Thomas Müller

Goethe-Universität Frankfurt am Main, Frankfurt, Hesse, Germany

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Publications (116)330.57 Total impact

  • No preview · Article · Dec 2015 · Ecology
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    ABSTRACT: Background: Vaccines are the most effective prophylactic public health tools. With the help of vaccines, prevention of infectious disease spread and, in concert with other measures, even eradication has become possible. Until now, licensing and quality control require the determination of consensus genome sequences of replication competent infectious agents contained in vaccines. Recent improvements in sequencing technologies now enable the sequencing of complete genomes and the genetic analysis of populations with high reliability and resolution. The latter is particularly important for RNA viruses, which consist of fluctuating heterogeneous populations rather than genetically stable entities. This information now has to be integrated into the existing regulatory framework, challenging both licensing authorities and vaccine producers to develop new quality control criteria. Methods: Commercially available modified-live oral rabies vaccines and their precursor strains were deep-sequenced to assess strain identity and relations between strains based on population diversity. Strain relations were inferred based on the Manhattan distances calculated between the compositions of the viral populations of the strains. Results: We provide a novel approach to assess viral strain relations with high resolution and reliability by deep sequencing with subsequent analysis of the overall genetic diversity within the viral populations. A comparison of our novel approach of inferring strain relations based on population data with consensus sequence analysis clearly shows that consensus sequence analysis of diverse viral populations can be misleading. Therefore, for quality control of viral vaccines deep sequencing analysis is to be preferred over consensus sequence analysis. Conclusions: The presented methodology allows for routine integration of deep sequencing data in vaccine quality control and licensing for highly reliable assessment of strain identity and stability.
    No preview · Article · Sep 2015 · Vaccine
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    ABSTRACT: In 2005, six patients in Germany received solid organs and both corneas from a donor with an unrecognized rabies infection. Initial virological diagnostics with the machinery available at the two national reference laboratories could quickly clarify the situation. Rabies virus antigen was detected in the organ donor's brain. In two of the three recipients with neurological alterations, intra vitam diagnosis was achieved by conventional RT-PCRs. Comparison of the phylogenetic relatedness of the different viral isolates proved transmission from the donor and, consequently, also established the diagnosis for the third patient. As indicated by the titre of neutralizing antibodies, the liver transplant recipient was protected from the lethal infection due to a vaccination against rabies virus, which he had received more than 15 years ago. All samples from the recipients of the corneas were invariably negative. Re-evaluation of the molecular data by real-time PCR did not lead to an improvement of intra vitam diagnosis but provided intriguing insights regarding the relative amounts of rabies virus RNA in different body fluids and peripheral organs. In saliva and skin, they were 250-200,000 times lower than in the infected patient's brains. Furthermore, in saliva samples taken serially from the same patient fluctuations by a factor of 160-500 were recorded. These findings highlight the problems of intra vitam diagnosis of rabies virus infections and make understandable why the virus can escape from all diagnostic attempts. Finally, in this context one should recall an almost trivial fact: Simple and appropriate postexposure prophylaxis could not only have saved the young organ donor's life but would also have prevented the whole transplantation-associated rabies "outbreak" in Germany.
    No preview · Article · Sep 2015 · International journal of medical microbiology: IJMM
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    ABSTRACT: A brain sample of a straw-coloured fruit bat (Eidolon helvum) from Ghana without evident signs of disease tested positive by generic Lyssavirus RT-PCR and direct antigen staining. Sequence analysis confirmed the presence of a Lagos bat virus belonging to phylogenetic lineage A. Virus neutralization tests using the isolate with sera from the same group of bats yielded neutralizing antibodies in 74% of 567 animals. No cross-neutralization was observed against a different Lagos bat virus (lineage B). Copyright © 2015. Published by Elsevier B.V.
    No preview · Article · Jul 2015 · Virus Research
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    ABSTRACT: Aiming to achieve new insights into rabies dynamics, this paper is the first to investigate fox rabies in Germany from a space-time pattern perspective. Based on a locally restricted dataset covering a fourteen month period, our findings indicate a strongly aggregated spatiotemporal point pattern resulting from an inhomogeneous stochastic process. In contrast to spatial or temporal approaches or cellular automata, our analysis focuses on the disease dynamics in time and space in a continuous time domain. Our findings confirm existing theories regarding fox rabies control highlighting the potential risk of urban areas and the need for effective rabies vaccination.
    Preview · Article · May 2015 · Geospatial health
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    ABSTRACT: Rabies is a notoriously underreported and neglected disease of low-income countries. This study aims to estimate the public health and economic burden of rabies circulating in domestic dog populations, globally and on a country-by-country basis, allowing an objective assessment of how much this preventable disease costs endemic countries. We established relationships between rabies mortality and rabies prevention and control measures, which we incorporated into a model framework. We used data derived from extensive literature searches and questionnaires on disease incidence, control interventions and preventative measures within this framework to estimate the disease burden. The burden of rabies impacts on public health sector budgets, local communities and livestock economies, with the highest risk of rabies in the poorest regions of the world. This study estimates that globally canine rabies causes approximately 59,000 (95% Confidence Intervals: 25-159,000) human deaths, over 3.7 million (95% CIs: 1.6-10.4 million) disability-adjusted life years (DALYs) and 8.6 billion USD (95% CIs: 2.9-21.5 billion) economic losses annually. The largest component of the economic burden is due to premature death (55%), followed by direct costs of post-exposure prophylaxis (PEP, 20%) and lost income whilst seeking PEP (15.5%), with only limited costs to the veterinary sector due to dog vaccination (1.5%), and additional costs to communities from livestock losses (6%). This study demonstrates that investment in dog vaccination, the single most effective way of reducing the disease burden, has been inadequate and that the availability and affordability of PEP needs improving. Collaborative investments by medical and veterinary sectors could dramatically reduce the current large, and unnecessary, burden of rabies on affected communities. Improved surveillance is needed to reduce uncertainty in burden estimates and to monitor the impacts of control efforts.
    Full-text · Article · Apr 2015 · PLoS Neglected Tropical Diseases
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    ABSTRACT: Animal migration is a global phenomenon, but few studies have examined the substantial within- and between-species variation in migration distances. We built a global database of 94 land migrations of large mammalian herbivore populations ranging from 10 to 1638 km. We examined how resource availability, spatial scale of resource variability and body size affect migration distance among populations. Resource availability measured as normalised difference vegetation index had a strong negative effect, predicting a tenfold difference in migration distances between low- and high-resource areas and explaining 23% of the variation in migration distances. We found a weak, positive effect of the spatial scale of resource variability but no effect of body size. Resource-poor environments are known to increase the size of mammalian home ranges and territories. Here, we demonstrate that for migratory populations as well, animals living in resource-poor environments travel farther to fulfil their resource needs. © 2015 John Wiley & Sons Ltd/CNRS.
    No preview · Article · Apr 2015 · Ecology Letters
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    ABSTRACT: Author Summary Despite being one of the oldest recognised infectious diseases, rabies continues to cause thousands of preventable human deaths per year. As a zoonotic disease, control of infection in the reservoir has been proven the most efficient route to reduction of human cases. In some regions, the epidemiology is well understood, with either dogs or wildlife known to be the primary reservoir and with little or no movement from, or into other regions. This is not the case in the Middle East, where rabies is underreported in animals and humans, there is little laboratory confirmation of infection, and the extent of rabies spread from country to country is not known. Previous studies have demonstrated trans-boundary movement of rabies but have been limited by a low number of available samples from some countries, and the direction of spread has been difficult to estimate. Here we use rabies virus partial genome sequences of 183 viruses from over 20 countries, combined with geographical and temporal information, to reconstruct the evolution of rabies viruses circulating in the Middle East. The results reveal an apparent barrier to spread between some regions but regular movement between others. These analyses will support policy on rabies control by indicating the relative importance of local control and animal movement restrictions when allocating resources.
    Full-text · Article · Mar 2015 · PLoS Neglected Tropical Diseases
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    ABSTRACT: Quantifying animals' home ranges is a key problem in ecology and has important conservation and wildlife management applications. Kernel density estimation (KDE) is a workhorse technique for range delineation problems that is both statistically efficient and nonparametric. KDE assumes that the data are independent and identically distributed (IID). However, animal tracking data, which are routinely used as inputs to KDEs, are inherently autocorrelated and violate this key assumption. As we demonstrate, using realistically autocorrelated data in conventional KDEs results in grossly underestimated home ranges. We further show that the performance of conventional KDEs actually degrades as data quality improves, because autocorrelation strength increases as movement paths become more finely resolved. To remedy these flaws with the traditional KDE method, we derive an autocorrelated KDE (AKDE) from first principles to use autocorrelated data, making it perfectly suited for movement data sets. We illustrate the vastly improved performance of AKDE using analytical arguments, relocation data from Mongolian gazelles, and simulations based upon the gazelle's observed movement process. By yielding better minimum area estimates for threatened wildlife populations, we believe that future widespread use of AKDE will have significant impact on ecology and conservation biology.
    No preview · Article · Jan 2015 · Ecology
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    ABSTRACT: Rabies is one of the oldest known zoonoses. Recognized etiological agents consist of at least 15 proposed species of lyssaviruses with primary reservoirs residing in the Orders Carnivora and Chiroptera. A plethora of viral variants, maintained by a diverse set of abundant hosts, presents a formidable challenge to a strict concept of true disease eradication. Despite the availability of affordable and efficacious animal and human vaccines, today however dog rabies continues to escalate unabated across much of Asia and Africa, causing millions of suspect human exposures and tens of thousands of human rabies deaths annually. By identifying what hampers global human rabies elimination this chapter emphasizes that, given the global epidemiology of rabies, the “One Health” concept is key to solving the problem. Next to state of the art human rabies prevention, immunization and experimental therapy, it is obvious that human rabies can only be eliminated through rabies control at the animal source. This ‘paradigm shift’, however, needs new grassroot initiatives as well as political will and the closing of ranks of all stakeholders in the near future.
    No preview · Chapter · Jan 2015
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    ABSTRACT: Due to the implementation of oral rabies vaccination (ORV) programmes, the European Union (EU) is becoming progressively free of red fox (Vulpes vulpes)-mediated rabies. Over the past three decades, the incidence of rabies had decreased substantially and vast areas of Western and Central Europe have been freed from rabies using this method of controlling an infectious disease in wildlife. Since rabies control is a top priority in the EU, the disease is expected to be eliminated from the animal source in the near future. While responsible authorities may consider the mission of eliminating fox rabies from the EU almost accomplished, there are still issues to be dealt with and challenges to be met that have not yet been in the focus of attention, but could jeopardise the ultimate goal. Among them are increasing illegal movements of animals, maintaining funding support for vaccination campaigns, devising alternative vaccine strategies in neighbouring Eastern European countries and the expanding distribution range of several potential rabies reservoir species in Europe.
    No preview · Article · Oct 2014 · The Veterinary Journal
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    ABSTRACT: The European Union has used IPA (Instrument for Pre-Accession) funds to provide technical assistance and supplies for the eradication, monitoring and control of rabies in several pre-Accession countries. As a result, since 2010, multi-annual oral rabies vaccination (ORV) programmes for eliminating fox rabies have been launched in six Western Balkan countries. Here the implementation of the ORV programme in Kosovo, the smallest of the West Balkan countries, is described. Associated challenges under difficult political conditions, potential biases, and the results of rabies surveillance and monitoring of ORV campaigns (bait-uptake and immunisation rates) since 2010 are reported.
    Full-text · Article · Oct 2014 · International Journal of Medical Microbiology
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    ABSTRACT: Background: Rabies is a neglected zoonotic disease caused by viruses belonging to the genus lyssavirus. In endemic countries of Asia and Africa, where the majority of the estimated 60,000 human rabies deaths occur, it is mainly caused by the classical rabies virus (RABV) transmitted by dogs. Over the last decade new species within the genus lyssavirus have been identified. Meanwhile 15 (proposed or classified) species exist, including Australian bat lyssavirus (ABLV), European bat lyssavirus (EBLV-1 and -2), Duvenhage virus (DUVV), as well as Lagos bat virus (LBV) and Mokola virus (MOKV) and recently identified novel species like Bokeloh bat lyssavirus (BBLV), Ikoma bat lyssavirus (IKOV) or Lleida bat lyssavirus (LLBV). The majority of these lyssavirus species are found in bat reservoirs and some have caused human infection and deaths. Previous work has demonstrated that Purified Chick Embryo Cell Rabies Vaccine (PCECV) not only induces immune responses against classical RABV, but also elicits cross-neutralizing antibodies against ABLV, EBLV-1 and EBLV-2. Material & methods: Using the same serum samples as in our previous study, this study extension investigated cross-neutralizing activities of serum antibodies measured by rapid fluorescent focus inhibition test (RFFIT) against selected other non-classical lyssavirus species of interest, namely DUVV and BBLV, as well as MOKV and LBV. Results: Antibodies developed after vaccination with PCECV have neutralizing capability against BBLV and DUVV in the same range as against ABLV and EBLV-1 and -2. As expected, for the phylogenetically more distant species LBV no cross-neutralizing activity was found. Interestingly, 15 of 94 serum samples (16%) with a positive neutralizing antibody titer against RABV displayed specific cross-neutralizing activity (65-fold lower than against RABV) against one specific MOKV strain (Ethiopia isolate), which was not seen against a different strain (Nigeria isolate). Conclusion: Cross-neutralizing activities partly correlate with the phylogenetic distance of the virus species. Cross-neutralizing activities against the species BBLV and DUVV of phylogroup 1 were demonstrated, in line with previous results of cross-neutralizing activities against ABLV and EBLV-1 and -2. Potential partial cross-neutralizing activities against more distant lyssavirus species like selected MOKV strains need further research.
    Full-text · Article · Oct 2014 · Human Vaccines and Immunotherapeutics
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    ABSTRACT: Large scale vaccination with glycoprotein E (gE)-deleted marker vaccines and the rapid and reliable differentiation of wild-type and marker vaccine strains are important aspects in eradication programs for Suid herpesvirus 1 [SuHV-1, syn. Aujeszky's disease virus (ADV) or pseudorabies virus (PrV)]. Therefore, two multiplex real-time PCR (qPCR) assays for the genetic differentiation of wild-type and gE-deleted vaccine SuHV-1 strains have been developed. In the first multiplex qPCR SuHV-1 gB-gene specific detection was combined with a gE-gene specific assay and an internal control based on heterologous DNA. In the second system, a SuHV-1 UL19 (major capsid protein gene) assay, a different gE-gene specific assay and an internal control based on the beta-actin gene were combined. The gB-gene, UL19 as well as both gE-gene specific assays had an analytical sensitivity of less than 10 genome copies per reaction in the respective multiplex approaches. A series of reference strains including field isolates obtained from domestic and wild animals, and gE-deleted SuHV-1 were reliably detected, while genetically related non-SuHV-1 herpesviruses tested negative. Both newly developed triplex SuHV-1-specific qPCR assays are specific and sensitive methods for the rapid genetic differentiation of wild-type viruses and gE-deleted vaccine strains in a single reaction.
    No preview · Article · Sep 2014 · Journal of Virological Methods
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    ABSTRACT: Background/Question/Methods Kernel-density estimation (KDE) is unique in its role as a statistically efficient yet non-parametric method for estimating the probability-density function of independent and identically distributed data. Despite its widespread application to home-range estimation, animal tracking data violates the underlying assumption of independence via the presence of autocorrelation. Here, we rederive the kernel-density estimator from first principles, dropping the assumption of independence, and allowing for the presence of autocorrelation. Our new kernel-density estimator is valid for autocorrelated data, which makes it perfectly suited for movement data. Results/Conclusions We test our method against both real and simulated data using a sample of Mongolian gazelles and their previously identified autocorrelated movement model. For the individual gazelle with the longest span of data, our autocorrelated KDE predicts a home-range area of 350,000 -- 800,000 km2, while the conventional estimate is only 46,000 -- 53,000 km2. These results are consistent with those from simulated data. As the sampling rate increases and data quality improves, the conventional home-range estimate shrinks with tightening confidence intervals.
    No preview · Conference Paper · Aug 2014
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    ABSTRACT: 1. Reproductive asynchrony, a temporal mismatch in reproductive maturation between an individual and potential mates, may contribute to mate-finding failure and Allee effects that influence the establishment and spread of invasive species. Variation in elevation is likely to promote variability in maturation times for species with temperature-dependent development, but it is not known how strongly this influences reproductive asynchrony or the population growth of invasive species.2. We examined whether spatial variation in reproductive asynchrony, due to differences in elevation and local heterogeneity in elevation (hilliness), can explain spatial heterogeneity in the population growth rate of the gypsy moth, Lymantria dispar (L.), along its invasion front in Virginia and West Virginia, USA.3. We used a spatially explicit model of the effects of reproductive asynchrony on mating success to develop predictions of the influences of elevation and elevational heterogeneity on local population growth rates. Population growth rates declined with increased elevation and more modestly with increased elevational heterogeneity. As in earlier work, we found a positive relationship between the population growth rate and the number of introduced egg masses, indicating a demographic Allee effect. At high elevations and high heterogeneity in elevation, the population growth rate was lowest and the density at which the population tended to replace itself (i.e., the Allee threshold) was highest.4. An analysis of 22 years of field data also showed decreases in population growth rates with elevation and heterogeneity in elevation that were largely consistent with the model predictions. 5. These results highlight how topographic characteristics can affect reproductive asynchrony and influence mate-finding Allee effects in an invading non-native insect population. Given the dependence of developmental rates on temperature in poikilotherms, topographic effects on reproductive success could potentially be important to the population dynamics of many organisms.This article is protected by copyright. All rights reserved.
    No preview · Article · Aug 2014 · Journal of Animal Ecology
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    ABSTRACT: Many animals hoard seeds for later consumption and establish seed caches that are often located at sites with specific environmental characteristics. One explanation for the selection of non-random caching locations is the avoidance of pilferage by other animals. Another possible hypothesis is that animals choose locations that hamper the perishability of stored food, allowing the consumption of unspoiled food items over long time periods.We examined seed perishability and pilferage avoidance as potential drivers for caching behaviour of spotted nutcrackers (Nucifraga caryocatactes) in the Swiss Alps where the birds are specialized on caching seeds of Swiss stone pine (Pinus cembra).We used seedling establishment as an inverse measure of seed perishability, as established seedlings cannot longer be consumed by nutcrackers. We recorded the environmental conditions (i.e. canopy openness and soil moisture) of seed caching, seedling establishment and pilferage sites.Our results show that sites of seed caching and seedling establishment had opposed microenvironmental conditions. Canopy openness and soil moisture were negatively related to seed caching but positively related to seedling establishment, i.e. nutcrackers cached seeds preferentially at sites where seed perishability was low. We found no effects of environmental factors on cache pilferage, i.e. neither canopy openness nor soil moisture had significant effects on pilferage rates. We thus could not relate caching behaviour to pilferage avoidance.Our study highlights the importance of seed perishability as a mechanism for seed-caching behaviour, which should be considered in future studies. Our findings could have important implications for the regeneration of plants whose seeds are dispersed by seed-caching animals, as the potential of seedlings to establish may strongly decrease if animals cache seeds at sites that favour seed perishability rather than seedling establishment.
    Full-text · Article · Aug 2014 · Journal of Animal Ecology
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    ABSTRACT: Studies on the ranging behaviour of birds often suggest that ranges vary seasonally with larger ranges in the non-breeding compared to the breeding season. However, due to limitations in tracking methods very little is known about the underlying processes driving seasonal differences in ranging behaviour, especially in fragmented, heterogeneous landscapes. Such knowledge is particularly important if movements deliver essential ecosystem functions such as seed dispersal. We contrasted the daily ranging behaviour between the breeding and non-breeding season of a frugivorous bird and demonstrate how larger seasonal ranges in the non-breeding season emerge through switching from a stationary home range behaviour to nomadism. We tracked movements of 29 male trumpeter hornbills Bycanistes bucinator across a fragmented landscape of eastern South Africa during different breeding and non-breeding seasons using high temporal resolution GPS data-loggers. Birds in the breeding seasons showed a typical, stationary home range pattern. In the non-breeding seasons birds, rather than expanding their stationary daily ranges, switched to nomadic movements that were characterized by shifts of the general location of daily ranges to a different area every couple of days. We also found that during the breeding seasons hornbills were mostly located in large continuous forests; birds in the non-breeding seasons frequently used forest patches within the agricultural landscape and residential areas. These seasonal differences in the movement behaviour of trumpeter hornbills may have important consequences for seed dispersal of plant species. Our findings show how seasonal range expansion of frugivorous birds may be driven by fundamental behavioural changes that have important consequences for ecosystem processes.
    No preview · Article · Jun 2014 · Ecography
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    ABSTRACT: Long-term trends in photosynthetic capacity measured with the satellite-derived Normalized Difference Vegetation Index (NDVI) are usually associated with climate change. Human impacts on the global land surface are typically not accounted for. Here, we provide the first global analysis quantifying the effect of the earth's human footprint on NDVI trends. Globally, more than 20% of the variability in NDVI trends was explained by anthropogenic factors such as land use, nitrogen fertilization, and irrigation. Intensely used land classes, such as villages, showed the greatest rates of increase in NDVI, more than twice than those of forests. These findings reveal that factors beyond climate influence global long-term trends in NDVI and suggest that global climate change models and analyses of primary productivity should incorporate land use effects.
    Preview · Article · Jun 2014 · Remote Sensing
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    ABSTRACT: Abstract Understanding animal movement is a key challenge in ecology and conservation biology. Relocation data often represent a complex mixture of different movement behaviors, and reliably decomposing this mix into its component parts is an unresolved problem in movement ecology. Traditional approaches, such as composite random walk models, require that the timescales characterizing the movement are all similar to the usually arbitrary data-sampling rate. Movement behaviors such as long-distance searching and fine-scale foraging, however, are often intermixed but operate on vastly different spatial and temporal scales. An approach that integrates the full sweep of movement behaviors across scales is currently lacking. Here we show how the semivariance function (SVF) of a stochastic movement process can both identify multiple movement modes and solve the sampling rate problem. We express a broad range of continuous-space, continuous-time stochastic movement models in terms of their SVFs, connect them to relocation data via variogram regression, and compare them using standard model selection techniques. We illustrate our approach using Mongolian gazelle relocation data and show that gazelle movement is characterized by ballistic foraging movements on a 6-h timescale, fast diffusive searching with a 10-week timescale, and asymptotic diffusion over longer timescales.
    Full-text · Article · May 2014 · The American Naturalist

Publication Stats

2k Citations
330.57 Total Impact Points


  • 2013-2015
    • Goethe-Universität Frankfurt am Main
      Frankfurt, Hesse, Germany
    • Loyola University Maryland
      Baltimore, Maryland, United States
    • Institute of Molecular Biology
      Mayence, Rheinland-Pfalz, Germany
  • 2008-2015
    • University of Maryland, College Park
      • Department of Biology
      CGS, Maryland, United States
  • 2005-2015
    • Friedrich Loeffler Institute
      • • Institute of Molecular Biology
      • • Institute of Epidemiology
      Griefswald, Mecklenburg-Vorpommern, Germany
  • 2010
    • MSD Animal Health, Germany
      Schleisheim, Bavaria, Germany
  • 2009
    • Philipps University of Marburg
      Marburg, Hesse, Germany