytotoxic properties. Several compounds under study decreased by >50% the activity of Aurora A, B, and C, and WEE1 kinase activity at concentrations <10% of their IC₅₀ growth inhibitory ones, accounting, at least partly, for their cytostatic effects in cancer cells and to a lesser extent in normal cells. Compounds 6b and 13c represent interesting starting points for the development of cytostatic agents to combat cancers, which are naturally resistant to pro-apoptotic stimuli, including metastatic malignancies.     

PROTICdb: a web-based application to store, track, query, and compare plant proteome data

PROTICdb is a web-based application, mainly designed to store and analyze plant proteome data obtained by two-dimensional polyacrylamide gel electrophoresis (2-D PAGE) and mass spectrometry (MS). The purposes of PROTICdb are (i) to store, track, and query information related to proteomic experiments, i.e., from tissue sampling to protein identification and quantitative measurements, and (ii) to integrate information from the user's own expertise and other sources into a knowledge base, used to support data interpretation (e.g., for the determination of allelic variants or products of post-translational modifications). Data insertion into the relational database of PROTICdb is achieved either by uploading outputs of image analysis and MS identification software, or by filling web forms. 2-D PAGE annotated maps can be displayed, queried, and compared through a graphical interface. Links to external databases are also available. Quantitative data can be easily exported in a tabulated format for statistical analyses. PROTICdb is based on the Oracle or the PostgreSQL Database Management System and is freely available upon request at the following URL: http://moulon.inra.fr/ bioinfo/PROTICdb.     

Crystal structures of novel non-peptidic, non-zinc chelating inhibitors bound to MMP-12

Human macrophage elastase (MMP-12) plays an important role in inflammatory processes and has been implicated in diseases such as emphysema and chronic obstructive pulmonary disease (COPD). It is therefore an attractive target for therapeutic agents.As part of a structure-based drug design programme to find new inhibitors of MMP-12, the crystal structures of the MMP-12 catalytic domain (residues 106-268) complexed to three different non-peptidic small molecule inhibitors have been determined. The structures reveal that all three ligands bind in the S1′ pocket but show varying degrees of interaction with the Zn atom. The structures of the complexes with inhibitors CP-271485 and PF-00356231 reveal that their central morpholinone and thiophene rings, respectively, sit over the Zn atom at a distance of approximately 5 Å, locating the inhibitors halfway down the S1′ pocket. In both of these structures, an acetohydroxamate anion, an artefact of the crystallisation solution, chelates the zinc atom. By contrast, the acetohydroxamate anion is displaced by the ligand in the structure of MMP-12 complexed to PD-0359601 (Bayer), a potent zinc chelating N-substituted biaryl butyric acid, used as a reference compound for crystallisation. Although a racemate was used for the crystallisation, the S enantiomer only is bound in the crystal. Important hydrophobic interactions between the inhibitors and residues from the S1′ pocket are observed in all of the structures. The relative selectivity displayed by these ligands for MMP-12 over other MMP family members is discussed.     

Seasonal variation in energy expenditure and body composition in captive White Storks (Ciconia ciconia)

North Western European populations of White Storks (Ciconia ciconia) appear to have been saved from extinction by settling, i.e. stopping migration. Settled storks exposed to winter conditions must cope with periods of potentially high energy demands that would otherwise be avoided by the migration process. Doubly labeled water (DLW) was therefore used to examine the seasonal variation (summer vs winter) in daily energy expenditure (DEE) and the body composition of adult and immature storks of both sexes. Male White Storks showed a higher DEE over the winter period than in summer compared with females; in particular, immature males exhibited greater energy expenditure in winter than adult males. Thus, the DEE did not significantly differ between summer and winter (except for immature males), reflecting an absence of thermoregulation cost in winter. For both age classes, total body mass increased in winter, which was mainly due to an increase in fat mass. Adult storks were 5% heavier than immature storks. The sexes differed in body mass, with males weighing significantly more than females by 11%. Mean LBM (lean body mass) was 8.5% higher in adults than in immatures, and was 11.5% higher in males compared with females. Between their first and second summers, immatures accumulated a lean body mass to finally reach the same values as adults, indicating a phase of muscle development. The mean fat mass of the storks did not differ between age classes or between sexes. Based on physiological parameters, this study shows that settled White Storks are able to cope with mild winter periods when they are artificially provided with food. In a view to preserve favourable habitats for this species, it is therefore necessary to decide on a plan of action for breeding areas.     

Comparative histological and immunohistochemical study of sea star tube feet (Echinodermata, Asteroidea)

Adhesion in sea stars is the function of specialized structures, the tube feet or podia, which are the external appendages of the water-vascular system. Adhesive secretions allow asteroid tube feet to perform multiple functions. Indeed, according to the sea star species considered, the tube feet may be involved in locomotion, fixation, or burrowing. Different tube foot shapes usually correspond to this variety of function. In this study, we investigated the variability of the morphology of sea star tube feet as well as the variability of the composition of their adhesive secretions. This second aspect was addressed by a comparative immunohistochemical study using antibodies raised against the adhesive material of the forcipulatid Asterias rubens. The tube feet from 14 sea star species representing five orders and 10 families of the Class Asteroidea were examined. The histological study revealed three main tube foot morphotypes, i.e., knob-ending, simple disc-ending, and reinforced disc-ending. Analysis of the results suggests that tube foot morphology is influenced by species habitat, but within limits imposed by the evolutionary lineage. In immunohistochemistry, on the other hand, the results were very homogeneous. In every species investigated there was a very strong immunolabeling of the adhesive cells, independently of the taxon considered, of the tube foot morphotype or function, or of the species habitat. This indicates that the adhesives in all the species considered are closely related, probably sharing many identical molecules or, at least, many identical epitopes on their constituents.     

Adaptation to resistant hosts increases fitness on susceptible hosts in the plant parasitic nematode Globodera pallida

Trade‐offs between virulence (defined as the ability to infect a resistant host) and life‐history traits are of particular interest in plant pathogens for durable management of plant resistances. Adaptation to plant resistances (i.e., virulence acquisition) is indeed expected to be associated with a fitness cost on susceptible hosts. Here, we investigated whether life‐history traits involved in the fitness of the potato cyst nematode Globodera pallida are affected in a virulent lineage compared to an avirulent one. Both lineages were obtained from the same natural population through experimental evolution on resistant and susceptible hosts, respectively. Unexpectedly, we found that virulent lineages were more fit than avirulent lineages on susceptible hosts: they produced bigger cysts, containing more larvae and hatching faster. We thus discuss possible reasons explaining why virulence did not spread into natural G. pallida populations.     

Adaptation of Maize to Temperate Climates: Mid-Density Genome-Wide Association Genetics and Diversity Patterns Reveal Key Genomic Regions,with a Major Contribution of the Vgt2 (ZCN8) Locus

The migration of maize from tropical to temperate climates was accompanied by a dramatic evolution in flowering time. To gain insight into the genetic architecture of this adaptive trait, we conducted a 50K SNP-based genome-wide association and diversity investigation on a panel of tropical and temperate American and European representatives. Eighteen genomic regions were associated with flowering time. The number of early alleles cumulated along these regions was highly correlated with flowering time. Polymorphism in the vicinity of the ZCN8 gene, which is the closest maize homologue to Arabidopsis major flowering time (FT) gene, had the strongest effect. This polymorphism is in the vicinity of the causal factor of Vgt2 QTL. Diversity was lower, whereas differentiation and LD were higher for associated loci compared to the rest of the genome, which is consistent with selection acting on flowering time during maize migration. Selection tests also revealed supplementary loci that were highly differentiated among groups and not associated with flowering time in our panel, whereas they were in other linkage-based studies. This suggests that allele fixation led to a lack of statistical power when structure and relatedness were taken into account in a linear mixed model. Complementary designs and analysis methods are necessary to unravel the architecture of complex traits. Based on linkage disequilibrium (LD) estimates corrected for population structure, we concluded that the number of SNPs genotyped should be at least doubled to capture all QTLs contributing to the genetic architecture of polygenic traits in this panel. These results show that maize flowering time is controlled by numerous QTLs of small additive effect and that strong polygenic selection occurred under cool climatic conditions. They should contribute to more efficient genomic predictions of flowering time and facilitate the dissemination of diverse maize genetic resources under a wide range of environments.