Dopamine : a versatile player in development, regeneration and disease

The dopamine neurotransmitter is present in all multicellular organisms. In the brain, the dopaminergic system orchestrates reward-motivation pathways and is involved in the control of voluntary movements and endocrine hormone secretion. Dysfunction of dopamine signalling may lead to pathological conditions such as Parkinson’s disease, where dopaminergic neurons of the midbrain degenerate. Moreover, modulation of dopamine receptor signalling influences tumour growth. The aim of this work was to explore the regeneration capacity of the dopaminergic system in the vertebrate brain and to test whether dopamine may control the growth of brain tumours. To this end we performed two sets of studies. Initially, we investigated the development and regeneration of the dopaminergic system in newts, which are aquatic salamanders capable of complete regeneration of the dopaminergic system in the brain. Thereafter, we investigated how dopaminergic ligands impinge specifically on brain tumour cells. In paper I, we screened a library of dopaminergic ligands for their ability to stimulate or to inhibit glioblastoma cell growth and survival. We identified the dopamine receptor 2 antagonist, trifluoperazine, as an inhibitor of glioblastoma growth. We also showed that susceptibility to trifluoperazine correlates with the dopamine receptor expression profile of the investigated glioblastoma cell lines. We concluded that dopamine receptor signalling pathways are promising targets for pharmacological interventions to inhibit glioblastoma growth. In paper II, we characterized the cellular basis of brain development and stereotyped behaviour in two regeneration model salamander species. These data provide insight into the maturation of neural stem cells that are found in the adult salamander brain. Furthermore, we showed how lesioning of the dopaminergic innervation affects neurogenesis in the forebrain and behavioural performance. This study provides a new evolutionary perspective on the genesis and dynamics of brain cells in the salamander brain, including dopaminergic cells. In paper III, we developed a tissue clearing method, CUBICe, to extend our study of dopaminergic neurite outgrowth during development as well as regeneration. We demonstrated that CUBICe is compatible for high resolution imaging of whole salamander brains. It is also a faster and more robust method, which allows to maintain a better sample integrity of embryonic brains in general, compared to Advanced CUBIC and Advanced CLARITY. In addition, using CUBICe we achieved tracing of genetically marked cells with neurite outgrowth of over 3600 µm. Ultimately, we showed that our method is ideal for tracing genetically marked dopaminergic cells in the salamander brain and for quantifying dopaminergic neurite density and regeneration in whole brain regions. In summary, this thesis provides insight into the versatile role of dopamine in both normal and pathological conditions of the vertebrate brain, as well as offers innovative tools for studying the regeneration of the dopaminergic system

Classifying Privacy and Verifiability Requirements for Electronic Voting

Abstract: Voter privacy and verifiability are fundamental security concepts for elec-tronic voting. Existing literature on electronic voting provides many definitions and interpretations of these concepts, both informal and formal. While the informal defini-tions are often vague and imprecise, the formal definitions tend to be very complex and restricted in their scope as they are usually tailored for specific scenarios. Moreover, some of the existing interpretations are contradictory. This paper provides informal, yet precise definitions of anonymity, receipt-freeness and coercion-resistance and identifies different levels of individual and universal veri-fiability. The overarching goal of this paper is to investigate which levels are conceiv-able for implementing these requirements in e-voting systems for elections of different significance (for instance political elections vs. elections in associations).

Silver covalently bound to cyanographene overcomes bacterial resistance to silver nanoparticles and antibiotics

The ability of bacteria to develop resistance to antibiotics is threatening one of the pillars of modern medicine. It was recently understood that bacteria can develop resistance even to silver nanoparticles by starting to produce flagellin, a protein which induces their aggregation and deactivation. This study shows that silver covalently bound to cyanographene (GCN/Ag) kills silver-nanoparticle-resistant bacteria at concentrations 30 times lower than silver nanoparticles, a challenge which has been so far unmet. Tested also against multidrug resistant strains, the antibacterial activity of GCN/Ag is systematically found as potent as that of free ionic silver or 10 nm colloidal silver nanoparticles. Owing to the strong and multiple dative bonds between the nitrile groups of cyanographene and silver, as theory and experiments confirm, there is marginal silver ion leaching, even after six months of storage, and thus very high cytocompatibility to human cells. Molecular dynamics simulations suggest strong interaction of GCN/Ag with the bacterial membrane, and as corroborated by experiments, the antibacterial activity does not rely on the release of silver nanoparticles or ions. Endowed with these properties, GCN/Ag shows that rigid supports selectively and densely functionalized with potent silver-binding ligands, such as cyanographene, may open new avenues against microbial resistance.Web of Scienceart. no. 200309

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung’s disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung’s disease) from 264 hospitals (89 in high-income countries, 166 in middleincome countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in lowincome countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. Interpretation Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between lowincome, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

Privacy and Verifiability in Electronic Voting

Privacy and verifiability refer to fundamental principles of democratic elections and therefore belong to the set of established security requirements which each electronic voting scheme is expected to meet. However, very different ideas and opinions about privacy and verifiability exist in the scientific community, which shows that both properties are not well understood yet. Moreover, although the desired properties (captured by the security requirements) should be separated from the assumed adversary model (expressed by adversary capabilities), specific adversary capabilities are inherently assumed for the privacy-related security requirements of receipt-freeness and coercion-resistance, which complicates the analysis of voting schemes. The first part of this thesis presents a taxonomy for privacy and verifiability in electronic voting. We compile the conceivable levels of privacy and verifiability and investigate the relation between both properties. To this end, we introduce a conceptual model capturing both privacy and verifiability. We also provide a comprehensive adversary model for electronic voting by considering different adversary capabilities. The conceptual model, the levels of privacy and verifiability, and the adversary capabilities together form our taxonomy for privacy and verifiability in electronic voting. The presented taxonomy provides a deeper understanding of privacy and verifiability and their correlation in electronic voting. We show how the taxonomy can be used to analyze the security of voting schemes by identifying the level of privacy and verifiability provided depending on the adversary capabilities assumed. Moreover, the taxonomy allows to select appropriate levels of the requirements for different types of elections, and to determine reasonable adversary models for individual election scenarios. The second part of this thesis considers long-term aspects of verifiability in remote electronic voting. The lawfulness of any legally binding election must be provable for several years due to possible scrutiny proceedings. Therefore, specific documents such as the ballots must be retained. The election records are usually retained for the legislative period of the elected body; however, this period may be extended if scrutiny procedures are pending. Retention obligations apply not only to conventional paper-based elections, but also to remote electronic voting. But contrary to the case of paper-based elections, general regulations or guidelines on retention of remote electronic election data have not been issued so far. In particular, the question which records should be retained is yet unanswered. The second part of this thesis sets out to identify the election records that have to be retained in order to prove the proper conduct of a remote electronic election. We derive retention requirements for online elections from legal regulations which apply to Federal Elections for the German Bundestag, and we make recommendations on how to meet these requirements. Establishing Internet voting in parliamentary elections presupposes that its technical implementation meets certain legal requirements, and conclusive retention of election data is one of them. Thus, our work contributes to establishing online voting as an additional voting channel in parliamentary elections in Germany. It may support legislative organs when issuing a legal framework on remote electronic voting. Moreover, our work is valuable for developing legally compliant voting systems as the need for record keeping should be considered already when designing and implementing a remote electronic voting scheme