The complementary roles of deletion and regulation in transplantation tolerance

Neonatal tolerance of alloantigens was described in mice nearly half a century ago, but unfortunately, the translation of these early findings into the clinical arena proved to be much more challenging than was first anticipated. However, the past decade has seen considerable progress in our understanding of the mechanisms that contribute to transplantation tolerance in experimental models. This review outlines our current understanding of the mechanisms of allograft tolerance, emphasizing the complementary roles of deletion and regulation of alloreactive T cells.     

Distribution of the species of the Anopheles gambiae complex and first evidence of Anopheles merus as a malaria vector in Madagascar

BACKGROUND: Members of the Anopheles gambiae complex are amongst the best malaria vectors in the world, but their vectorial capacities vary between species and populations. A large-scale sampling of An. gambiae sensu lato was carried out in various bioclimatic domains of Madagascar. Local abundance of an unexpected member of this complex raised questions regarding its role in malaria transmission. METHODS: Sampling took place at 38 sites and 2,067 females were collected. Species assessment was performed using a PCR targeting a sequence in the IGS of the rDNA. Analysis focused on the relative prevalence of the species per site, bioclimatic domain and altitude. Infectivity of Anopheles merus was assessed using an ELISA to detect the presence of malarial circumsporozoite protein in the head-thorax. RESULTS: Three species were identified: An. gambiae, Anopheles arabiensis and An. merus. The distribution of each species is mainly a function of bioclimatic domains and, to a lesser extent, altitude. An. arabiensis is present in all bioclimatic domains with highest prevalence in sub-humid, dry and sub-arid domains. An. gambiae has its highest prevalence in the humid domain, is in the minority in dry areas, rare in sub-humid and absent in sub-arid domains. An. merus is restricted to the coastal fringe in the south and west; it was in the majority in one southern village. The majority of sites were sympatric for at least two of the species (21/38) and two sites harboured all three species.The role of An. merus as malaria vector was confirmed in the case of two human-biting females, which were ELISA-positive for Plasmodium falciparum. CONCLUSION: Despite the huge environmental (mainly man-made) changes in Madagascar, the distribution of An. gambiae and An. arabiensis appears unchanged for the past 35 years. The distribution of An. merus is wider than was previously known, and its effectiveness as a malaria vector has been shown for the first time; this species is now on the list of Malagasy malaria vectors.     

Statistical decision theory and trade-offs in the control of motor response

We present a novel approach to the modeling of motor responses based on statistical decision theory. We begin with the hypothesis that subjects are ideal motion planners who choose movement trajectories to minimize expected loss. We derive predictions of the hypothesis for movement in environments where contact with specified regions carries rewards or penalties. The model predicts shifts in a subject's aiming point in response to changes in the reward and penalty structure of the environment and with changes in the subject's uncertainty in carrying out planned movements. We tested some of these predictions in an experiment where subjects were rewarded if they succeeded in touching a target region on a computer screen within a specified time limit. Near the target was a penalty region which, if touched, resulted in a penalty. We varied distance between the penalty region and the target and the cost of hitting the penalty region. Subjects shift their mean points of contact with the computer screen in response to changes in penalties and location of the penalty region relative to the target region in qualitative agreement with the predictions of the hypothesis. Thus, movement planning takes into account extrinsic costs and the subject's own motor uncertainty.     

Functional interaction between PARP-1 and PARP-2 in chromosome stability and embryonic development in mouse

The DNA damage-dependent poly(ADP-ribose) polymerases, PARP-1 and PARP-2, homo- and heterodimerize and are both involved in the base excision repair (BER) pathway. Here, we report that mice carrying a targeted disruption of the PARP-2 gene are sensitive to ionizing radiation. Following alkylating agent treatment, parp-2(-/-)-derived mouse embryonic fibroblasts exhibit increased post-replicative genomic instability, G(2)/M accumulation and chromosome mis-segregation accompanying kinetochore defects. Moreover, parp-1(-/-)parp-2(-/-) double mutant mice are not viable and die at the onset of gastrulation, demonstrating that the expression of both PARP-1 and PARP-2 and/or DNA-dependent poly(ADP-ribosyl) ation is essential during early embryogenesis. Interestingly, specific female embryonic lethality is observed in parp-1(+/-)parp-2(-/-) mutants at E9.5. Meta phase analyses of E8.5 embryonic fibroblasts highlight a specific instability of the X chromosome in those females, but not in males. Together, these results support the notion that PARP-1 and PARP-2 possess both overlapping and non-redundant functions in the maintenance of genomic stability.     

Using multiple sequence correlation analysis to characterize functionally important protein regions

Protein co-evolution under structural and functional constraints necessitates the preservation of important interactions. Identifying functionally important regions poses many obstacles in protein engineering efforts. In this paper, we present a bioinformatics-inspired approach (residue correlation analysis, RCA) for predicting functionally important domains from protein family sequence data. RCA is comprised of two major steps: (i) identifying pairs of residue positions that mutate in a coordinated manner, and (ii) using these results to identify protein regions that interact with an uncommonly high number of other residues. We hypothesize that strongly correlated pairs result not only from contacting pairs, but also from residues that participate in conformational changes involved during catalysis or important interactions necessary for retaining functionality. The results show that highly mobile loops that assist in ligand association/dissociation tend to exhibit high correlation. RCA results exhibit good agreement with the findings of experimental and molecular dynamics studies for the three protein families that are analyzed: (i) DHFR (dihydrofolate reductase), (ii) cyclophilin, and (iii) formyl-transferase. Specifically, the specificity (percentage of correct predictions) in all three cases is substantially higher than those obtained by entropic measures or contacting residue pairs. In addition, we use our approach in a predictive fashion to identify important regions of a transmembrane amino acid transporter protein for which there is limited structural and functional information available.     

The effect of manipulating ecdysteroid signaling on embryonic eye development in the locust<Emphasis Type="Italic"> Schistocerca americana</Emphasis>

Adult body plan differentiation in holometabolous insects depends on global induction and control by ecdysteroid hormones during the final phase of postembryogenesis. Studies in Drosophila melanogaster and Manduca sexta have shown that this pertains also to the development of the compound eye retina. It is unclear whether the hormonal control of postembryonic eye development in holometabolous insects represents evolutionary novelty or heritage from hemimetabolous insects, which develop compound eyes during embryogenesis. We therefore investigated the effect of manipulating ecdysteroid signaling in cultured embryonic eye primordia of the American desert locust Schistocerca americana, in which ecdysteroid level changes are known to induce three rounds of embryonic molt. Although at a considerably reduced rate compared to in vivo development, early differentiation and terminal maturation of the embryonic retina was observed in culture even if challenged with the ecdysteroid antagonist cucurbitacin B. Supplementing cultures with 20-hydroxyecdysone (20E) accelerated differentiation and maturation, and enhanced cell proliferation. Considering these results, and the relation between retina differentiation and ecdysteroid level changes during locust embryogenesis, we conclude that ecdysteroids are not an essential but possibly a modulatory component of embryonic retina development in S. americana. We furthermore found evidence that 20E initiated precocious epithelial morphogenesis of the posterior retinal margin indicating a more general role of ecdysteroids in insect embryogenesis.Electronic Supplementary Material Supplementary material is available in the online version of this article at Edited by C. Desplan