1-20 von 272 Publikationen

    • Zeitschriftenartikel

      Sexual dimorphism of AMBRA1-related autistic features in human and mouse. 

      Mitjans, M.; Begemann, M.; Ju, A.; Dere, E.; Wüstefeld, L.; Hofer, S.; Hassouna, I.; Balkenhol, J.; Oliveira, B.; van der Auwera, S.; et al.
      Tammer, R.Hammerschmidt, K.Völzke, H.Homuth, G.Cecconi, F.Chowdhury, K.Grabe, H.Frahm, J.Boretius, S.Dandekar, T.Ehrenreich, H.
      Translational psychiatry 2017-10-10; 7(10): Art. e1247
      Ambra1 is linked to autophagy and neurodevelopment. Heterozygous Ambra1 deficiency induces autism-like behavior in a sexually dimorphic manner. Extraordinarily, autistic features are seen in female mice only, combined with stronger Ambra1 protein reduction in brain compared to males. However, significance of AMBRA1 for autistic phenotypes in humans and, apart from behavior, for other autism-typical features, namely early brain enlargement or increased seizure propensity, has remained unexplored. Here we show in two independent human samples that a single normal AMBRA1 genotype, the intronic SNP rs3802890-AA, is associated with autistic features in women, who also display lower AMBRA1 mRNA expression in peripheral blood mononuclear cells relative to female GG carriers. Located within a non-coding RNA, likely relevant for mRNA and protein interaction, rs3802890 (A versus G allele) may affect its stability through modification of folding, as predicted by in silico analysis. Searching for further autism-relevant characteristics in Ambra1(+/-) mice, we observe reduced interest of female but not male mutants regarding pheromone signals of the respective other gender in the social intellicage set-up. Moreover, altered pentylentetrazol-induced seizure propensity, an in vivo readout of neuronal excitation-inhibition dysbalance, becomes obvious exclusively in female mutants. Magnetic resonance imaging reveals mild prepubertal brain enlargement in both genders, uncoupling enhanced brain dimensions from the primarily female expression of all other autistic phenotypes investigated here. These data support a role of AMBRA1/Ambra1 partial loss-of-function genotypes for female autistic traits. Moreover, they suggest Ambra1 heterozygous mice as a novel multifaceted and construct-valid genetic mouse model for female autism.
      Dokument ansehen Zusammenfassung
    • Zeitschriftenartikel

      Changes of Microrna Levels in Plasma of Patients with Rectal Cancer during Chemoradiotherapy 

      Jo, Peter; Azizian, Azadeh; Salendo, Junius; Kramer, Frank; Bernhardt, Markus; Wolff, Hendrik; Gruber, Jens; Grade, Marian; Beißbarth, Tim; Ghadimi, B.; et al.
      Gaedcke, Jochen
      International Journal of Molecular Sciences 2017; 18(6): Art. 1140
      Dokument ansehen
    • Zeitschriftenartikel

      Self-cytoplasmic DNA upregulates the mutator enzyme APOBEC3A leading to chromosomal DNA damage 

      Suspène, Rodolphe; Mussil, Bianka; Laude, Hélène; Caval, Vincent; Berry, Noémie; Bouzidi, Mohamed S.; Thiers, Valérie; Wain-Hobson, Simon; Vartanian, Jean-Pierre
      Nucleic Acids Research 2017; 45(6) p.3231-3241
      Foreign and self-cytoplasmic DNA are recognized by numerous DNA sensor molecules leading to the production of type I interferons. Such DNA agonists should be degraded otherwise cells would be chronically stressed. Most human APOBEC3 cytidine deaminases can initiate catabolism of cytoplasmic mitochondrial DNA. Using the human myeloid cell line THP-1 with an interferon inducible APOBEC3A gene, we show that cytoplasmic DNA triggers interferon α and β production through the RNA polymerase III transcription/RIG-I pathway leading to massive upregulation of APOBEC3A. By catalyzing C→U editing in single stranded DNA fragments, the enzyme prevents them from re-annealing so attenuating the danger signal. The price to pay is chromosomal DNA damage in the form of CG→TA mutations and double stranded DNA breaks which, in the context of chronic inflammation, could drive cells down the path toward cancer.
      Dokument ansehen Zusammenfassung
    • Zeitschriftenartikel

      Differential contribution of immune effector mechanisms to cortical demyelination in multiple sclerosis 

      Lagumersindez-Denis, Nielsen; Wrzos, Claudia; Mack, Matthias; Winkler, Anne; van der Meer, Franziska; Reinert, Marie C.; Hollasch, Heiko; Flach, Anne; Brühl, Hilke; Cullen, Eilish; et al.
      Schlumbohm, ChristinaFuchs, EberhardLinington, ChristopherBarrantes-Freer, AlonsoMetz, ImkeWegner, ChristianeLiebetanz, DavidPrinz, MarcoBrück, WolfgangStadelmann, ChristineNessler, Stefan
      Acta Neuropathologica 2017; 134(1) p.15-34
      Cortical demyelination is a widely recognized hallmark of multiple sclerosis (MS) and correlate of disease progression and cognitive decline. The pathomechanisms initiating and driving gray matter damage are only incompletely understood. Here, we determined the infiltrating leukocyte subpopulations in 26 cortical demyelinated lesions of biopsied MS patients and assessed their contribution to cortical lesion formation in a newly developed mouse model. We find that conformation-specific anti-myelin antibodies contribute to cortical demyelination even in the absence of the classical complement pathway. T cells and natural killer cells are relevant for intracortical type 2 but dispensable for subpial type 3 lesions, whereas CCR2+ monocytes are required for both. Depleting CCR2+ monocytes in marmoset monkeys with experimental autoimmune encephalomyelitis using a novel humanized CCR2 targeting antibody translates into significantly less cortical demyelination and disease severity. We conclude that biologics depleting CCR2+ monocytes might be attractive candidates for preventing cortical lesion formation and ameliorating disease progression in MS.
      Dokument ansehen Zusammenfassung
    • Zeitschriftenartikel

      Recent expansion and adaptive evolution of the carcinoembryonic antigen family in bats of the Yangochiroptera subgroup 

      Kammerer, Robert; Mansfeld, Martin; Hänske, Jana; Mißbach, Sophie; He, Xiaocui; Köllner, Bernd; Mouchantat, Susan; Zimmermann, Wolfgang
      BMC Genomics 2017; 18(1)
      BACKGROUND: Expansions of gene families are predictive for ongoing genetic adaptation to environmental cues. We describe such an expansion of the carcinoembryonic antigen (CEA) gene family in certain bat families. Members of the CEA family in humans and mice are exploited as cellular receptors by a number of pathogens, possibly due to their function in immunity and reproduction. The CEA family is composed of CEA-related cell adhesion molecules (CEACAMs) and secreted pregnancy-specific glycoproteins (PSGs). PSGs are almost exclusively expressed by trophoblast cells at the maternal-fetal interface. The reason why PSGs exist only in a minority of mammals is still unknown. RESULTS: Analysis of the CEA gene family in bats revealed that in certain bat families, belonging to the subgroup Yangochiroptera but not the Yinpterochiroptera subgroup an expansion of the CEA gene family took place, resulting in approximately one hundred CEA family genes in some species of the Vespertilionidae. The majority of these genes encode secreted PSG-like proteins (further referred to as PSG). Remarkably, we found strong evidence that the ligand-binding domain (IgV-like domain) of PSG is under diversifying positive selection indicating that bat PSGs may interact with structurally highly variable ligands. Such ligands might represent bacterial or viral pathogen adhesins. We have identified two distinct clusters of PSGs in three Myotis species. The two PSG cluster differ in the amino acids under positive selection. One cluster was only expanded in members of the Vespertilionidae while the other was found to be expanded in addition in members of the Miniopteridae and Mormoopidae. Thus one round of PSG expansion may have occurred in an ancestry of all three families and a second only in Vespertilionidae. Although maternal ligands of PSGs may exist selective challenges by two distinct pathogens seem to be likely responsible for the expansion of PSGs in Vespertilionidae. CONCLUSIONS: The rapid expansion of PSGs in certain bat species together with selection for diversification suggest that bat PSGs could be part of a pathogen defense system by serving as decoy receptors and/or regulators of feto-maternal interactions.
      Dokument ansehen Zusammenfassung
    • Zeitschriftenartikel

      Hair cortisol concentrations correlate negatively with survival in a wild primate population 

      Rakotoniaina, Josué H.; Kappeler, Peter M.; Kaesler, Eva; Hämäläinen, Anni M.; Kirschbaum, Clemens; Kraus, Cornelia
      BMC Ecology 2017; 17(1)
      BACKGROUND: Glucocorticoid hormones are known to play a key role in mediating a cascade of physiological responses to social and ecological stressors and can therefore influence animals' behaviour and ultimately fitness. Yet, how glucocorticoid levels are associated with reproductive success or survival in a natural setting has received little empirical attention so far. Here, we examined links between survival and levels of glucocorticoid in a small, short-lived primate, the grey mouse lemur (Microcebus murinus), using for the first time an indicator of long-term stress load (hair cortisol concentration). Using a capture-mark-recapture modelling approach, we assessed the effect of stress on survival in a broad context (semi-annual rates), but also under a specific period of high energetic demands during the reproductive season. We further assessed the power of other commonly used health indicators (body condition and parasitism) in predicting survival outcomes relative to the effect of long-term stress. RESULTS: We found that high levels of hair cortisol were associated with reduced survival probabilities both at the semi-annual scale and over the reproductive season. Additionally, very good body condition (measured as scaled mass index) was related to increased survival at the semi-annual scale, but not during the breeding season. In contrast, variation in parasitism failed to predict survival. CONCLUSION: Altogether, our results indicate that long-term increased glucocorticoid levels can be related to survival and hence population dynamics, and suggest differential strength of selection acting on glucocorticoids, body condition, and parasite infection.
      Dokument ansehen Zusammenfassung
    • Zeitschriftenartikel

      What makes a reach movement effortful? Physical effort discounting supports common minimization principles in decision making and motor control. 

      Morel, Pierre; Ulbrich, Philipp; Gail, Alexander
      PLoS biology 2017-06; 15(6): Art. e2001323
      When deciding between alternative options, a rational agent chooses on the basis of the desirability of each outcome, including associated costs. As different options typically result in different actions, the effort associated with each action is an essential cost parameter. How do humans discount physical effort when deciding between movements? We used an action-selection task to characterize how subjective effort depends on the parameters of arm transport movements and controlled for potential confounding factors such as delay discounting and performance. First, by repeatedly asking subjects to choose between 2 arm movements of different amplitudes or durations, performed against different levels of force, we identified parameter combinations that subjects experienced as identical in effort (isoeffort curves). Movements with a long duration were judged more effortful than short-duration movements against the same force, while movement amplitudes did not influence effort. Biomechanics of the movements also affected effort, as movements towards the body midline were preferred to movements away from it. Second, by introducing movement repetitions, we further determined that the cost function for choosing between effortful movements had a quadratic relationship with force, while choices were made on the basis of the logarithm of these costs. Our results show that effort-based action selection during reaching cannot easily be explained by metabolic costs. Instead, force-loaded reaches, a widely occurring natural behavior, imposed an effort cost for decision making similar to cost functions in motor control. Our results thereby support the idea that motor control and economic choice are governed by partly overlapping optimization principles.
      Dokument ansehen Zusammenfassung
    • Zeitschriftenartikel

      Different residues in the SARS-CoV spike protein determine cleavage and activation by the host cell protease TMPRSS2. 

      Reinke, Lennart Michel; Spiegel, Martin; Plegge, Teresa; Hartleib, Anika; Nehlmeier, Inga; Gierer, Stefanie; Hoffmann, Markus; Hofmann-Winkler, Heike; Winkler, Michael; Pöhlmann, Stefan
      PloS one 2017; 12(6): Art. e0179177
      The spike (S) protein of severe acute respiratory syndrome coronavirus (SARS-CoV) mediates viral entry into target cells. Cleavage and activation of SARS S by a host cell protease is essential for infectious viral entry and the responsible enzymes are potential targets for antiviral intervention. The type II transmembrane serine protease TMPRSS2 cleaves and activates SARS S in cell culture and potentially also in the infected host. Here, we investigated which determinants in SARS S control cleavage and activation by TMPRSS2. We found that SARS S residue R667, a previously identified trypsin cleavage site, is also required for S protein cleavage by TMPRSS2. The cleavage fragments produced by trypsin and TMPRSS2 differed in their decoration with N-glycans, suggesting that these proteases cleave different SARS S glycoforms. Although R667 was required for SARS S cleavage by TMPRSS2, this residue was dispensable for TMPRSS2-mediated S protein activation. Conversely, residue R797, previously reported to be required for SARS S activation by trypsin, was dispensable for S protein cleavage but required for S protein activation by TMPRSS2. Collectively, these results show that different residues in SARS S control cleavage and activation by TMPRSS2, suggesting that these processes are more complex than initially appreciated.
      Dokument ansehen Zusammenfassung
    • Zeitschriftenartikel

      Meerkat close calling patterns are linked to sex, social category, season and wind, but not fecal glucocorticoid metabolite concentrations 

      Mausbach, Jelena; Braga Goncalves, Ines; Heistermann, Michael; Ganswindt, André; Manser, Marta B.
      PLOS ONE 2017; 12(5): Art. e0175371
      It is well established that animal vocalizations can encode information regarding a sender’s identity, sex, age, body size, social rank and group membership. However, the association between physiological parameters, particularly stress hormone levels, and vocal behavior is still not well understood. The cooperatively breeding African meerkats (Suricata suricatta) live in family groups with despotic social hierarchies. During foraging, individuals emit close calls that help maintain group cohesion. These contact calls are acoustically distinctive and variable in rate across individuals, yet, information on which factors influence close calling behavior is missing. The aim of this study was to identify proximate factors that influence variation in call rate and acoustic structure of meerkat close calls. Specifically, we investigated whether close calling behavior is associated with sex, age and rank, or stress hormone output (i.e., measured as fecal glucocorticoid metabolite (fGCM) concentrations) as individual traits of the caller, as well as with environmental conditions (weather) and reproductive seasonality. To disentangle the effects of these factors on vocal behavior, we analyzed sound recordings and assessed fGCM concentrations in 64 wild but habituated meerkats from 9 groups during the reproductive and non-reproductive seasons. Dominant females and one-year old males called at significantly higher rates compared to other social categories during the reproductive season. Additionally, dominant females produced close calls with the lowest mean fundamental frequencies (F0) and the longest mean pulse durations. Windy conditions were associated with significantly higher call rates during the non-reproductive season. Fecal GCM concentrations were unrelated to close calling behavior. Our findings suggest that meerkat close calling behavior conveys information regarding the sex and social category of the caller, but shows no association with fGCM concentrations. The change in call rate in response to variation in the social and ecological environments individuals experience indicates some degree of flexibility in vocal production.
      Dokument ansehen Zusammenfassung
    • Zeitschriftenartikel

      Non-human primate orthologues of TMPRSS2 cleave and activate the influenza virus hemagglutinin 

      Zmora, Pawel; Molau-Blazejewska, Paulina; Bertram, Stephanie; Walendy-Gnirß, Kerstin; Nehlmeier, Inga; Hartleib, Anika; Moldenhauer, Anna-Sophie; Konzok, Sebastian; Dehmel, Susann; Sewald, Katherina; et al.
      Brinkmann, ConstantinCurths, ChristophKnauf, SaschaGruber, JensMätz-Rensing, KerstinDahlmann, FranziskaBraun, ArminPöhlmann, Stefan
      PLOS ONE 2017; 12(5): Art. e0176597
      The cellular serine protease TMPRSS2, a member of the type II transmembrane serine protease (TTSP) family, cleaves and activates the hemagglutinin of influenza A viruses (FLUAV) in cell culture and is essential for spread of diverse FLUAV in mice. Non-human primates (NHP), in particular rhesus and cynomolgus macaques, serve as animal models for influenza and experimental FLUAV infection of common marmosets has recently also been reported. However, it is currently unknown whether the NHP orthologues of human TMPRSS2 cleave and activate FLUAV hemagglutinin and contribute to viral spread in respiratory tissue. Here, we cloned and functionally analyzed the macaque and marmoset orthologues of human TMPRSS2. In addition, we analyzed the macaque orthologues of human TMPRSS4 and HAT, which also belong to the TTSP family. We found that all NHP orthologues of human TMPRSS2, TMPRSS4 and HAT cleave and activate HA upon directed expression and provide evidence that endogenous TMPRSS2 is expressed in the respiratory epithelium of rhesus macaques. Finally, we demonstrate that a serine protease inhibitor active against TMPRSS2 suppresses FLUAV spread in precision-cut lung slices of human, macaque and marmoset origin. These results indicate that FLUAV depends on serine protease activity for spread in diverse NHP and in humans. Moreover, our findings suggest that macaques and marmosets may serve as models to study FLUAV activation by TMPRSS2 in human patients.
      Dokument ansehen Zusammenfassung
    • Zeitschriftenartikel

      Dissecting miRNA gene repression on single cell level with an advanced fluorescent reporter system 

      Lemus-Diaz, Nicolas; Böker, Kai O.; Rodriguez-Polo, Ignacio; Mitter, Michael; Preis, Jasmin; Arlt, Maximilian; Gruber, Jens
      Scientific Reports 2017; 7
      Despite major advances on miRNA profiling and target predictions, functional readouts for endogenous miRNAs are limited and frequently lead to contradicting conclusions. Numerous approaches including functional high-throughput and miRISC complex evaluations suggest that the functional miRNAome differs from the predictions based on quantitative sRNA profiling. To resolve the apparent contradiction of expression versus function, we generated and applied a fluorescence reporter gene assay enabling single cell analysis. This approach integrates and adapts a mathematical model for miRNA-driven gene repression. This model predicts three distinct miRNA-groups with unique repression activities (low, mid and high) governed not just by expression levels but also by miRNA/target-binding capability. Here, we demonstrate the feasibility of the system by applying controlled concentrations of synthetic siRNAs and in parallel, altering target-binding capability on corresponding reporterconstructs. Furthermore, we compared miRNA-profiles with the modeled predictions of 29 individual candidates. We demonstrate that expression levels only partially reflect the miRNA function, fitting to the model-projected groups of different activities. Furthermore, we demonstrate that subcellular localization of miRNAs impacts functionality. Our results imply that miRNA profiling alone cannot define their repression activity. The gene regulatory function is a dynamic and complex process beyond a minimalistic conception of “highly expressed equals high repression”.
      Dokument ansehen Zusammenfassung
    • Zeitschriftenartikel

      Acquisition and functional consequences of social knowledge in macaques 

      Tiddi, Barbara; di Sorrentino, Eugenia Polizzi; Fischer, Julia; Schino, Gabriele
      Royal Society Open Science 2017; 4(2)
      To manoeuvre in complex societies, it is beneficial to acquire knowledge about the social relationships existing among group mates, so as to better predict their behaviour. Although such knowledge has been firmly established in a variety of animal taxa, how animals acquire such knowledge, as well as its functional significance, remains poorly understood. In order to understand how primates acquire and use their social knowledge, we studied kin-biased redirected aggression in Japanese macaques (Macaca fuscata) relying on a large database of over 15 000 aggressive episodes. Confirming previous research, macaques redirected aggression preferentially to the kin of their aggressor. An analysis that controlled for the rate of affiliation between aggressors and targets of redirection showed that macaques identified the relatives of group mates on the basis of the frequency of their ongoing associations. By contrast, having observed group mates interact with their mother as infants did not increase the monkeys’ success in correctly identifying kin relationships among third parties. Inter-individual variation in the successful identification of the kin of aggressors and in redirecting aggression accordingly translated into differences in the amount of aggression received, highlighting a selective advantage for those individuals that were better able to acquire and use social knowledge.
      Dokument ansehen Zusammenfassung
    • Zeitschriftenartikel

      Factors determining human-to-human transmissibility of zoonotic pathogens via contact 

      Richard, Mathilde; Knauf, Sascha; Lawrence, Philip; Mather, Alison E.; Munster, Vincent J.; Müller, Marcel A.; Smith, Derek; Kuiken, Thijs
      Current Opinion in Virology 2017; 22 p.7-12
      The pandemic potential of zoonotic pathogens lies in their ability to become efficiently transmissible amongst humans. Here, we focus on contact-transmitted pathogens and discuss the factors, at the pathogen, host and environmental levels that promote or hinder their human-to-human transmissibility via the following modes of contact transmission: skin contact, sexual contact, respiratory contact and multiple route contact. Factors common to several modes of transmission were immune evasion, high viral load, low infectious dose, crowding, promiscuity, and co-infections; other factors were specific for a pathogen or mode of contact transmission. The identification of such factors will lead to a better understanding of the requirements for human-to-human spread of pathogens, as well as improving risk assessment of newly emerging pathogens.
      Dokument ansehen Zusammenfassung
    • Zeitschriftenartikel

      Rhesus macaque IFITM3 gene polymorphisms and SIV infection 

      Winkler, Michael; Gärtner, Sabine; Wrensch, Florian; Krawczak, Michael; Sauermann, Ulrike; Pöhlmann, Stefan
      PLOS ONE 2017; 12(3): Art. e0172847
      nterferon-induced transmembrane proteins (IFITMs) have been recognized as important antiviral effectors of the innate immune system, both in cell culture and in infected humans. In particular, polymorphisms of the human IFITM3 gene have been shown to affect disease severity and progression in influenza A virus (FLUAV) and human immunodeficiency virus (HIV) infection, respectively. Rhesus macaques (Macaca mulatta) are commonly used to model human infections and the experimental inoculation of these animals with simian immunodeficiency virus (SIV) is one of the best models for HIV/AIDS in humans. However, information on the role of IFITM3 in SIV infection of rhesus macaques is currently lacking. We show that rhesus macaque (rh) IFITM3 inhibits SIV and FLUAV entry in cell culture, although with moderately reduced efficiency as compared to its human counterpart. We further report the identification of 16 polymorphisms in the rhIFITM3 gene, three of which were exonic and synonymous while the remainder was located in non-coding regions. Employing previously characterized samples from two cohorts of SIV-infected rhesus macaques, we investigated the relationship between these rhIFITM3 polymorphisms and both AIDS-free survival time and virus load. In cohort 1, several intronic polymorphisms were significantly associated with virus load or survival. However, an association with both parameters was not observed and significance was lost in most cases when animals were stratified for the presence of MHC allele Mamu-A1*001. Moreover, no significant genotype-phenotype associations were detected in cohort 2. These results suggest that, although IFITM3 can inhibit SIV infection in cell culture, genetic variation in rhIFITM3 might have only a minor impact on the course of SIV infection in experimentally infected animals.
      Dokument ansehen Zusammenfassung
    • Zeitschriftenartikel

      Chimpanzee Personality and the Arginine Vasopressin Receptor 1A Genotype 

      Wilson, V. A. D.; Weiss, A.; Humle, T.; Morimura, N.; Udono, T.; Idani, G.; Matsuzawa, T.; Hirata, S.; Inoue-Murayama, M.
      Behavior Genetics 2016; 47(2) p.215-226
      Polymorphisms of the arginine vasopressin receptor 1a (AVPR1a) gene have been linked to various measures related to human social behavior, including sibling conflict and agreeableness. In chimpanzees, AVPR1a polymorphisms have been associated with traits important for social interactions, including sociability, joint attention, dominance, conscientiousness, and hierarchical personality dimensions named low alpha/stability, disinhibition, and negative emotionality/low dominance. We examined associations between AVPR1a and six personality domains and hierarchical personality dimensions in 129 chimpanzees (Pan troglodytes) living in Japan or in a sanctuary in Guinea. We fit three linear and three animal models. The first model included genotype, the second included sex and genotype, and the third included genotype, sex, and sex × genotype. All personality phenotypes were heritable. Chimpanzees possessing the long form of the allele were higher in conscientiousness, but only in models that did not include the other predictors; however, additional analyses suggested that this may have been a consequence of study design. In animal models that included sex and sex × genotype, chimpanzees homozygous for the short form of the allele were higher in extraversion. Taken with the findings of previous studies of chimpanzees and humans, the findings related to conscientiousness suggest that AVPR1a may be related to lower levels of impulsive aggression. The direction of the association between AVPR1a genotype and extraversion ran counter to what one would expect if AVPR1a was related to social behaviors. These results help us further understand the genetic basis of personality in chimpanzees.
      Dokument ansehen Zusammenfassung
    • Zeitschriftenartikel

      Highly Variable Streptococcus oralis Strains Are Common among Viridans Streptococci Isolated from Primates 

      Denapaite, Dalia; Rieger, Martin; Köndgen, Sophie; Brückner, Reinhold; Ochigava, Irma; Kappeler, Peter; Mätz-Rensing, Kerstin; Leendertz, Fabian; Hakenbeck, Regine
      mSphere 2016; 1(2): Art. e00041-15
      Viridans streptococci were obtained from primates (great apes, rhesus monkeys, and ring-tailed lemurs) held in captivity, as well as from free-living animals (chimpanzees and lemurs) for whom contact with humans is highly restricted. Isolates represented a variety of viridans streptococci, including unknown species. Streptococcus oralis was frequently isolated from samples from great apes. Genotypic methods revealed that most of the strains clustered on separate lineages outside the main cluster of human S. oralis strains. This suggests that S. oralis is part of the commensal flora in higher primates and evolved prior to humans. Many genes described as virulence factors in Streptococcus pneumoniae were present also in other viridans streptococcal genomes. Unlike in S. pneumoniae, clustered regularly interspaced short palindromic repeat (CRISPR)–CRISPR-associated protein (Cas) gene clusters were common among viridans streptococci, and many S. oralis strains were type PI-2 (pilus islet 2) variants. S. oralis displayed a remarkable diversity of genes involved in the biosynthesis of peptidoglycan (penicillin-binding proteins and MurMN) and choline-containing teichoic acid. The small noncoding cia-dependent small RNAs (csRNAs) controlled by the response regulator CiaR might contribute to the genomic diversity, since we observed novel genomic islands between duplicated csRNAs, variably present in some isolates. All S. oralis genomes contained a -Nacetyl- hexosaminidase gene absent in S. pneumoniae, which in contrast frequently harbors the neuraminidases NanB/C, which are absent in S. oralis. The identification of S. oralis-specific genes will help us to understand their adaptation to diverse habitats.
      Dokument ansehen Zusammenfassung
    • Zeitschriftenartikel

      Age, but not anthelmintic treatment, is associated with urinary neopterin levels in semi-free ranging Barbary macaques 

      Müller, Nadine; Heistermann, Michael; Strube, Christina; Schülke, Oliver; Ostner, Julia
      Scientific Reports 2017; 7
      Studying host parasite interactions and their implications for evolution and ecology recently received increasing attention, particularly with regard to host physiology and immunity. Here we assess variation of urinary neopterin (uNEO), a marker of cellular immune activation and iummunosenescence, in response to age and anthelmintic treatment in semi-free ranging Barbary macaques (Macaca sylvanus). Urinary NEO levels were measured via enzyme-immunoassay from 179 urine samples of 43 individuals between 5–29 years of age. Efficiency of treatment was assessed by Mc Master flotation on repeated faecal samples, including 18 untreated individuals as control group. We used linear mixed models with age and parasite status as main effects, controlling for sex and physical condition, assessed through urinary C-Peptide-levels, with social group and ID as random factors. Urinary NEO levels significantly increased with age, suggesting that changes in aging Barbary macaque immune responses are consistent with immunosenescence described in human and nonhuman primates and can be detected via uNEO measurements. Anthelmintic treatment, however, had no influence on uNEO levels, potentially due to quick reinfections or attenuated immune responses in repeated infections. We conclude that uNEO is a potential non-invasive marker for immune function and particularly immunosenescence in wildlife.
      Dokument ansehen Zusammenfassung
    • Zeitschriftenartikel

      Mother-male bond, but not paternity, influences male-infant affiliation in wild crested macaques 

      Kerhoas, Daphne; Kulik, Lars; Perwitasari-Farajallah, Dyah; Agil, Muhammad; Engelhardt, Antje; Widdig, Anja
      Behavioral Ecology and Sociobiology 2016; 70(8) p.1117-1130
      In promiscuous primates, interactions between adult males and infants have rarely been investigated. However, recent evidence suggests that male affiliation towards infants has an influence on several aspects of the infants' life. Furthermore, affiliations may be associated with male reproductive strategy. In this study, we examined which social factors influenced male-infant affiliation initiated by either male or infant, in wild crested macaques (Macaca nigra). We combined behavioral data and genetic paternity analysis from 30 infants living in three wild groups in Tangkoko Reserve, Indonesia. Our results indicate that adult males and infants do not interact at random, but rather form preferential associations. The social factors with the highest influence on infant-initiated interactions were male rank and male association with the infant's mother. While infants initiated affiliations with males more often in the absence of their mothers, adult males initiated more affiliations with infants when their mothers were present. Furthermore, males initiated affiliations more often when they were in the same group at the time the infant was conceived, when they held a high dominance rank, or when they had a close relationship with the mother. Interestingly, paternity did not affect male-infant affiliation despite being highly skewed in this species. Overall, our results suggest that adult males potentially associate with an infant to secure future mating with the mother. Infants are more likely to associate with a male to receive better support, suggesting a strategy to increase the chance of infant survival in a primate society with high infant mortality. SIGNIFICANCE STATEMENT: We explore social relationships between males and infants in a promiscuous primate, the wild crested macaque. Our novel approach addresses the nature of affiliations both from males' and infants' perspectives. The results show that males and infants form preferential associations. Male-female affiliation, but not paternity, was a significant predictor of interactions initiated both by males and infants. Males initiated more interactions towards infants when the mother was in proximity, while infants initiated more interactions in her absence. Finally, high-ranking males were more likely to initiate interactions towards infants. We demonstrated that paternity is not a good predictor of male-infant affiliations, even in a species with a high reproductive skew and a relatively high confidence of paternity. Our paper is one of the first to show that infants are active agents in establishing and maintaining preferential relationships with males.
      Dokument ansehen Zusammenfassung
    • Zeitschriftenartikel

      Molecular genetic aetiology of general cognitive function is enriched in evolutionarily conserved regions 

      Hill, W. D.; Davies, G.; Harris, S. E.; Hagenaars, S. P.; Davies, Gail; Deary, Ian J.; Debette, Stephanie; Verbaas, Carla I.; Bressler, Jan; Schuur, Maaike; et al.
      Smith, Albert V.Bis, Joshua C.Bennett, David A.Ikram, M. ArfanLauner, Lenore J.Fitzpatrick, Annette L.Seshadri, Sudhavan Duijn, Cornelia M.Mosley Jr, Thomas H.Liewald, D. C.Penke, L.Gale, C. R.Deary, I. J.
      Translational Psychiatry 2016; 6(12): Art. e980
      Differences in general cognitive function have been shown to be partly heritable and to show genetic correlations with several psychiatric and physical disease states. However, to date, few single-nucleotide polymorphisms (SNPs) have demonstrated genome-wide significance, hampering efforts aimed at determining which genetic variants are most important for cognitive function and which regions drive the genetic associations between cognitive function and disease states. Here, we combine multiple large genome-wide association study (GWAS) data sets, from the CHARGE cognitive consortium (n = 53 949) and UK Biobank (n = 36 035), to partition the genome into 52 functional annotations and an additional 10 annotations describing tissuespecific histone marks. Using stratified linkage disequilibrium score regression we show that, in two measures of cognitive function, SNPs associated with cognitive function cluster in regions of the genome that are under evolutionary negative selective pressure. These conserved regions contained ~ 2.6% of the SNPs from each GWAS but accounted for ~ 40% of the SNP-based heritability. The results suggest that the search for causal variants associated with cognitive function, and those variants that exert a pleiotropic effect between cognitive function and health, will be facilitated by examining these enriched regions.
      Dokument ansehen Zusammenfassung
    • Zeitschriftenartikel

      Pre-infection transcript levels of FAM26F in peripheral blood mononuclear cells inform about overall plasma viral load in acute and post-acute phase after simian immunodeficiency virus infection 

      Javed, Aneela; Leuchte, Nicole; Salinas, Gabriela; Opitz, Lennart; Stahl-Hennig, Christiane; Sopper, Sieghart; Sauermann, Ulrike
      Journal of General Virology 2016; 97(12) p.3400-3412
      CD8+ cells from simian immunodeficiency virus (SIV)-infected long-term non-progressors and some uninfected macaques can suppress viral replication in vitro without killing the infected cells. The aim of this study was to identify factors responsible for non-cytolytic viral suppression by transcriptional profiling and to investigate their potential impact on SIV replication. Results of microarray experiments and further validation with cells from infected and uninfected macaques revealed that FAM26F RNA levels distinguished CD8+ cells of controllers and non-controllers (P=0.001). However, FAM26F was also expressed in CD4+ T-cells and B-cells. FAM26F expression increased in lymphocytes after in vitro IFN-γ treatment on average 40-fold, and ex vivo FAM26F RNA levels in peripheral blood mononuclear cells correlated with plasma IFN-γ but not with IFN-α. Baseline FAM26F expression appeared to be stable for months, albeit the individual expression levels varied up to tenfold. Investigating its role in SIV-infection revealed that FAM26F was upregulated after infection (P<0.0008), but did not directly correlate with viral load in contrast to MX1 and CXCL10. However, pre-infection levels of FAM26F correlated inversely with overall plasma viral load (AUC) during the acute and post-acute phases of infection (e.g. AUC weeks post infection 0–8; no AIDS vaccine: P<0.0001, Spearman rank correlation coefficient (rs)=−0.89, n=16; immunized with an AIDS vaccine: P=0.033, rs=−0.43; n=25). FAM26F transcript levels prior to infection can provide information about the pace and strength of the antiviral immune response during the early stage of infection. FAM26F expression represented, in our experiments, one of the earliest prognostic markers, and could supplement major histocompatibility complex (MHC)-typing to predict disease progression before SIV-infection.
      Dokument ansehen Zusammenfassung