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International audience; Objective: It was previously shown that HLA–B27 subtypes predisposing to spondyloarthritis (SpA), i.e., B*27:02, B*27:05, and B*27:07, displayed an increased propensity to form intracellular oligomers and to accumulate at a high density in cytoplasmic vesicles, as compared to the non–SpA-associated HLA–B*07:02 and HLA–B*27:06. This study was undertaken to characterize the nature and content of HLA–B–containing vesicles and to further examine their relevance to SpA predisposition. Methods: Vesicles containing HLA–B proteins were detected in transfected HeLa cells and in cells from SpA patients or HLA–B27/human β2-microglobulin (hβ2m)–transgenic rats, by microscopy. The nature and content of HLA–B–containing vesicles were characterized in colocalization experiments with appropriate markers. Results: The SpA-associated HLA–B*27:04 subtype accumulated at higher levels (P < 10−5) in cytoplasmic vesicles compared to HLA–B*27:06, from which it differs only by 2 substitutions, reinforcing the correlation between vesicle formation and SpA predisposition. Colocalization studies showed that those vesicles contained misfolded HLA–B heavy chain along with β2m and endoplasmic reticulum (ER) chaperones (calnexin, calreticulin, BiP, glucose-regulated protein 94-kd) and belonged to the ER but were distinct from the peptide-loading complex (PLC). Similar vesicles were observed in immune cells from HLA–B27+ SpA patients, in greater abundance than in healthy controls (P < 0.01), and in dendritic cells from HLA–B27/hβ2m transgenic rats, correlating with SpA susceptibility. Conclusion: Accumulation of misfolded HLA–B heavy chain along with β2m and ER chaperones into ER-derived vesicles distinct from the PLC is a characteristic feature of HLA–B27 subtypes predisposing to SpA. This phenomenon could contribute to HLA–B27 pathogenicity, via a noncanonical mechanism.

Wildlife sanctuaries rescue, rehabilitate, reintroduce and provide life-long care for orphaned and injured animals. Understanding a sanctuary’s population dynamics—patterns in arrival, mortality and projected changes in population size—allows careful planning for future needs. Building on previous work on the population dynamics of chimpanzees (Pan troglodytes) in sanctuaries of the Pan African Sanctuary Alliance (PASA; Faust et al. 2011), this chapter extends analyses to the only PASA bonobo sanctuary. Its authors analysed historic demographic patterns and projected future population dynamics using an individual-based demographic model. The population has been growing at 6.7 per cent per year, driven by arrivals of new individuals (mean = 5.5 arrivals per year). Several model scenarios projecting varying arrival rates, releases and breeding scenarios clarify potential future growth trajectories for the sanctuary. This research illustrates how data on historic dynamics can be modelled to inform future sanctuary capacity and management needs. Les sanctuaires de faune secourent, réhabilitent, réintroduisent, et fournissent des soins pour toute la vie aux animaux orphelins et blessés. Comprendre les dynamiques de la population d’un sanctuaire—les motifs d’arrivée, mortalité, et de changements projetés de la taille de la population—permet une planification prudente pour les nécessités du futur. En se basant sur le travail déjà fait sur les dynamiques de la population chimpanzé (Pan troglodytes) dans les sanctuaires du Pan African Sanctuary Alliance (PASA; Faust et al. 2011), nous étendons notre analyse au seul sanctuaire bonobo par PASA. Nous avons analysé les motifs démographiques historiques et avons projeté les futures dynamiques de la population en utilisant un modèle démographique basé sur l’individu. La population augmente de 6.7 per cent par an, poussée par l’arrivée de nouveaux individus (moyenne = 5.5 arrivées par an). Plusieurs scénarios modèles montrent une trajectoire de potentielle croissance pour le sanctuaire. Cette recherche illustre comment modeler les données sur les dynamiques historiques pour informer la capacité future du sanctuaire et les besoins gestionnaires.

Background After more than 40 years of research, the mechanisms underlying the association of HLA-B27 with spondyloarthritis (SpA) remain poorly understood. We hypothesised that Drosophila might be a relevant model to study HLA-B27 and particularly for deciphering the cellular cascade and the genetic pathways affected by HLA-B27 mutation. To do so, we developed HLA-B2705, HLA-B0702 (control) and human Beta-2-microglobulin (hB2m) transgenic Drosophila. Methods Gateway Technology and UAS-Gal4 system used for developing transgenic HLA-B/human hB2m Drosophila. UAS-hB2m transgene was inserted in the long arm of chromosome 3 and UAS-HLA-B2705 and UAS-HLA-B0702 were alternatively inserted at another position in the short arm of the same chromosome. For each construct, various transgenic lines were obtained and crossed with several tissue specific driver strains, to induce the expression of the sequence coding for HLA-B0702 and hB2m or HLA-B2705 and hB2m placed under the control of UAS sequences. Results HLA-B2705/hB2m transgenes were first expressed in Drosophila thanks to the vestigialGa4 driver line allowing to produce targeted proteins in the Vestigial domain (dorso-ventral frontier of the wing epithelia). We observed positive staining with HC10 antibodies (class I heavy chain) and W6/32 antibody (HLA-A, HLA-B and HLA-C conformation) for both tested HLA-B/hB2m but only HLA-B27/hB2m was labelled with ME1 (anti-HLA B/C) antibodies, suggesting a different conformation of HLA-B27 and HLA-B7 with hB2m in the wing epithelia. Furthermore, by mean of the nubbin or engrailed drivers which drive the expression in a larger part of the wing, we observed specific loss of the posterior cross-vein following HLA-B27/hB2m expression but not HLA-B7/hB2m. Conclusion Drosophila lines were established allowing tissue specific expression of different HLA-B alleles. Our data suggest that the expression of HLA-B/hB2m transgenes in epithelial cells leads to a plasma membrane localization for HLA-B2705/hB2m but not for HLA-B0702/hB2m. Furthermore, we observed that tissue specific expression of HLA-B27/hB2m but not HLA-B7/hB2m induced specific loss of cross-vein suggesting it interferes with developmental pathways involved in differentiation. This is the first time that differences in localization between HLA-B2705, a subtype associated with SpA, and HLA-B0702, which is not associated with the disease are reported. These results show that transgenic Drosophila might be a pertinent model to decipher molecular mechanisms involved in HLA-B27 trafficking and to better understand potential different behaviours of HLA-B subtypes.

Objective Mechanisms underlying the striking association of spondyloarthritis (SpA) with the class I major histocompatibility complex molecule HLA–B27 remain poorly understood. SpA-like disease develops spontaneously in B*2705-transgenic rats, in conjunction with high HLA–B27 expression levels. This study was undertaken to examine the effects of increased expression of HLA–B27 alleles that are differentially associated with SpA on oligomerization and intracellular redistribution. Methods HeLa cells were transfected with complementary DNA encoding for HLA–B proteins fused to yellow fluorescent protein and/or Renilla luciferase and harvested at an early phase and a later phase of expression. We monitored HLA–B intracellular trafficking and localization by means of microscopy and live-cell imaging. Bioluminescence resonance energy transfer (BRET) and Western blotting were used to monitor HLA–B oligomerization. Results At low expression levels, BRET signals were similarly elevated for all SpA-associated HLA–B27 alleles tested, but were lower for the nonassociated B*2706. Of note, at higher expression levels, HLA–B27 signals remained steady while signal for HLA–B7 decreased sharply, reaching the level observed for B*2706. This was due at least in part to a decreased oligomer proportion without unfolded protein response outbreak. Such differential behavior was not abrogated by proteasome inhibition. With increased expression, all HLA–B proteins accumulated to a high density in cytoplasmic vesicles with labile form and size. The extent of this phenomenon was closely correlated with the level of association with predisposition to SpA. Conclusion To our knowledge, this is the first report of a correlation between the level of predisposition to SpA conferred by HLA–B27 alleles and their biochemical behavior. These findings open new perspectives for understanding the pathogenicity of HLA–B27.

This paper examines, by means of some concepts and methodological tools offered in the great œuvre of Levi-Strauss, the mytho-logical ideologemes of certain forms of orientalism, using the example of Austria. A so-called “frontier orientalism” is contrasted against classic colonial orientalism, in order to identify its particularities. The figure of the “nearby stranger” jeopardizes the boundaries of the own, ever uncertain national identity and serves right-wing populists and neo-nationalists as an indispensable ingredient of their own aspirations.

The rapid molecular evolution of reproductive genes is nearly ubiquitous across animals, yet the selective forces and functional targets underlying this divergence remain poorly understood. Humans and closely related species of great apes show strongly divergent mating systems, providing a powerful system to investigate the influence of sperm competition on the evolution of reproductive genes. This is complemented by detailed information on male reproductive biology and unparalleled genomic resources in humans. Here, we have used custom microarrays to capture and sequence 285 genes encoding proteins present in the ejaculate as well as 101 randomly selected control genes in 21 gorillas, 20 chimpanzees, 20 bonobos, and 20 humans. In total, we have generated >25� average genomic coverage per individual for over 1 million target base pairs. Our analyses indicate high levels of evolutionary constraint across much of the ejaculate combined with more rapid evolution of genes involved in immune defense and proteolysis. We do not find evidence for appreciably more positive selection along the lineage leading to bonobos and chimpanzees, although this would be predicted given more intense sperm competition in these species. Rather, the extent of positive and negative selection depended more on the effective population sizes of the species. Thus, general patterns of male reproductive protein evolution among apes and humans depend strongly on gene function but not on inferred differences in the intensity of sperm competition among extant species.

Background Fatal myocarditis from encephalomyocarditis virus (EMCV) infection has previously been identified in sporadic and epidemic forms in many species of captive non-human primates probably including one bonobo (Pan paniscus). Methods We investigated the deaths of two bonobos that were suspicious of EMCV using a combination of histopathology, immunohistochemistry and, for one of the two bonobos, reverse transcription PCR. Results Histopathological examination of heart tissue from the two bonobos showed changes characteristic of EMCV. Immunohistochemical studies confirmed the presence of EMCV antigen in heart tissue of both and in kidney and intestine of one of the bonobos. EMCV RNA was also isolated from the serum of the bonobo tested. Conclusion Together, these findings confirm that EMCV was responsible for deaths of the two bonobos. Strict separation of bonobos in particular and captive primates in general from potential sources of EMCV contamination should be maintained to prevent mortality caused by EMCV.

Background This case report describes the first placental retention in an 11-year-old female bonobo (Pan paniscus) following the delivery of a healthy infant. Methods After unsuccessful medical treatment with oxytocin, the placenta was manually extracted. Results and conclusions Both the dam and infant survived.

Objective To examine whether and to what extent the intracellular trafficking features of HLA–B*2705, which is associated with the development of spondylarthritis (SpA), differ from those of HLA–B*2709 and HLA–B*0702, which are not associated with SpA. Methods HeLa cells were transfected with complementary DNA encoding for HLA–B proteins fused to Renilla luciferase or yellow fluorescent protein. The subcellular distribution of properly folded and unfolded/misfolded HLA–B proteins was examined by flow cytometry and confocal microscopy of cells labeled with ME1 and HC-10 antibodies, respectively. HLA–B/HLA–B interactions were monitored in endoplasmic reticulum (ER)– and plasma membrane–enriched subcellular fractions, by bioluminescence resonance energy transfer (BRET). Results All 3 HLA–B alleles displayed a similar distribution pattern (properly folded heavy chain at the cell surface, unfolded/misfolded proteins only in the cytoplasm). By means of BRET, we provided evidence that both HLA–B*2705 and HLA–B*2709 formed more oligomers in the ER and the plasma membrane than did HLA–B*0702. The propensity of HLA–B*2705 to form oligomers in the ER was partly attributable to residue Cys67 of the molecule. For all 3 alleles, increased expression of HLA–B proteins was associated with intracytoplasmic accumulation of unfolded/misfolded proteins and intracellular vesicles, probably corresponding to expanded ER–Golgi intermediate compartments, in which these proteins accumulated together with the stress sensor BiP. Conclusion Our results suggest that the difference in disease susceptibility conferred by HLA–B*2705 and HLA–B*2709 cannot be explained by their different propensity to form dimers or misfolded proteins, thus presumably implicating other, still unknown factors.

Spondyloarthritis (SpA) refers to a variety of inflammatory rheumatic disorders with strong heritability. Shared genetic predisposition, as shown by familial aggregation, is largely attributable to the major histocompatibility complex (MHC) locus, which was estimated to account for approximately half of the whole disease heritability. The first predisposing allele identified more than 40 years ago is HLA-B27, which is a major gene predisposing to all forms of SpA. However, despite intensive research, its pathogenesis remains uncertain. Other MHC alleles belonging to the class I and class II regions have been identified to exert additional effect. Candidate-gene approaches and genome-wide studies have recently allowed identification of several new loci residing outside of the MHC region that are involved in the predisposition to SpA. Interestingly, some of those new genes, such as ERAP1, ERAP2, and NPEPPS, code for aminopeptidases that are involved in MHC class I presentation and were shown to interact with HLA-B27.

We report the first probable identification of encephalomyocarditis virus (EMCV) in a bonobo (Pan paniscus) that had been part of a forest re-introduction programme. Clinical presentation was of episodic acute on chronic heart failure and cerebral infarction with end-stage renal failure rather than sudden death which is more commonly associated with EMCV infection. A postmortem diagnosis of probable EMCV was made using gross pathological and histopathological examination. Findings included acute on chronic heart failure combined with the unusual but characteristic histopathological features of non-suppurative necrotizing myocarditis with mononuclear, inflammatory infiltration of the brain.

Elevated Lipoprotein(a) (Lp(a)) plasma concentrations are a risk factor for cardiovascular disease in humans, largely controlled by the LPA gene encoding apolipoprotein(a) (apo(a)). Lp(a) is composed of low-density lipoprotein (LDL) and apo(a) and restricted to Catarrhini. A variable number of kringle IV (KIV) domains in LPA lead to a size polymorphism of apo(a) that is inversely correlated with Lp(a) concentrations. Smaller apo(a) isoforms and higher Lp(a) levels in central chimpanzees (Pan troglodytes troglodytes [PTT]) compared to humans from Europe had been reported. We studied apo(a) isoforms and Lp(a) concentrations in 75 western (Pan troglodytes verus [PTV]) and 112 central chimpanzees, and 12 bonobos (Pan paniscus [PPA]), all wild born and living in sanctuaries in Sierra Leone, Republic of the Congo, and DR Congo, respectively, and 116 humans from Gabon. Lp(a) levels were severalfold higher in western than in central chimpanzees (181.0 ± 6.7 mg/dl vs. 56.5 ± 4.3 mg/dl), whereas bonobos showed intermediate levels (134.8 ± 33.4 mg/dl). Apo(a) isoform sizes differed significantly between subspecies (means 20.9 ± 2.2, 22.9 ± 4.4, and 23.8 ± 3.8 KIV repeats in PTV, PTT, and PPA, respectively). However, far higher isoform-associated Lp(a) concentrations for all isoform sizes in western chimpanzees offered the main explanation for the higher overall Lp(a) levels in this subspecies. Human Lp(a) concentrations (mean 47.9 ± 2.8 mg/dl) were similar to those in central chimpanzees despite larger isoforms (mean 27.1 ± 4.9 KIV). Lp(a) and LDL, apoB-100, and total cholesterol levels only correlated in PTV. This remarkable differentiation between chimpanzees from different African habitats and the trait's similarity in humans and chimpanzees from Central Africa poses the question of a possible impact of an environmental factor that has shaped the genetic architecture of LPA. Overall, studies on the cholesterol-containing particles of Lp(a) and LDL in chimpanzees should consider differentiation between subspecies.

Balancing selection maintains advantageous genetic and phenotypic diversity in populations. When selection acts for long evolutionary periods selected polymorphisms may survive species splits and segregate in present-day populations of different species. Here, we investigate the role of long-term balancing selection in the evolution of protein-coding sequences in the Homo-Pan clade. We sequenced the exome of 20 humans, 20 chimpanzees, and 20 bonobos and detected eight coding trans-species polymorphisms (trSNPs) that are shared among the three species and have segregated for approximately 14 My of independent evolution. Although the majority of these trSNPs were found in three genes of the major histocompatibility locus cluster, we also uncovered one coding trSNP (rs12088790) in the gene LAD1. All these trSNPs show clustering of sequences by allele rather than by species and also exhibit other signatures of long-term balancing selection, such as segregating at intermediate frequency and lying in a locus with high genetic diversity. Here, we focus on the trSNP in LAD1, a gene that encodes for Ladinin-1, a collagenous anchoring filament protein of basement membrane that is responsible for maintaining cohesion at the dermal-epidermal junction; the gene is also an autoantigen responsible for linear IgA disease. This trSNP results in a missense change (Leucine257Proline) and, besides altering the protein sequence, is associated with changes in gene expression of LAD1.

Les activités éducatives au sanctuaire « Lola ya bonobo » de l’association ABC à Kinshasa relèvent quelques réactions encourageantes pour la conservation notamment : (a) La dénonciation d’orphelins bonobos détenus chez des particuliers, (b) La remise volontaire des bonobos par certains détenteurs, ignorants de la loi et du danger à posséder un Grand singe chez soi, (c) L’intérêt à mieux connaître le bonobo par des visites plus fréquentes du sanctuaire. La sensibilisation à Kinshasa pour la protection des Grands singes est d’autant plus nécessaire qu’il constitue un centre non négligeable de consommation de viande de chasse. Par conséquent, la demande accrue encouragerait les massacres de la faune sauvage en amont, pour le besoin citadin. Ainsi, il semble plus logique de pouvoir éduquer les consommateurs en aval. Avec l’utilisation à Kinshasa de la malle pédagogique « les Grands singes et leur habitat » créée par l’Association Projet pour la Conservation des Grands Singes et mise à disposition par le RAPAC (Réseau des Aires Protégées d’Afrique Centrale), le programme d’Education au sanctuaire « Lola ya bonobo » s’est fixé les quatre objectifs suivants : (1) Relever les similarités des Grands singes entre eux et avec l’homme, (2) Ressortir l’importance de la forêt pour les Grands singes et la nécessité à la conserver, (3) Susciter l’intérêt des participants à protéger les Grands singes, (4) Contribuer au changement de comportement des populations pour la protection des Grands singes. Ce présent rapport présente les résultats de la sensibilisation des enfants d’environ 11 à 12 ans avec le module « Forêt, habitat des Grands singes ». La méthodologie a été axée sur quatre étapes suivantes : 1) une pré-évaluation sur base d’un questionnaire préétabli ; 2) des explications participatives de l’éducateur sur la forêt avec toutes ses composantes et leurs interrelations ; 3) la constitution de la forêt sur une bâche par les élèves participants et 4) une post-évaluation avec le même questionnaire. L’évaluation a été faite sur 160 enfants répartis équitablement en deux groupes dont le premier était constitué des membres des Clubs de la bonté pour la nature initiés par l’ABC et le deuxième par des enfants non membres et n’ayant participé à l’avance à aucune activité éducative de l’ABC. Il ressort de cette enquête que le matériel pédagogique utilisé a permis aux participants de mieux assimiler les messages de conservation enseignés. En effet, pour le premier groupe (membres des clubs de bonté pour la nature), 63,3% de bonnes réponses ont été enregistrées à la pré-évaluation contre 90,0% à la post-évaluation ; pour le deuxième groupe (n’ayant pas participé aux activités éducatives de l’ABC), 30,6% de bonnes réponses ont été enregistrées à la pré-évaluation contre 82,5% à la post-évaluation. Les résultats de la pré-évaluation révèlent clairement que les participants du premier groupe (les membres des clubs de la bonté pour la nature) avaient déjà beaucoup plus de connaissances sur la forêt par rapport à ceux du deuxième groupe. L’amélioration des résultats à la post-évaluation dans les deux groupes est une preuve de l’apport positif du matériel pédagogique utilisé.

Un jeune mâle bonobo nommé Kipolo, âgé de 10 ans, est arrivé au sanctuaire en Juin 2010 en bonne santé. Quelques mois après son arrivée, sa « maman de substitution » (personne employée par le sanctuaire, prenant soin d’un jeune orphelin) avait remarqué qu’il commençait à perdre la vue, parce qu’il avait du mal à prendre de la nourriture qu’on lui tendait et qu’un voile bleu apparaissait sur ses yeux. Le Dr Kaimbo, ophtalmologue aux Cliniques universitaires de Kinshasa, avait diagnostiqué une cataracte bilatérale. Ainsi, la seule solution pour l’épanouissement du jeune Kipolo était la chirurgie. Tous les examens préopératoires sur l’étiologie de cette cataracte se sont révélés négatifs. Avec le concours du Dr Patrick Brabant (ophtalmologue belge, volontaire à Ophtalmology worldwide), Kipolo a été opéré en octobre 2012, par la technique de phaco-émulsification. L’anesthésie et la réanimation étaient gérées par l’équipe de santé du sanctuaire « Lola ya bonobo » (2 vétérinaires et 1 infirmière). L’opération s’est bien déroulée même si elle a duré plus longtemps que les opérations chez les humains. Les deux yeux ont été opérés avec intervalle de trois jours. Pendant les deux mois post-opératoires, Kipolo a toléré le traitement par collyre. Il a désormais retrouvé la vue et se porte bien.

Stimulation of the cAMP-signaling pathway modulates apoptosis in several cell types and inhibits Jo2-mediated apoptosis in cultured rat hepatocytes. No information is yet available as to whether the hepatic β2-adrenergic receptor (AR) expression level, including β2-AR-dependent adenylyl cyclase activation, modulates hepatocyte sensitivity to apoptosis in vivo or whether this sensitivity can be modified by β2-AR ligands. We have examined this using C57BL/6 mice, in which hepatic β2-AR densities are low, and transgenic F28 mice, which overexpress β2-ARs and have elevated basal liver adenylyl cyclase activity. The F28 mice were resistant to Jo2-induced liver apoptosis and death. The β-AR antagonist propranolol sensitized the F28 livers to Jo2. In normal mice clenbuterol, a β2-AR-specific agonist, considerably reduced Jo2-induced liver apoptosis and death; salbutamol, another β2-AR-selective agonist, also reduced Jo2-induced apoptosis and retarded death but with less efficacy than clenbuterol; and propranolol blocked the protective effect of clenbuterol. This indicates that the expression level of functional β2-ARs modulates Fas-regulated liver apoptosis and that this apoptosis can be inhibited in vivo by giving β2-AR agonists. This may well form the basis for a new therapeutic approach to diseases involving abnormal apoptosis.

Mechanisms underlying the striking association of spondyloarthritis (SpA) with the class I major histocompatibility complex molecule HLA-B27 remain poorly understood. SpA-like disease develops spontaneously in B*2705-transgenic rats, in conjunction with high HLA-B27 expression levels. This study was undertaken to examine the effects of increased expression of HLA-B27 alleles that are differentially associated with SpA on oligomerization and intracellular redistribution.HeLa cells were transfected with complementary DNA encoding for HLA-B proteins fused to yellow fluorescent protein and/or Renilla luciferase and harvested at an early phase and a later phase of expression. We monitored HLA-B intracellular trafficking and localization by means of microscopy and live-cell imaging. Bioluminescence resonance energy transfer (BRET) and Western blotting were used to monitor HLA-B oligomerization.At low expression levels, BRET signals were similarly elevated for all SpA-associated HLA-B27 alleles tested, but were lower for the nonassociated B*2706. Of note, at higher expression levels, HLA-B27 signals remained steady while signal for HLA-B7 decreased sharply, reaching the level observed for B*2706. This was due at least in part to a decreased oligomer proportion without unfolded protein response outbreak. Such differential behavior was not abrogated by proteasome inhibition. With increased expression, all HLA-B proteins accumulated to a high density in cytoplasmic vesicles with labile form and size. The extent of this phenomenon was closely correlated with the level of association with predisposition to SpA.To our knowledge, this is the first report of a correlation between the level of predisposition to SpA conferred by HLA-B27 alleles and their biochemical behavior. These findings open new perspectives for understanding the pathogenicity of HLA-B27.

Up to now, transgenic mice models created to study the physiological impact of alterations in the human beta-adrenoceptor system have only focused on cardiac tissues and carried hybrid transgenes with strong cardiac promoters. We have developed a transgenic mouse strain (F28) carrying the human beta 2-adrenoceptor gene with its natural promoter region with the aim of producing a model that more closely reproduces the natural human beta 2-adrenoceptor tissue expression pattern. By means of northern blot analyses, using the appropriate probes, we have obtained evidence that (a) the human beta 2-adrenoceptor's structural gene is transcribed in several tissues of F28 mice; (b) the tissue distribution pattern of human beta 2-adrenoceptor mRNA in F28 mice completely differs from that of mouse beta 2-adrenoceptor mRNA; and (c) the tissue distribution pattern of mouse beta 2-adrenoceptor mRNA in F28 mice is very similar to that observed in their non-transgenic littermates. Like humans, F28 mice express human beta 2-adrenoceptor mRNA in liver, lung, brain, heart, and muscle. However, unlike humans, F28 mice do not accumulate human beta 2-adrenoceptor mRNA in kidney and spleen. By using [125I]iodocyanopindolol to label all beta-adrenoceptors and ICI 118,551 to discriminate between the binding to beta 2- and beta 1-adrenoceptors we have demonstrated that the beta 2-adrenoceptor binding activity increases over control values in F28 mouse tissues that accumulate transgenic mRNA. Accordingly, the number of beta 2-adrenoceptors increased slightly over the control values in muscle, heart, brain, and lung of F28 mice, while in liver these receptors were strongly overexpressed. We further showed that transgene beta 2-adrenoceptors couple to GTP-binding proteins, mediate beta-adrenoceptor agonist-stimulated adenylyl cyclase activation, and cause a strong enhancement of this response in liver membranes of F28 versus control mice. Finally, F28 mice show a phenotype of depressed ponderal development and perturbed hindquarter movements. This unique model should be useful to further investigate beta 2-adrenoceptor causal relationships with human pathologies.

Prüfer, K. et al.-- This article is distributed under the terms of the Creative Commons Attribution-Non-Commercial-Share Alike licence, Two African apes are the closest living relatives of humans: the chimpanzee (Pan troglodytes) and the bonobo (Pan paniscus). Although they are similar in many respects, bonobos and chimpanzees differ strikingly in key social and sexual behaviours, and for some of these traits they show more similarity with humans than with each other. Here we report the sequencing and assembly of the bonobo genome to study its evolutionary relationship with the chimpanzee and human genomes. We find that more than three per cent of the human genome is more closely related to either the bonobo or the chimpanzee genome than these are to each other. These regions allow various aspects of the ancestry of the two ape species to be reconstructed. In addition, many of the regions that overlap genes may eventually help us understand the genetic basis of phenotypes that humans share with one of the two apes to the exclusion of the other. © 2012 Macmillan Publishers Limited. All rights reserved.

The origin of Plasmodium falciparum, the etiological agent of the most dangerous forms of human malaria, remains controversial. Although investigations of homologous parasites in African Apes are crucial to resolve this issue, studies have been restricted to a chimpanzee parasite related to P. falciparum, P. reichenowi, for which a single isolate was available until very recently. Using PCR amplification, we detected Plasmodium parasites in blood samples from 18 of 91 individuals of the genus Pan, including six chimpanzees (three Pan troglodytes troglodytes, three Pan t. schweinfurthii) and twelve bonobos (Pan paniscus). We obtained sequences of the parasites' mitochondrial genomes and/or from two nuclear genes from 14 samples. In addition to P. reichenowi, three other hitherto unknown lineages were found in the chimpanzees. One is related to P. vivax and two to P. falciparum that are likely to belong to distinct species. In the bonobos we found P. falciparum parasites whose mitochondrial genomes indicated that they were distinct from those present in humans, and another parasite lineage related to P. malariae. Phylogenetic analyses based on this diverse set of Plasmodium parasites in African Apes shed new light on the evolutionary history of P. falciparum. The data suggested that P. falciparum did not originate from P. reichenowi of chimpanzees (Pan troglodytes), but rather evolved in bonobos (Pan paniscus), from which it subsequently colonized humans by a host-switch. Finally, our data and that of others indicated that chimpanzees and bonobos maintain malaria parasites, to which humans are susceptible, a factor of some relevance to the renewed efforts to eradicate malaria., Author Summary Chimpanzees and gorillas are known to have malaria parasites (genus Plasmodium) similar to those that infect humans. It is likely that detailed molecular studies of these parasites will help understand important aspects of the malaria disease and of immune defences in humans, and could then guide the development of novel control measures. However, few studies of parasites in African Apes have been conducted to date. Here we present the results of a survey of malaria parasites in chimpanzees and bonobos, our closest relatives. In chimpanzees, we identified two new parasite species closely related to P. falciparum, the most dangerous of the parasites in humans. We also found that bonobos harbour malaria parasites including P. falciparum. Phylogenetic analyses of these parasites strongly suggested that P. falciparum evolved in bonobos, and that it was introduced into humans from bonobos at a later date. Overall, our findings have substantially altered our perception of the origin of malaria parasites in humans.

Objective Spondylarthritis (SpA) is characterized by spinal and peripheral joint inflammation, frequently combined with extraarticular manifestations. Despite the well-established association of SpA with the class I major histocompatibility complex (MHC) allele HLA–B27, there are still different, parallel hypotheses on the relationship between HLA–B27 and disease mechanisms. The present study was undertaken to investigate several characteristics of mature dendritic cells (DCs), which are believed to be essential for triggering disease in a model of SpA in HLA–B27–transgenic rats. Methods We combined different whole-proteome approaches (2-dimensional polyacrylamide gel electrophoresis and iTRAQ) to define the most aberrant molecular processes occurring in spleen DCs. Videomicroscopy and flow cytometry were used to confirm both cytoskeletal and class II MHC expression deficiencies. Results Our proteome studies provided evidence of up-regulation of proteins involved in class I MHC loading, and unfolded protein response, along with a striking down-regulation of several cytoskeleton-reorganizing proteins. The latter result was corroborated by findings of deficient motility, altered morphology, and decreased immunologic synapse formation. Furthermore, class II MHC surface expression was reduced in DCs from B27-transgenic rats, and this could be linked to differences in class II MHC–induced apoptotic sensitivity. Finally, we found reduced viability of the CD103+CD4− DC subpopulation, which likely exerts tolerogenic function. Conclusion Taken together, our findings have different important implications regarding the physiology of B27-transgenic rat DCs, which have a putative role in spontaneous disease in these rats. In particular, the reduced motility and viability of putatively tolerogenic CD4+ DCs could play an important role in initiating the inflammatory process, resulting in SpA.

Have you been to a football game lately? Think of the last time you were in an arena that seated fifty or even a hundred thousand people. That many people can make a lot of noise, but of course only represent a tiny piece of humanity today. If we could convince all the bonobos in the world to attend such a game, you could not come close to filling even the smallest professional football stadium. Our closest living relative is slipping off the precipice; their extinction in our own lifetime is a real possibility. The best estimates of the current bonobo population in the wild are somewhere between 5,000–50,000 individuals; all live in the Democratic Republic of Congo (DRC), the only country in which they are found indigenously (Teleki and Baldwin 1979, Kano 1984, Van Krunkelsven 2001). While it might seem an administrative blessing to have bonobos concentrated in one single large country, this rare species still shares all the problems of population fragmentation, habitat loss, and victimization due to the bushmeat trade practice by their African cousins. In addition, by being concentrated in one country, this species’ survival is dependent upon the state of one single nation – for better or worse. The ubiquitous threats to African apes seem particularly acute in the case of the bonobo as a result of DRC’s ill fortune during the past decade. However, the DRC has begun recovering from a decade of wars and now has the chance to jump from an impoverished victim of an oft forgotten war between seven nations, to a regional power as it struggles to redevelop its shattered economy through what to many must seem like an infinite supply of natural resources (Clark 2002). What will the

Objective To investigate the molecular mechanism responsible for the reduced capacity of dendritic cells (DCs) from HLA–B27–transgenic rats to form conjugates with naive T cells. Methods We monitored interactions between DCs derived from HLA–B27–transgenic, HLA–B7–transgenic control, and nontransgenic rats and naive CD4+ T cells. Chemoattraction was studied in Transwell assays, and the formation of an immunologic synapse was examined by videomicroscopy and electron microscopy. Involvement of specific molecules in the defective interaction was examined in antibody-blocking assays. Results T cells migrated normally toward B27 DCs, but upon contact, the frequency of T cells undergoing a Ca2+ response was decreased, indicating impaired immunologic synapse formation. The immunologic synapse formed between B27 DCs and T cells appeared to be normal, as assessed by electron microscopy and by the Ca2+ response. Blocking lymphocyte function−associated antigen 1 on T cells or blocking activated leukocyte cell adhesion molecules on DCs inhibited an equivalent proportion of conjugates from forming between B27 or control DCs and T cells, whereas blocking CD86 on DCs and blocking CD28, CD2, or CD4 on T cells inhibited a greater number of conjugates from forming with control DCs, indicating specific involvement of costimulatory molecules in the reduced formation of conjugates with B27 DCs. Mature B27 molecules on the DC surface were responsible for this decreased formation of conjugates. Conclusion In the HLA–B27–transgenic rat model of spondylarthropathy, mature B27 molecules expressed by DCs impair the formation of an antigen-independent immunologic synapse with naive CD4+ T cells by interfering with the engagement of costimulatory molecules. This phenomenon could potentially affect the production and/or maintenance of regulatory T cells and contribute to the expansion of pathogenic CD4+ T cells.

In the livers of humans and many other mammalian species, β2-adrenergic receptors (β2-ARs) play an important role in the modulation of glucose production by glycogenolysis and gluconeogenesis. In male mice and rats, however, the expression and physiological role of hepatic β2-ARs are rapidly lost with development under normal physiological conditions. We previously described a line of transgenic mice, F28 (André C, Erraji L, Gaston J, Grimber G, Briand P, and Guillet JG. Eur J Biochem 241: 417–424, 1996), which carry the human β2-AR gene under the control of its own promoter. In these mice, hepatic β2-AR levels are shown to increase rapidly after birth and, as in humans, be maintained at an elevated level in adulthood. F28 mice display strongly enhanced adenylyl cyclase responses to β-AR agonists in their livers and, compared with normal mice, have increased basal hepatic adenylyl cyclase activity. In this report we demonstrate that, under normal physiological conditions, this increased β2-AR activity affects the expression of the gluconeogenic and glycolytic key enzymes phospho enolpyruvate carboxykinase, glucose-6-phosphatase, and l-pyruvate kinase and considerably decreases hepatic glycogen levels. Furthermore, we show that the effects of β-adrenergic ligands on liver glycogen observed in humans are reproduced in these mice: liver glycogen levels are strongly decreased by the β2-AR agonist clenbuterol and increased by the β-AR antagonist propranolol. These transgenic mice open new perspectives for studying in vivo the hepatic β2-AR system physiopathology and for testing the effects of β-AR ligands on liver metabolism.

Muscarinic acetylcholine receptors were identified in the microsomal P fraction of rat forebrain by the specific binding of the radiolabeled antagonist [3H]dexetimide. Binding occurred to a single class of noncooperative sites (3.25 mumol/mg protein) with an equilibrium dissociation constant of 1.1 nM. Agonist/[3H]-dexetimide competition binding experiments allowed the distinction between two major muscarinic receptor subpopulations, having respectively high affinity (20% of the total receptor population) and low affinity for agonists, but with the same affinity for antagonists. A 610-fold difference in affinity was calculated for carbamoyl-choline, the agonist extensively investigated in this study. The alkylating reagent N-ethylmaleimide did not affect the total receptor number, antagonist binding to the high-affinity and low-affinity sites, nor agonist binding to the high-affinity sites. The reagent, however, caused a net increase in agonist affinity for the low-affinity sites. This process was dependent on time and dose of N-ethylmaleimide, until a maximal increase in affinity (fourfold increase for carbamoylcholine) was attained. This suggests a quantal conversion of the low-affinity sites by the reagent into an alkylated form, which possesses a higher affinity for agonists but an unchanged affinity for antagonists. The rate of alkylation was enhanced by the presence of agonists but not of antagonists, which is indicative for the ability of agonists to mediate a conformational change of these sites. The close correlation between the N-ethylmaleimide-mediated increase in drug affinity for the low-affinity sites and the ability of the drugs to enhance alkylation of these sites by N-ethylmaleimide can be explained by the ability of (a) muscarinic drugs to interact with the low-affinity sites according to the Monod-Wyman-Changeux 'Plausible Model' and (b) N-ethylmaleimide to freeze these sites in the 'active' conformation by alkylation.