Private Diplomats, Mediation Professionals, and Peace Activists: Can Non-governmental Actors Bring Peace to Civil Wars?

This dissertation investigates how actors without the means of state power can affect the behavior of warring parties in order to end civil conflicts. Drawing on the intervention and mediation literature, I propose a theoretical framework that presents causal mechanisms for various forms of non-state conflict management to contribute to conflict resolution. The research distinguishes between direct mediation, capacity-building, and problem-solving approaches, and analyzes the approaches’ potential contributions to shorter wars and more sustainable peace. On the one hand, non-state actors can be substitutes for governmental or inter-governmental mediators. They derive legitimacy from long-standing relations with the conflict parties, and their claims to neutrality are more believable than those of powerful states with strong national interests. Further, a confidential and deliberate process can lead to more stable agreements. On the other hand, NGOs and others can prepare or enhance ongoing high-level negotiations by giving parties the tools they need to engage with each other constructively, and by improving attitudes and changing perceptions. The data collected for this dissertation allows me to test hypotheses for the sample of African internal conflicts (1990-2010) with econometric means. Results confirm that non-state conflict management is a significant precursor to high-level mediation. I find further that conflict dyads that experience non-state conflict management in one year are significantly more likely to end in the following year. Unofficial diplomacy is significantly related to lower conflict severity, as well as to a more stable post-conflict peace. The findings challenge the common assumption that governments are the only actors in international relations that matter. In fact, non-state actors make important contributions to conflict resolution, and conflict parties as well as governmental mediators should consider cooperating with them in their search for peace

How Transnational Advocacy Networks Mobilize: Applying the Literature on Interest Groups to International Action

Transnational advocacy networks (TANs) receive increasing attention in international relations, but little has been written so far about the initial formation of networks and the ways concerned organizations or individuals build a transnational coalition. Difficulties of group mobilization pose a particular puzzle: Why do actors in one country organize around an issue in another country, especially when the resolution of the issue apparently benefits only local actors? When do national/international groups become active and how do local actors facilitate their mobilization? In this paper I argue that in order to get support from international organizations, local groups acting as entrepreneurs will frame the issue in a way attractive to the international organization. I apply concepts of interest group formation and mobilization to the case of the transnational advocacy network that formed in response to near-extermination of black-necked swans in the Carlos Anwandter Natural Sanctuary in southern Chile after the opening of a pulp mill in 2004

Private Diplomats, Mediation Professionals, and Peace Activists: Can Non-governmental Actors Bring Peace to Civil Wars?

This dissertation investigates how actors without the means of state power can affect the behavior of warring parties in order to end civil conflicts. Drawing on the intervention and mediation literature, I propose a theoretical framework that presents causal mechanisms for various forms of non-state conflict management to contribute to conflict resolution. The research distinguishes between direct mediation, capacity-building, and problem-solving approaches, and analyzes the approaches’ potential contributions to shorter wars and more sustainable peace. On the one hand, non-state actors can be substitutes for governmental or inter-governmental mediators. They derive legitimacy from long-standing relations with the conflict parties, and their claims to neutrality are more believable than those of powerful states with strong national interests. Further, a confidential and deliberate process can lead to more stable agreements. On the other hand, NGOs and others can prepare or enhance ongoing high-level negotiations by giving parties the tools they need to engage with each other constructively, and by improving attitudes and changing perceptions. The data collected for this dissertation allows me to test hypotheses for the sample of African internal conflicts (1990-2010) with econometric means. Results confirm that non-state conflict management is a significant precursor to high-level mediation. I find further that conflict dyads that experience non-state conflict management in one year are significantly more likely to end in the following year. Unofficial diplomacy is significantly related to lower conflict severity, as well as to a more stable post-conflict peace. The findings challenge the common assumption that governments are the only actors in international relations that matter. In fact, non-state actors make important contributions to conflict resolution, and conflict parties as well as governmental mediators should consider cooperating with them in their search for peace

Tuneable endogenous mammalian target complementation via multiplexed plasmidbased recombineering

Understanding the quantitative functional consequences of human disease mutations requires silencing of endogenous genes and expression of mutants at close to physiological levels. Changing protein levels above or below these levels is also important for system perturbation and modelling. Fast design optimization demands flexible interchangeable cassettes for endogenous gene silencing and tuneable expression. Here, we introduce ‘TEMTAC’, a multigene recombineering and delivery system for simultaneous siRNA-based knockdown and regulated mutant (or other variant) expression with different dynamic ranges. We show its applicability by confirming known phenotypic effects for selected mutations for BRAF, HRAS, and SHP2

Pleiotropic Locus 15q24.1 Reveals a Gender-Specific Association with Neovascular but Not Atrophic Age-Related Macular Degeneration (AMD)

Funding This research was funded by the Deutsche Forschungsgemeinschaft (GR5065/1-1) and institutional funds (Titel 77). Acknowledgments All contributing sites and additional funding information for the IAMDGC data are acknowledged in this publication: Fritsche et al. (2016) Nature Genetics 48 134–143, (doi:10.1038/ng.3448); The International AMD Genomics consortium’s web page is: http://eaglep.case.edu/iamdgc_web/, and additional information is available on: http://csg.sph.umich.edu/abecasis/public/amd2015/. GERA data came from a grant, the Resource for Genetic Epidemiology Research in Adult Health and Aging (RC2 AG033067; Schaefer and Risch, PIs) awarded to the Kaiser Permanente Research Program on Genes, Environment, and Health (RPGEH) and the UCSF Institute for Human Genetics. The RPGEH was supported by grants from the Robert Wood Johnson Foundation, the Wayne and Gladys Valley Foundation, the Ellison Medical Foundation, Kaiser Permanente Northern California, and the Kaiser Permanente National and Northern California Community Benefit Programs. The RPGEH and the Resource for Genetic Epidemiology Research in Adult Health and Aging are described in the following publication, Schaefer C, et al., The Kaiser Permanente Research Program on Genes, Environment and Health: Development of a Research Resource in a Multi-Ethnic Health Plan with Electronic Medical Records, In preparation, 2013. This research has been conducted using the UK Biobank Resource under Application Number 44862. The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health (commonfund.nih.gov/GTEx). Additional funds were provided by the NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. Donors were enrolled at Biospecimen Source Sites funded by NCI\Leidos Biomedical Research, Inc. subcontracts to the National Disease Research Interchange (10XS170), Roswell Park Cancer Institute (10XS171), and Science Care, Inc. (X10S172). The Laboratory, Data Analysis, and Coordinating Center (LDACC) was funded through a contract (HHSN268201000029C) to The Broad Institute, Inc. Biorepository operations were funded through a Leidos Biomedical Research, Inc. subcontract to Van Andel Research Institute (10ST1035). Additional data repository and project management were provided by Leidos Biomedical Research, Inc. (HHSN261200800001E). The Brain Bank was supported supplements to University of Miami grant DA006227. Statistical Methods development grants were made to the University of Geneva (MH090941 & MH101814), the University of Chicago (MH090951, MH090937, MH101825, & MH101820), the University of North Carolina—Chapel Hill (MH090936), North Carolina State University (MH101819), Harvard University (MH090948), Stanford University (MH101782), Washington University (MH101810), and to the University of Pennsylvania (MH101822). The datasets used for the analyses described in this manuscript were obtained from dbGaP at http://www.ncbi.nlm.nih.gov/gap through dbGaP accession number phs000424.v8.p2.Peer reviewedPublisher PD

Seed sequence polymorphism rs2168518 and allele-specific target gene regulation of hsa-miR-4513

Acknowledgements We thank Lisa Michaelis and Dr Karolina Plößl (Institute of Human Genetics, University of Regensburg) for excellent technical help and thorough proofreading of the manuscript, respectively. We thank Marina Sauer and Franz-Stephan Attenkofer (Institute of Human Genetics, University of Regensburg) for their support in generating the luciferase reporter vectors. Conflict of Interest statement. The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. Funding German Research Foundation (GR5065/1-1 to F.G.); and the Helmut Ecker Foundation (Ingolstadt, Germany) (no. 05/17 to B.H.F.W).Peer reviewedPublisher PD

Systems level expression correlation of Ras GTPase regulators

Background: Proteins of the ubiquitously expressed core proteome are quantitatively correlated across multiple eukaryotic species. In addition, it was found that many protein paralogues exhibit expression anticorrelation, suggesting that the total level of protein with a given functionality must be kept constant. Methods: We performed Spearman’s rank correlation analyses of gene expression levels for the RAS GTPase subfamily and their regulatory GEF and GAP proteins across tissues and across individuals for each tissue. A large set of published data for normal tissues from a wide range of species, human cancer tissues and human cell lines was analysed. Results: We show that although the multidomain regulatory proteins of Ras GTPases exhibit considerable tissue and individual gene expression variability, their total amounts are balanced in normal tissues. In a given tissue, the sum of activating (GEFs) and deactivating (GAPs) domains of Ras GTPases can vary considerably, but each person has balanced GEF and GAP levels. This balance is impaired in cell lines and in cancer tissues for some individuals. Conclusions: Our results are relevant for critical considerations of knock out experiments, where functionally related homologs may compensate for the down regulation of a protein

A Circulating MicroRNA Profile in a Laser-Induced Mouse Model of Choroidal Neovascularization

Funding: This research was funded by the Deutsche Forschungsgemeinschaft (GR5065/1-1). Author Contributions: Conceptualization, F.G. and B.H.F.W.; Data curation, T.S.; Formal analysis, P.B., M.K., A.A., and T.S.; Funding acquisition, C.K. and F.G.; Investigation, M.K. and B.H.F.W.; Methodology, C.K. and A.A.;Project administration, B.H.F.W.; Resources, M.K., A.A., T.L., and F.G.; Software, C.K. and T.S.; Supervision, T.L., F.G., and B.H.F.W.; Validation, P.B.; Visualization, C.K.; Writing—original draft, C.K. and P.B.; Writing—review & editing, B.H.F.W. All authors have read and agreed to the published version of the manuscript.Peer reviewedPublisher PD

Assigning Co-Regulated Human Genes and Regulatory Gene Clusters

Elucidating the role of genetic variation in the regulation of gene expression is key to understanding the pathobiology of complex diseases which, in consequence, is crucial in devising targeted treatment options. Expression quantitative trait locus (eQTL) analysis correlates a genetic variant with the strength of gene expression, thus defining thousands of regulated genes in a multitude of human cell types and tissues. Some eQTL may not act independently of each other but instead may be regulated in a coordinated fashion by seemingly independent genetic variants. To address this issue, we combined the approaches of eQTL analysis and colocalization studies. Gene expression was determined in datasets comprising 49 tissues from the Genotype-Tissue Expression (GTEx) project. From about 33,000 regulated genes, over 14,000 were found to be co-regulated in pairs and were assembled across all tissues to almost 15,000 unique clusters containing up to nine regulated genes affected by the same eQTL signal. The distance of co-regulated eGenes was, on average, 112 kilobase pairs. Of 713 genes known to express clinical symptoms upon haploinsufficiency, 231 (32.4%) are part of at least one of the identified clusters. This calls for caution should treatment approaches aim at an upregulation of a haploinsufficient gene. In conclusion, we present an unbiased approach to identifying co-regulated genes in and across multiple tissues. Knowledge of such common effects is crucial to appreciate implications on biological pathways involved, specifically when a treatment option targets a co-regulated disease gen

Pleiotropic Locus 15q24.1 Reveals a Gender-Specific Association with Neovascular but Not Atrophic Age-Related Macular Degeneration (AMD)

Genome-wide association studies (GWAS) have identified an abundance of genetic loci associated with complex traits and diseases. In contrast, in-depth characterization of an individual genetic signal is rarely available. Here, we focus on the genetic variant rs2168518 in 15q24.1 previously associated with age-related macular degeneration (AMD), but only with suggestive evidence. In a two-step procedure, we initially conducted a series of association analyses to further delineate the association of rs2168518 with AMD but also with other complex phenotypes by using large independent datasets from the International AMD Genomics Consortium (IAMDGC) and the UK Biobank. We then performed a functional annotation with reference to gene expression regulation based on data from the Genotype-Tissue Expression (GTEx) project and RegulomeDB. Association analysis revealed a gender-specific association with male AMD patients and an association predominantly with choroidal neovascularization. Further, the AMD association colocalizes with an association signal of several blood pressure-related phenotypes and with the gene expression regulation of CYP1A1, a member of the cytochrome P450 superfamily of monooxygenases. Functional annotation revealed altered transcription factor (TF) binding sites for gender-specific TFs, including SOX9 and SRY. In conclusion, the pleiotropic 15q24.1 association signal suggests a shared mechanism between blood pressure regulation and choroidal neovascularization with a potential involvement of CYP1A1