Recent Submissions

  • Journal Article

    Is implicit Theory of Mind real but hard to detect? Testing adults with different stimulus materials 

    Kulke, Louisa; Wübker, Marieke; Rakoczy, Hannes
    Royal Society Open Science 2019; 6(7): Art. 190068
    Recently, Theory of Mind (ToM) research has been revolutionized by new methods. Eye-tracking studies measuring subjects' looking times or anticipatory looking have suggested that implicit and automatic forms of ToM develop much earlier in ontogeny than traditionally assumed and continue to operate outside of subjects’ awareness throughout the lifespan. However, the reliability of these implicit methods has recently been put into question by an increasing number of non-replications. What remains unclear from these accumulating non-replication findings, though, is whether they present true negatives (there is no robust phenomenon of automatic ToM) or false ones (automatic ToM is real but difficult to tap). In order to address these questions, the current study implemented conceptual replications of influential anticipatory looking ToM tasks with a new variation in the stimuli. In two separate preregistered studies, we used increasingly realistic stimuli and controlled for potential confounds. Even with these more realistic stimuli, previous results could not be replicated. Rather, the anticipatory looking pattern found here remained largely compatible with more parsimonious explanations. In conclusion, the reality and robustness of automatic ToM remains controversial.
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  • Journal Article

    Pro-Angiogenic Macrophage Phenotype to Promote Myocardial Repair 

    Ferraro, Bartolo; Leoni, Giovanna; Hinkel, Rabea; Ormanns, Steffen; Paulin, Nicole; Ortega-Gomez, Almudena; Viola, Joana R.; de Jong, Renske; Bongiovanni, Dario; Bozoglu, Tarik; et al.
    Maas, Sanne L.D’Amico, MicheleKessler, ThorstenZeller, TanjaHristov, MichaelReutelingsperger, ChrisSager, Hendrik B.Döring, YvonneNahrendorf, MatthiasKupatt, ChristianSoehnlein, Oliver
    Journal of the American College of Cardiology 2019; 73(23) p.2990-3002
    BACKGROUND: Heart failure following myocardial infarction (MI) remains one of the major causes of death worldwide, and its treatment is a crucial challenge of cardiovascular medicine. An attractive therapeutic strategy is to stimulate endogenous mechanisms of myocardial regeneration. OBJECTIVES: This study evaluates the potential therapeutic treatment with annexin A1 (AnxA1) to induce cardiac repair after MI. METHODS: AnxA1 knockout (AnxA1-/-) and wild-type mice underwent MI induced by ligation of the left anterior descending coronary artery. Cardiac functionality was assessed by longitudinal echocardiographic measurements. Histological, fluorescence-activated cell sorting, dot blot analysis, and in vitro/ex vivo studies were used to assess the myocardial neovascularization, macrophage content, and activity in response to AnxA1. RESULTS: AnxA1-/- mice showed a reduced cardiac functionality and an expansion of proinflammatory macrophages in the ischemic area. Cardiac macrophages from AnxA1-/- mice exhibited a dramatically reduced ability to release the proangiogenic mediator vascular endothelial growth factor (VEGF)-A. However, AnxA1 treatment enhanced VEGF-A release from cardiac macrophages, and its delivery in vivo markedly improved cardiac performance. The positive effect of AnxA1 treatment on cardiac performance was abolished in wild-type mice transplanted with bone marrow derived from Cx3cr1creERT2Vegfflox/flox or in mice depleted of macrophages. Similarly, cardioprotective effects of AnxA1 were obtained in pigs in which full-length AnxA1 was overexpressed by use of a cardiotropic adeno-associated virus. CONCLUSIONS: AnxA1 has a direct action on cardiac macrophage polarization toward a pro-angiogenic, reparative phenotype. AnxA1 stimulated cardiac macrophages to release high amounts of VEGF-A, thus inducing neovascularization and cardiac repair.
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  • Journal Article

    Future Directions for Personality Research: Contributing New Insights to the Understanding of Animal Behavior 

    Wilson, Vanessa; Guenther, Anja; Øverli, Øyvind; Seltmann, Martin W.; Altschul, Drew
    Animals 2019; 9(5): Art. 240
    As part of the European Conference on Behavioral Biology 2018, we organized a symposium entitled, "Animal personality: providing new insights into behavior?" The aims of this symposium were to address current research in the personality field, spanning both behavioral ecology and psychology, to highlight the future directions for this research, and to consider whether differential approaches to studying behavior contribute something new to the understanding of animal behavior. In this paper, we discuss the study of endocrinology and ontogeny in understanding how behavioral variation is generated and maintained, despite selection pressures assumed to reduce this variation. We consider the potential mechanisms that could link certain traits to fitness outcomes through longevity and cognition. We also address the role of individual differences in stress coping, mortality, and health risk, and how the study of these relationships could be applied to improve animal welfare. From the insights provided by these topics, we assert that studying individual differences through the lens of personality has provided new directions in behavioral research, and we encourage further research in these directions, across this interdisciplinary field.
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  • Journal Article

    Species-Specific Conservation of Linear Antigenic Sites on Vaccinia Virus A27 Protein Homologs of Orthopoxviruses 

    Ahsendorf, Henrike; Gan, Li; Eltom, Kamal; Abd El Wahed, Ahmed; Hotop, Sven-Kevin; Roper, Rachel; Beutling, Ulrike; Broenstrup, Mark; Stahl-Hennig, Christiane; Hoelzle, Ludwig; et al.
    Czerny, Claus-Peter
    Viruses 2019; 11(6): Art. 493
    The vaccinia virus (VACV) A27 protein and its homologs, which are found in a large number of members of the genus Orthopoxvirus (OPXV), are targets of viral neutralization by host antibodies. We have mapped six binding sites (epitopes #1A: aa 32-39, #1B: aa 28-33, #1C: aa 26-31, #1D: 28-34, #4: aa 9-14, and #5: aa 68-71) of A27 specific monoclonal antibodies (mAbs) using peptide arrays. MAbs recognizing epitopes #1A-D and #4 neutralized VACV Elstree in a complement dependent way (50% plaque-reduction: 12.5-200 µg/mL). Fusion of VACV at low pH was blocked through inhibition of epitope #1A. To determine the sequence variability of the six antigenic sites, 391 sequences of A27 protein homologs available were compared. Epitopes #4 and #5 were conserved among most of the OPXVs, while the sequential epitope complex #1A-D was more variable and, therefore, responsible for species-specific epitope characteristics. The accurate and reliable mapping of defined epitopes on immuno-protective proteins such as the A27 of VACV enables phylogenetic studies and insights into OPXV evolution as well as to pave the way to the development of safer vaccines and chemical or biological antivirals.
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  • Journal Article

    Ultrafast optogenetic stimulation of the auditory pathway by targeting‐optimized Chronos 

    Keppeler, Daniel; Merino, Ricardo Martins; Lopez de la Morena, David; Bali, Burak; Huet, Antoine Tarquin; Gehrt, Anna; Wrobel, Christian; Subramanian, Swati; Dombrowski, Tobias; Wolf, Fred; et al.
    Rankovic, VladanNeef, AndreasMoser, Tobias
    The EMBO Journal 2018; 37(24): Art. e99649
    Optogenetic tools, providing non‐invasive control over selected cells, have the potential to revolutionize sensory prostheses for humans. Optogenetic stimulation of spiral ganglion neurons (SGNs) in the ear provides a future alternative to electrical stimulation used in cochlear implants. However, most channelrhodopsins do not support the high temporal fidelity pertinent to auditory coding because they require milliseconds to close after light‐off. Here, we biophysically characterized the fast channelrhodopsin Chronos and revealed a deactivation time constant of less than a millisecond at body temperature. In order to enhance neural expression, we improved its trafficking to the plasma membrane (Chronos‐ES/TS). Following efficient transduction of SGNs using early postnatal injection of the adeno‐associated virus AAV‐PHP.B into the mouse cochlea, fiber‐based optical stimulation elicited optical auditory brainstem responses (oABR) with minimal latencies of 1 ms, thresholds of 5 μJ and 100 μs per pulse, and sizable amplitudes even at 1,000 Hz of stimulation. Recordings from single SGNs demonstrated good temporal precision of light‐evoked spiking. In conclusion, efficient virus‐mediated expression of targeting‐optimized Chronos‐ES/TS achieves ultrafast optogenetic control of neurons.
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  • Journal Article

    Guanylate-Binding Proteins 2 and 5 Exert Broad Antiviral Activity by Inhibiting Furin-Mediated Processing of Viral Envelope Proteins 

    Braun, Elisabeth; Hotter, Dominik; Koepke, Lennart; Zech, Fabian; Groß, Rüdiger; Sparrer, Konstantin M.J.; Müller, Janis A.; Pfaller, Christian K.; Heusinger, Elena; Wombacher, Rebecka; et al.
    Sutter, KathrinDittmer, UlfWinkler, MichaelSimmons, GrahamJakobsen, Martin R.Conzelmann, Karl-KlausPöhlmann, StefanMünch, JanFackler, Oliver T.Kirchhoff, FrankSauter, Daniel
    Cell Reports 2019; 27(7): Art. 2104.e10
    Guanylate-binding protein (GBP) 5 is an interferon (IFN)-inducible cellular factor reducing HIV-1 infectivity by an incompletely understood mechanism. Here, we show that this activity is shared by GBP2, but not by other members of the human GBP family. GBP2/5 decrease the activity of the cellular proprotein convertase furin, which mediates conversion of the HIV-1 envelope protein (Env) precursor gp160 into mature gp120 and gp41. Because this process primes HIV-1 Env for membrane fusion, viral particles produced in the presence of GBP2/5 are poorly infectious due to increased incorporation of non-functional gp160. Furin activity is critical for the processing of envelope glycoproteins of many viral pathogens. Consistently, GBP2/5 also inhibit Zika, measles, and influenza A virus replication and decrease infectivity of viral particles carrying glycoproteins of Marburg and murine leukemia viruses. Collectively, our results show that GPB2/5 exert broad antiviral activity by suppressing the activity of the virus-dependency factor furin.
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  • Journal Article

    Catalyzing Transitions to Sociality: Ecology Builds on Parental Care 

    Socias-Martínez, Lluís; Kappeler, Peter M.
    Frontiers in Ecology and Evolution 2019; 7: Art. 160
    In the context of social evolution research, great emphasis on kin-selected benefits has led to an understanding of parental care as one of the activities that helpers can perform in extended cooperative families. Nevertheless, this perspective might have precluded a deeper understanding of the implications of parental care for social evolution. We argue that parental care is a broader set of processes playing a key role both before and during the emergence of sociality. The care system of a species may be understood as the result of long coevolutionary processes with environmental pressures during presocial stages that impact transitions to sociality. We evaluate the present framework against evidence on the evolution of parental care and transitions toward sociality in subsocial and parasocial vertebrate and invertebrate species. Moreover, following previous evidence for the importance of modes of foraging and resting, we structure our inquiry by classifying societies into three types. Our results suggest that in “central place foragers” and “fortress defenders”, ecological factors promoting the evolution of parental care foster a set of coevolutionary feedback loops resulting in increases in parental effort and offspring needs. Offspring needs alone or in combination with limited breeding options enhance the relative benefits of positive social interactions, catalyzing transitions to sociality. In “itinerant foragers”, sociality is associated with colonizing new niches. Changes in predation pressure entail changes in the modes of care or selection for certain types of care already present in solitary ancestors. Further changes in the form of collective defense may be needed for permanent sociality to evolve. We conclude that there is evidence that social transitions to different types of societies are the result of long coevolutionary processes between environmental pressures and the care systems in a wide variety of taxa. Therefore, advances in the study of the origins of sociality may require further investigation of parental care evolution in solitary ancestors of today’s social species.
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  • Journal Article

    Thalamus exhibits less sensory variability quenching than cortex 

    Poland, E.; Donner, T. H.; Müller, K. -M.; Leopold, D. A.; Wilke, M.
    Scientific Reports 2019; 9(1): Art. 7590
    Spiking activity exhibits a large degree of variability across identical trials, which has been shown to be significantly reduced by stimulus onset in a wide range of cortical areas. Whether similar dynamics apply to the thalamus and in particular to the pulvinar is largely unknown. Here, we examined electrophysiological recordings from two adult rhesus macaques performing a perceptual task and comparatively investigated trial-to-trial variability in higher-order thalamus (ventral and dorsal pulvinar), the lateral geniculate nucleus (LGN) and visual cortex (area V4) prior to and following the presentation of a visual stimulus. We found spiking variability during stable fixation prior to stimulus onset to be considerably lower in both pulvinar and the LGN as compared to area V4. In contrast to the prominent variability reduction in V4 upon stimulus onset, variability in the thalamic nuclei was largely unaffected by visual stimulation. There was a small but significant variability decrease in the dorsal pulvinar, but not in the ventral portion of the pulvinar, which is closely connected to visual cortices and would thus have been expected to reflect cortical response properties. This dissociation did not stem from differences in response strength or mean firing rates and indicates fundamental differences in variability quenching between thalamus and cortex.
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  • Journal Article

    Right on track? Performance of satellite telemetry in terrestrial wildlife research 

    Hofman, M. P. G.; Hayward, M. W.; Heim, M.; Marchand, P.; Rolandsen, C. M.; Mattisson, J.; Urbano, F.; Heurich, M.; Mysterud, A.; Melzheimer, J.; et al.
    Morellet, N.Voigt, U.Allen, B. L.Gehr, B.Rouco, C.Ullmann, W.Holand, Ø.Jørgensen, N. H.Steinheim, G.Cagnacci, F.Kroeschel, M.Kaczensky, P.Buuveibaatar, B.Payne, J. C.Palmegiani, I.Jerina, K.Kjellander, P.Johansson, Ö.LaPoint, S.Bayrakcismith, R.Linnell, J. D. C.Zaccaroni, M.Jorge, M. L. S.Oshima, J. E. F.Songhurst, A.Fischer, C.Mc Bride, R. T.Thompson, J. J.Streif, S.Sandfort, R.Bonenfant, C.Drouilly, M.Klapproth, M.Zinner, D.Yarnell, R.Stronza, A.Wilmott, L.Meisingset, E.Thaker, M.Vanak, A. T.Nicoloso, S.Graeber, R.Said, S.Boudreau, M. R.Devlin, A.Hoogesteijn, R.May-Junior, J. A.Nifong, J. C.Odden, J.Quigley, H. B.Tortato, F.Parker, D. M.Caso, A.Perrine, J.Tellaeche, C.Zieba, F.Zwijacz-Kozica, T.Appel, C. L.Axsom, I.Bean, W. T.Cristescu, B.Périquet, S.Teichman, K. J.Karpanty, S.Licoppe, A.Menges, V.Black, K.Scheppers, T. L.Schai-Braun, S. C.Azevedo, F. C.Lemos, F. G.Payne, A.Swanepoel, L. H.Weckworth, B. V.Berger, A.Bertassoni, A.McCulloch, G.Šustr, P.Athreya, V.Bockmuhl, D.Casaer, J.Ekori, A.Melovski, D.Richard-Hansen, C.van de Vyver, D.Reyna-Hurtado, R.Robardet, E.Selva, N.Sergiel, A.Farhadinia, M. S.Sunde, P.Portas, R.Ambarli, H.Berzins, R.Kappeler, P. M.Mann, G. K.Pyritz, L.Bissett, C.Grant, T.Steinmetz, R.Swedell, L.Welch, R. J.Armenteras, D.Bidder, O. R.González, T. M.Rosenblatt, A.Kachel, S.Balkenhol, N.
    PLOS ONE 2019; 14(5): Art. e0216223
    Satellite telemetry is an increasingly utilized technology in wildlife research, and current devices can track individual animal movements at unprecedented spatial and temporal resolutions. However, as we enter the golden age of satellite telemetry, we need an in-depth understanding of the main technological, species-specific and environmental factors that determine the success and failure of satellite tracking devices across species and habitats. Here, we assess the relative influence of such factors on the ability of satellite telemetry units to provide the expected amount and quality of data by analyzing data from over 3,000 devices deployed on 62 terrestrial species in 167 projects worldwide. We evaluate the success rate in obtaining GPS fixes as well as in transferring these fixes to the user and we evaluate failure rates. Average fix success and data transfer rates were high and were generally better predicted by species and unit characteristics, while environmental characteristics influenced the variability of performance. However, 48% of the unit deployments ended prematurely, half of them due to technical failure. Nonetheless, this study shows that the performance of satellite telemetry applications has shown improvements over time, and based on our findings, we provide further recommendations for both users and manufacturers.
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  • Journal Article

    Near physiological spectral selectivity of cochlear optogenetics 

    Dieter, Alexander; Duque-Afonso, Carlos J.; Rankovic, Vladan; Jeschke, Marcus; Moser, Tobias
    Nature Communications 2019; 10(1): Art. 1962
    Cochlear implants (CIs) electrically stimulate spiral ganglion neurons (SGNs) and partially restore hearing to half a million CI users. However, wide current spread from intracochlear electrodes limits spatial selectivity (i.e. spectral resolution) of electrical CIs. Optogenetic stimulation might become an alternative, since light can be confined in space, promising artificial sound encoding with increased spectral selectivity. Here we compare spectral selectivity of optogenetic, electric, and acoustic stimulation by multi-channel recordings in the inferior colliculus (IC) of gerbils. When projecting light onto tonotopically distinct SGNs, we observe corresponding tonotopically ordered IC activity. An activity-based comparison reveals that spectral selectivity of optogenetic stimulation is indistinguishable from acoustic stimulation for modest intensities. Moreover, optogenetic stimulation outperforms bipolar electric stimulation at medium and high intensities and monopolar electric stimulation at all intensities. In conclusion, we demonstrate better spectral selectivity of optogenetic over electric SGN stimulation, suggesting the potential for improved hearing restoration by optical CIs.
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  • Journal Article

    Acoustic variation of spider monkey (Ateles geoffroyi) contact calls is related to caller isolation and affects listeners’ responses 

    Ordóñez-Gómez, José D.; Santillan-Doherty, Ana M.; Hammerschmidt, Kurt
    PLOS ONE 2019; 14(4): Art. e0213914
    Group living animals produce vocalizations denominated "contact calls" to maintain contact with out-of-sight group members. These calls have been shown to vary with caller identity and distance to potential listeners. However, it is not clear whether the acoustic variation of contact calls is related to caller social isolation (e.g., inside or outside a subgroup) and listeners' responses that can be helpful to maintain contact. Here, we addressed these questions in spider monkeys (Ateles geoffroyi), a Neotropical primate that exchanges contact calls denominated "whinnies", which show graded variation related to caller immediate behavior and distance between callers. Using 566 whinnies produced by 35 free-ranging adult spider monkeys recorded at ≤ 20 m from microphones, we first analyzed whether the acoustic variation of spontaneous whinnies (i.e., whinnies that are not responses to previous whinnies) is related to caller social isolation or whether acoustic variation is related to the likelihood of eliciting a response whinny from another individual. Secondly, we assessed whether listeners' responses (i.e., time to respond vocally, acoustic characteristics of response whinnies, orienting behaviors) were related to the acoustic variation of previous whinnies. Our study revealed that callers that were outside a subgroup produced whinnies with a lower fundamental frequency (F0), which travels longer distances, and increases the likelihood of producing a response whinny. Moreover, listeners (i.e., responders) responded faster to lower F0 whinnies. However, the acoustic variation (i.e., F0 variation) in response whinnies was better explained by the separation distance between callers, than by the acoustic variation of the previous whinny. Overall, our results suggest that whinny variation facilitates vocal contact to callers that are outside a subgroup, and that context and whinny variation affect listeners' responses.
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  • Journal Article

    Inhibitors of signal peptide peptidase and subtilisin/kexin-isozyme 1 inhibit Ebola virus glycoprotein-driven cell entry by interfering with activity and cellular localization of endosomal cathepsins 

    Plegge, Teresa; Spiegel, Martin; Krüger, Nadine; Nehlmeier, Inga; Winkler, Michael; González Hernández, Mariana; Pöhlmann, Stefan
    PLOS ONE 2019; 14(4): Art. e0214968
    Emerging viruses such as severe fever and thrombocytopenia syndrome virus (SFTSV) and Ebola virus (EBOV) are responsible for significant morbidity and mortality. Host cell proteases that process the glycoproteins of these viruses are potential targets for antiviral intervention. The aspartyl protease signal peptide peptidase (SPP) has recently been shown to be required for processing of the glycoprotein precursor, Gn/Gc, of Bunyamwera virus and for viral infectivity. Here, we investigated whether SPP is also required for infectivity of particles bearing SFTSV-Gn/Gc. Entry driven by the EBOV glycoprotein (GP) and the Lassa virus glycoprotein (LASV-GPC) depends on the cysteine proteases cathepsin B and L (CatB/CatL) and the serine protease subtilisin/kexin-isozyme 1 (SKI-1), respectively, and was examined in parallel for control purposes. We found that inhibition of SPP and SKI-1 did not interfere with SFTSV Gn + Gc-driven entry but, unexpectedly, blocked entry mediated by EBOV-GP. The inhibition occurred at the stage of proteolytic activation and the SPP inhibitor was found to block CatL/CatB activity. In contrast, the SKI-1 inhibitor did not interfere with CatB/CatL activity but disrupted CatB localization in endo/lysosomes, the site of EBOV-GP processing. These results underline the potential of protease inhibitors for antiviral therapy but also show that previously characterized compounds might exert broader specificity than initially appreciated and might block viral entry via diverse mechanisms.
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  • Journal Article

    Neural coding of intended and executed grasp force in macaque areas AIP, F5, and M1 

    Intveld, Rijk W.; Dann, Benjamin; Michaels, Jonathan A.; Scherberger, Hansjörg
    Scientific Reports 2018; 8(1): Art. 17985
    Considerable progress has been made over the last decades in characterizing the neural coding of hand shape, but grasp force has been largely ignored. We trained two macaque monkeys (Macaca mulatta) on a delayed grasping task where grip type and grip force were instructed. Neural population activity was recorded from areas relevant for grasp planning and execution: the anterior intraparietal area (AIP), F5 of the ventral premotor cortex, and the hand area of the primary motor cortex (M1). Grasp force was strongly encoded by neural populations of all three areas, thereby demonstrating for the first time the coding of grasp force in single- and multi-units of AIP. Neural coding of intended grasp force was most strongly represented in area F5. In addition to tuning analysis, a dimensionality reduction method revealed low-dimensional responses to grip type and grip force. Additionally, this method revealed a high correlation between latent variables of the neural population representing grasp force and the corresponding latent variables of electromyographic forearm muscle activity. Our results therefore suggest an important role of the cortical areas AIP, F5, and M1 in coding grasp force during movement execution as well as of F5 for coding intended grasp force.
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  • Journal Article

    Peri-hand space expands beyond reach in the context of walk-and-reach movements 

    Berger, Michael; Neumann, Peter; Gail, Alexander
    Scientific Reports 2019; 9(1): Art. 3013
    The brain incorporates sensory information across modalities to be able to interact with our environment. The peripersonal space (PPS), defined by a high level of crossmodal interaction, is centered on the relevant body part, e.g. the hand, but can spatially expand to encompass tools or reach targets during goal-directed behavior. Previous studies considered expansion of the PPS towards goals within immediate or tool-mediated reach, but not the translocation of the body as during walking. Here, we used the crossmodal congruency effect (CCE) to quantify the extension of the PPS and test if PPS can also expand further to include far located walk-and-reach targets accessible only by translocation of the body. We tested for orientation specificity of the hand-centered reference frame, asking if the CCE inverts with inversion of the hand orientation during reach. We show a high CCE with onset of the movement not only towards reach targets but also walk-and-reach targets. When participants must change hand orientation, the CCE decreases, if not vanishes, and does not simply invert. We conclude that the PPS can expand to the action space beyond immediate or tool-mediated reaching distance but is not purely hand-centered with respect to orientation.
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  • Journal Article

    Non-invasive genotyping with a massively parallel sequencing panel for the detection of SNPs in HPA-axis genes 

    Gutleb, D. R.; Ostner, J.; Schülke, O.; Wajjwalku, W.; Sukmak, M.; Roos, C.; Noll, A.
    Scientific Reports 2018; 8(1): Art. 15944
    We designed a genotyping panel for the investigation of the genetic underpinnings of inter-individual differences in aggression and the physiological stress response. The panel builds on single nucleotide polymorphisms (SNPs) in genes involved in the three subsystems of the hypothalamic-pituitary-adrenal (HPA)-axis: the catecholamine, serotonin and corticoid metabolism. To promote the pipeline for use with wild animal populations, we used non-invasively collected faecal samples from a wild population of Assamese macaques (Macaca assamensis). We targeted loci of 46 previously reported SNPs in 21 candidate genes coding for elements of the HPA-axis and amplified and sequenced them using next-generation Illumina sequencing technology. We compared multiple bioinformatics pipelines for variant calling and variant effect prediction. Based on this strategy and the application of different quality thresholds, we identified up to 159 SNPs with different types of predicted functional effects among our natural study population. This study provides a massively parallel sequencing panel that will facilitate integrating large-scale SNP data into behavioural and physiological studies. Such a multi-faceted approach will promote understanding of flexibility and constraints of animal behaviour and hormone physiology.
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  • Journal Article

    Functional analysis of potential cleavage sites in the MERS-coronavirus spike protein 

    Kleine-Weber, Hannah; Elzayat, Mahmoud Tarek; Hoffmann, Markus; Pöhlmann, Stefan
    Scientific Reports 2018; 8(1): Art. 16597
    The Middle East respiratory syndrome-related coronavirus (MERS-CoV) can cause severe disease and has pandemic potential. Therefore, development of antiviral strategies is an important task. The activation of the viral spike protein (S) by host cell proteases is essential for viral infectivity and the responsible enzymes are potential therapeutic targets. The cellular proteases furin, cathepsin L and TMPRSS2 can activate MERS-S and may cleave the S protein at two distinct sites, termed S1/S2 and S2'. Moreover, a potential cathepsin L cleavage site in MERS-S has been reported. However, the relative importance of these sites for MERS-S activation is incompletely understood. Here, we used mutagenic analysis and MERS-S-bearing vectors to study the contribution of specific cleavage sites to S protein-driven entry. We found that an intact S1/S2 site was only required for efficient entry into cells expressing endogenous TMPRSS2. In keeping with a previous study, pre-cleavage at the S1/S2 motif (RSVR) was important although not essential for subsequent MERS-S activation by TMPRSS2, and indirect evidence was obtained that this motif is processed by a protease depending on an intact RXXR motif, most likely furin. In contrast, the S2' site (RSAR) was required for robust viral entry into all cell lines tested and the integrity of one of the two arginines was sufficient for efficient entry. These findings suggest that cleavage at S2' is carried out by proteases recognizing a single arginine, most likely TMPRSS2 and cathepsin L. Finally, mutation of the proposed cathepsin L site did not impact viral entry and double mutation of S1/S2 and S2' site was compatible with cathepsin L- but not TMPRSS2-dependent host cell entry, indicating that cathepsin L can process the S protein at auxiliary sites. Collectively, our results indicate a rigid sequence requirement for S protein activation by TMPRSS2 but not cathepsin L.
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  • Journal Article

    Clarifying and expanding the social complexity hypothesis for communicative complexity 

    Peckre, Louise; Kappeler, Peter M.; Fichtel, Claudia
    Behavioral Ecology and Sociobiology 2019; 73(11)
    Variation in communicative complexity has been conceptually and empirically attributed to social complexity, with animals living in more complex social environments exhibiting more signals and/or more complex signals than animals living in simpler social environments.As compelling as studies highlighting a link between social and communicative variables are, this hypothesis remains challenged by operational problems, contrasting results, and several weaknesses of the associated tests. Specifically, how to best operationalize social and communicative complexity remains debated; alternative hypotheses, such as the role of a species’ ecology, morphology, or phylogenetic history, have been neglected; and the actual ways in which variation in signaling is directly affected by social factors remain largely unexplored. In this review, we address these three issues and propose an extension of the Bsocial complexity hypothesis for communicative complexity^ that resolves and acknowledges the above factors.We specifically argue for integrating the inherently multimodal nature of communication into a more comprehensive framework and for acknowledging the social context of derived signals and the potential of audience effects. By doing so, we believe it will be possible to generate more accurate predictions about which specific social parameters may be responsible for selection on new or more complex signals, as well as to uncover potential adaptive functions that are not necessarily apparent from studying communication in only one modality.
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  • Journal Article

    Human lung tissue provides highly relevant data about efficacy of new anti-asthmatic drugs 

    Danov, Olga; Jiménez Delgado, Sharon Melissa; Obernolte, Helena; Seehase, Sophie; Dehmel, Susann; Braubach, Peter; Fieguth, Hans-Gerd; Matschiner, Gabriele; Fitzgerald, Mary; Jonigk, Danny; et al.
    Knauf, SaschaPfennig, OlafWarnecke, GregorWichmann, JudyBraun, ArminSewald, Katherina
    PlOS ONE 2018; 13(11): Art. e0207767
    Subgroups of patients with severe asthma are insensitive to inhaled corticosteroids and require novel therapies on top of standard medical care. IL-13 is considered one of the key cytokines in the asthma pathogenesis, however, the effect of IL-13 was mostly studied in rodents. This study aimed to assess IL-13 effect in human lung tissue for the development of targeted therapy approaches such as inhibition of soluble IL-13 or its receptor IL-4Rα subunit. Precision-cut lung slices (PCLS) were prepared from lungs of rodents, non-human primates (NHP) and humans. Direct effect of IL-13 on human lung tissue was observed on inflammation, induction of mucin5AC, and airway constriction induced by methacholine and visualized by videomicroscopy. Anti-inflammatory treatment was evaluated by co-incubation of IL-13 with increasing concentrations of IL-13/IL-13 receptor inhibitors. IL-13 induced a two-fold increase in mucin5AC secretion in human bronchial tissue. Additionally, IL-13 induced release of proinflammatory cytokines eotaxin-3 and TARC in human PCLS. Anti-inflammatory treatment with four different inhibitors acting either on the IL-13 ligand itself (anti-IL-13 antibody, similar to Lebrikizumab) or the IL-4Rα chain of the IL-13/IL-4 receptor complex (anti-IL-4Rα #1, similar to AMG 317, and #2, similar to REGN668) and #3 PRS-060 (a novel anticalin directed against this receptor) could significantly attenuate IL-13 induced inflammation. Contrary to this, IL-13 did not induce airway hyperresponsiveness (AHR) in human and NHP PCLS, although it was effective in rodent PCLS. Overall, this study demonstrates that IL-13 stimulation induces production of mucus and biomarkers of allergic inflammation in human lung tissue ex-vivo but no airway hyperresponsiveness. The results of this study show a more distinct efficacy than known from animals models and a clear discrepancy in AHR induction. Moreover, it allows a translational approach in inhibitor profiling in human lung tissue.
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  • Journal Article

    A system for production of defective interfering particles in the absence of infectious influenza A virus 

    Bdeir, Najat; Arora, Prerna; Gärtner, Sabine; Hoffmann, Markus; Reichl, Udo; Pöhlmann, Stefan; Winkler, Michael
    PlOS ONE 2019; 14(3): Art. e0212757
    Influenza A virus (IAV) infection poses a serious health threat and novel antiviral strategies are needed. Defective interfering particles (DIPs) can be generated in IAV infected cells due to errors of the viral polymerase and may suppress spread of wild type (wt) virus. The antiviral activity of DIPs is exerted by a DI genomic RNA segment that usually contains a large deletion and suppresses amplification of wt segments, potentially by competing for cellular and viral resources. DI-244 is a naturally occurring prototypic segment 1-derived DI RNA in which most of the PB2 open reading frame has been deleted and which is currently developed for antiviral therapy. At present, coinfection with wt virus is required for production of DI-244 particles which raises concerns regarding biosafety and may complicate interpretation of research results. Here, we show that cocultures of 293T and MDCK cell lines stably expressing codon optimized PB2 allow production of DI-244 particles solely from plasmids and in the absence of helper virus. Moreover, we demonstrate that infectivity of these particles can be quantified using MDCK-PB2 cells. Finally, we report that the DI-244 particles produced in this novel system exert potent antiviral activity against H1N1 and H3N2 IAV but not against the unrelated vesicular stomatitis virus. This is the first report of DIP production in the absence of infectious IAV and may spur efforts to develop DIPs for antiviral therapy.
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  • Journal Article

    Diagnosing Zika virus infection against a background of other flaviviruses: Studies in high resolution serological analysis. 

    Hansen, Sören; Hotop, Sven-Kevin; Faye, Oumar; Ndiaye, Oumar; Böhlken-Fascher, Susanne; Pessôa, Rodrigo; Hufert, Frank; Stahl-Hennig, Christiane; Frank, Ronald; Czerny, Claus-Peter; et al.
    Schmidt-Chanasit, JonasSanabani, Sabri S.Sall, Amadou A.Niedrig, MatthiasBrönstrup, MarkFritz, Hans-JoachimAbd El Wahed, Ahmed
    Scientific Reports 2019; 9(1): Art. 3648
    Zika virus (ZIKV) is a mosquito-borne flavivirus. Homologous proteins of different flaviviruses display high degrees of sequence identity, especially within subgroups. This leads to extensive immunological cross-reactivity and corresponding problems for developing a ZIKV-specific serological assay. In this study, peptide microarrays were employed to identify individual ZIKV antibody targets with promise in differential diagnosis. A total of 1643 overlapping oligopeptides were synthesized and printed onto glass slides. Together, they encompass the full amino acid sequences of ZIKV proteomes of African, Brazilian, USA, and French Polynesian origins. The resulting ZIKV scanning microarray chips were used to screen three pools of sera from recent Zika outbreaks in Senegal and Cape Verde, in Brazil, and from overseas travelers returning to the EU. Together with a mixed pool of well characterized, archived sera of patients suffering from infections by dengue, yellow fever, tick-borne encephalitis, and West Nile viruses, a total of 42 sera went into the study. Sixty-eight antibody target regions were identified. Most of which were hitherto unknown. Alignments and sequence comparisons revealed 13 of which could be classified as bona fide ZIKV-specific. These identified antibody target regions constitute a founding set of analytical tools for serological discrimination of ZIKV from other flaviviruses.
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