Identification of the molecular basis of the lacrimo-auriculo-dento-digital (LADD) syndrome

Lacrimo-auriculo-dento-digital (LADD) syndrome, also known as Levy-Hollister syndrome, is a rare autosomal dominant developmental disorder, mainly characterized by abnormalities of the lacrimal system and salivary glands, ears and hearing, teeth and distal limb development. Besides these cardinal features, facial dysmorphism and malformations of the kidney and the respiratory system have been reported. In this study, the LADD1 locus was mapped to chromosome 10q26 by genome wide linkage analysis using the Affymetrix GeneChip 10K array in three large LADD families. In all three LADD families and in one sporadic case, heterozygous missense mutations were found in exon 16 of the gene encoding the fibroblast-growth-factor-receptor 2 (FGFR2). After exclusion of the FGFR2 locus by haplotype analysis in two additional LADD families, one missense mutation was identified in FGFR3 and one mutation was found in the fibroblast-growth-factor 10 (FGF10), a known ligand of FGFR2 [Rohmann et al., 2006]. The functional properties of FGF10 LADD and FGFR2 LADD mutants were analyzed and compared to the activities of their normal counterparts. Protein expression in BL21 cells and binding studies showed that each of the three analyzed FGF10 mutations demonstrated severely impaired activity by different mechanisms. Transient and stable expression studies exhibited that the FGFR2 mutations possess a reduced autophosphorylation and a weaker tyrosine kinase activity. Mutations also lead to diminished phosphorylation activity in FGFR2-mediated substrates (e. g. FRS2 and Shc) and to a decreased downstream signaling pathway, as shown by MAPK activity. While tested FGF10 LADD mutations caused haploinsufficiency, the FGFR2 LADD mutants could exert a dominant-negative effect on normal FGFR2 protein [Shams and Rohmann et al., 2007]. An in vitro kinase assay and crystallization of both, FGFR2 WT and the p.A628T missense mutation in the catalytic part of the tyrosine kinase domain, demonstrated that the A628T LADD mutation disrupts the catalytic activity due to conformational changes, leading to LADD syndrome. In addition, the newly described crystal structure of FGFR2 in comparison to FGFR1 revealed that the FGFR2 utilizes a less stringent mode of autoinhibition [Lew, Bae and Rohmann et al., 2007]

Christianity, Book-Burning and Censorship in Late Antiquity

It is estimated that only a small fraction, less than 1 per cent, of ancient literature has survived to the present day. The role of Christian authorities in the active suppression and destruction of books in Late Antiquity has received surprisingly little sustained consideration by academics. In an approach that presents evidence for the role played by Christian institutions, writers and saints, this book analyses a broad range of literary and legal sources, some of which have hitherto been little studied. Paying special attention to the problem of which genres and book types were likely to be targeted, the author argues that in addition to heretical, magical, astrological and anti-Christian books, other less obviously subversive categories of literature were also vulnerable to destruction, censorship or suppression through prohibition of the copying of manuscripts. These include texts from materialistic philosophical traditions, texts which were to become the basis for modern philosophy and science. This book examines how Christian authorities, theologians and ideologues suppressed ancient texts and associated ideas at a time of fundamental transformation in the late classical world

Essays on financial misreporting and audit quality

This dissertation comprises four articles. The first three articles analyze auditing research questions using analytical models. The fourth article uses an experimental empirical research method to analyze the rationalization of misreporting. The first article analyzes how enforcement institutions’ inspection focus disclosure influences the managers’ misreporting, the auditors’ effort choices, and thus the financial reporting quality. We, thereby, show that focus disclosure can enhance or deteriorate financial reporting quality. We also highlight conditions under which focus disclosure can yield a higher financial reporting quality and how enforcement institutions can influence these conditions. The second article analyzes how third-party auditor hiring (e.g., by a stock exchange) affects entrepreneurs’ misreporting choices and overall investment efficiency. I show that even though independence issues could be solved, third-party auditor hiring can enhance or deteriorate investment efficiency. Third-party hiring can harm investment efficiency as it reduces misreporting, and thus, misreporting cannot be used to compensate a conservative accounting system to prevent underinvestment. Further, I highlight conditions under which third-party hiring yields a higher or lower investment efficiency. The third article analyzes driving forces for audit firm split-ups into stand-alone audit and advisory firms, such as the once planned EY split-up. In addition, we explore the potential consequences of audit firm split-ups on audit quality and the role of enforcement strength. We find that three effects determine split-up preferences and its consequences: First, as the advisory partner wants to prevent an adverse audit opinion to keep the client, independence problems arise. Second, as the advisory partner loses reputation in case of an audit failure, an advisory project creates positive effort incentives. Third, spillovers from audit to advisory lower the advisory partner’s project costs. Enforcement strength, thereby, determines which of the first two effects dominates because enforcement strength determines effort incentives. These effects and, thus, enforcement strength determine the overall effect of audit split-ups on audit quality. The fourth article analyzes the rationalization of financial misreporting. Using a 2x2 between-subjects experiment, we find that an externally caused bad environmental state causes a higher misreporting likelihood. This effect only occurs if participants are aware of other environmental states. Observing other states where it is easier to achieve a bonus, managers in the bad environmental state feel a greater sense of entitlement and misreport more. Thus, we find that entitlement works as a mediator for financial misreporting.Diese Dissertation beinhaltet vier Beiträge. Die ersten drei Beiträge untersuchen Fragestellungen zur Prüfungsforschung mittels spieltheoretischer Modelle. Der vierte Beitrag nutzt eine experimentell empirische Methodik zur Analyse der inneren Rechtfertigung von Bilanzmanipulation. Der erste Beitrag analysiert, wie sich die Veröffentlichung von Prüfungsschwerpunkten durch Enforcement-Institutionen auf Bilanzmanipulation und Prüfungsqualität und somit auf die Qualität der Finanzberichterstattung auswirkt. Dabei kann gezeigt werden, dass die Qualität der Finanzberichterstattung durch die Veröffentlichung sowohl steigen als auch sinken kann. Außerdem wird gezeigt, welche Faktoren vorliegen müssen, damit eine Veröffentlichung von Prüfungsschwerpunkten die Qualität der Finanzberichterstattung steigern kann und wie Enforcement-Institutionen diese Faktoren beeinflussen können. Der zweite Beitrag untersucht, welche Effekte die Wahl des Abschlussprüfers durch eine unabhängige dritte Partei (bspw. eine Börse) auf Bilanzmanipulation und Investitionseffizienz hat. Der Beitrag zeigt auf, dass die Wahl des Abschlussprüfers durch eine dritte Partei die Investitionseffizienz nicht nur steigern, sondern auch senken kann. Die Wahl des Abschlussprüfers durch eine dritte Partei kann zwar Bilanzmanipulation mindern, Manipulation kann so jedoch nicht mehr zum Ausgleich vorsichtiger Rechnungslegung genutzt werden und somit Unterinvestitionen nicht verhindern. Der Beitrag zeigt auf, welche Faktoren zu einer Steigerung bzw. Senkung der Investitionseffizienz führen können. Der dritte Beitrag analysiert, welche Faktoren zu einer Aufspaltung von Prüfungsgesellschaften in reine Prüfungs- und Beratungsgesellschaften – wie einst von EY geplant – führen. Es wird gezeigt, wie sich eine Aufspaltung auf die Prüfungsqualität auswirkt und, welche Rolle die Stärke des Enforcement hierbei spielt. Drei Effekte beeinflussen maßgeblich die Entscheidung zur Aufspaltung und ihre Folgen. Zum einen entsteht ein Unabhängigkeitskonflikt, da der Beratungspartner verhindern will, einen Versagungsvermerk zu erteilen. Zweitens entstehen Arbeitsanreize für den Beratungspartner, da dieser aus Angst vor Reputationsverlusten verhindern will, dass es zu einem Fehlurteil in der Prüfung kommt. Drittens ergeben sich Kostenvorteile aus dem simultanen Anbieten von Prüfung und Beratung. Die Stärke des Enforcement determiniert hierbei, welcher der ersten beiden Effekte überwiegt. Der kumulierte Effekt einer Aufspaltung hängt daher von den genannten Effekten und der Stärke des Enforcement ab. Der vierte Beitrag untersucht die innere Rechtfertigung von Bilanzmanipulation. Dabei wird mittels eines 2x2 between-subjects Experiments analysiert, ob ein exogen verursachter schlechter Umweltzustand zu höherer Manipulation führt, wenn andere Zustände bekannt sind. Der Beitrag macht deutlich, dass dies die Anspruchshaltung (Entitlement) eines Managers und somit die Manipulationswahrscheinlichkeit erhöht

The Effect of Mortality Salience on Compromising Mate Selection Standards in Homosexual and Heterosexual Individuals

Terror management theory (TMT), proposed by Greenberg, Pyszcynski, and Solomon (1986), suggests that humans cope with terror resulting from the knowledge of their own mortality. The need for coping mechanisms arises when individuals are reminded of their own inevitable death; that is, when they experience mortality salience (MS). Hirschberger, Florian, and Mikulincer (2002) found that when primed with death reminders, heterosexual individuals tend to compromise their ideal mate selection to form close relationships. There has also been extensive research on the differences between homosexual and heterosexual mating preferences. This study examined the effect mortality salience has on an individuals’ mate selection standards, and if there is a difference based on individual’s sexuality. Data from 332 participants did not yield significant differences in compromising mate selection standards between the MS primed and control groups. Differences in willingness to compromise mate selection standards was found in varying sexualities, suggesting a need to further investigate sexuality differences in willingness to compromise

Migraine, headache, and mortality in women: a cohort study

Background: Migraine carries a high global burden, disproportionately affects women, and has been implicated as a risk factor for cardiovascular disease. Migraine with aura has been consistently associated with increased risk of cardiovascular mortality. However, published evidence on relationships between migraine or non-migraine headache and all-cause mortality is inconclusive. Therefore, we aimed to estimate the effect of non-migraine headache and migraine as well as migraine subtypes on all-cause and cause-specific mortality in women. Methods: In total, 27,844 Women’s Health Study participants, aged 45 years or older at baseline, were followed up for a median of 22.7 years. We included participants who provided information on migraine (past history, migraine without aura, or migraine with aura) or headache status and a blood sample at study start. An endpoints committee of physicians evaluated reports of incident deaths and used medical records to confirm deaths due to cardiovascular, cancer, or female-specific cancer causes. We used multivariable Cox proportional hazards models to estimate the effect of migraine or headache status on both all-cause and cause-specific mortality. Results: Compared to individuals without any headache, no differences in all-cause mortality for individuals suffering from non-migraine headache or any migraine were observed after adjustment for confounding (HR = 1.01, 95%CI, 0.93–1.10 and HR = 0.96, 95% CI: 0.89–1.04). No differences were observed for the migraine subtypes and all-cause death. Women having the migraine with aura subtype had a higher mortality due to cardiovascular disease (adjusted HR = 1.64, 95%CI: 1.06–2.54). As an explanation for the lack of overall association with all-cause mortality, we observed slightly protective signals for any cancer and female-specific cancers in this group. Conclusions: In this large prospective study of women, we found no association between non-migraine headache or migraine and all-cause mortality. Women suffering from migraine with aura had an increased risk of cardiovascular death. Future studies should investigate the reasons for the increased risk of cardiovascular mortality and evaluate whether changes in migraine patterns across the life course have differential effects on mortality

Christianity, Book-Burning and Censorship in Late Antiquity

It is estimated that only a small fraction, less than 1 per cent, of ancient literature has survived to the present day. The role of Christian authorities in the active suppression and destruction of books in Late Antiquity has received surprisingly little sustained consideration by academics. In an approach that presents evidence for the role played by Christian institutions, writers and saints, this book analyses a broad range of literary and legal sources, some of which have hitherto been little studied. Paying special attention to the problem of which genres and book types were likely to be targeted, the author argues that in addition to heretical, magical, astrological and anti-Christian books, other less obviously subversive categories of literature were also vulnerable to destruction, censorship or suppression through prohibition of the copying of manuscripts. These include texts from materialistic philosophical traditions, texts which were to become the basis for modern philosophy and science. This book examines how Christian authorities, theologians and ideologues suppressed ancient texts and associated ideas at a time of fundamental transformation in the late classical world

Die Rolle der Hyperkoagulabilität bei neurovaskulären Erkrankungen: Einblicke aus der klinischen Epidemiologie

Given their crucial role in preserving the hemostatic balance, coagulation factors are of great interest in the context of both venous and arterial thrombosis. Recent laboratory work has indicated that a hypercoagulable state increases risk for ischemic events. Furthermore, first clinical trials have found that temporarily lowering Factor XI levels prevents clots without increasing bleeds in knee arthroplasty patients, which may make these factors attractive therapeutic targets in secondary prevention of ischemic stroke. My dissertation subprojects aimed to study the role of coagulation factors in neurovascular disease using existing observational datasets. As such, these clinical epidemiologic investigations provided important first insights in a cost-effective way. My work describes diverse aspects of the processes by which coagulation factors are implicated in neurovascular diseases, with each subproject characterized by a different study design and population. We identified genetic determinants of contact factor levels (High Molecular Weight Kininogen (HMWK), Prekallikrein (PK), FXI and FXII) and probed their associations with vascular disease phenotypes in a case-control study. In addition to replicating known associations between single genetic variants and contact system factor levels, we identified two novel loci; one for PK antigen levels (KLKB1 rs4253243; βconditional=-12.38; 95% confidence interval (CI), -20.07 to -4.69) and one for HMWK antigen levels (KNG1 rs5029980; βconditional=5.86; 95%CI: 2.40 to 9.32). We estimated the effects of hypercoagulability on post-stroke outcomes in a cohort of 576 ischemic stroke patients. After controlling for confounding, compared with having low or normal levels, having high (>75th-percentile) FXI activity levels increased the hazard for the combined endpoint (recurrent stroke, myocardial infarction, or all-cause mortality) within three years of first ischemic stroke (Hazard Ratio (HR)=1.80, 95%CI: 1.09–2.98). High FVIII activity was also linked to worse outcomes (HR=2.05, 95%CI: 1.28–3.29), whereas high FXII activity was not (HR=0.86, 95%CI: 0.49–1.51). Finally, in a general population cohort of older persons, we found no evidence of a relevant contribution of factor VIII activity to the presence or worsening of white matter hyperintensities or cognitive performance over time. Each of these subprojects provided a substantial contribution to filling knowledge gaps in the field of hypercoagulability research. Taken together, this dissertation work contributes to a better understanding of genetic influences on coagulation factor levels as well as the longer-term effects of expressed hypercoagulability on outcomes among stroke patients and in a general population sample of older persons. My work concludes with a set of suggestions for future coagulation factor research, especially in the context of stroke, based on lessons learned during the process of synthesizing and critically evaluating my results.Aufgrund ihrer entscheidenden Rolle bei der Aufrechterhaltung der hämostatischen Balance, sind Gerinnungsfaktoren im Zusammenhang mit venösen sowie arteriellen Thrombosen von großem Interesse. Neuere Laborergebnisse zeigten ein erhöhtes Risiko für ischämische Ereignisse durch einen hyperkoagulablen Zustand. Erste klinische Studien zeigten eine vielversprechende Wirkung gegen Thrombosen durch die temporäre Senkung des Gerinnungsfaktor-XI-Spiegels – ohne Erhöhung des Blutungsrisikos bei Knieendoprothese-Patient*innen. Diese Erkenntnis ist auch im Kontext der Sekundärprävention von Schlaganfällen von hoher Relevanz. Das Ziel meiner Dissertation war, in drei Teilprojekten die Rolle bestimmter Gerinnungsfaktoren zu untersuchen, die zur Hyperkoagulabilität bei neurovaskulären Erkrankungen beitragen. Die auf klinisch-epidemiologischen Fragestellungen basierenden Sekundäranalysen von Beobachtungsdatensätzen liefern wichtige Erkenntnisse für die Zielpopulationen in kosten-effektiver Weise. Im Rahmen meiner Dissertation wurden genetische Determinanten von Gerinnungsfaktoren des Contact-Activation-Systems (hochmolekulares Kininogen (HMWK), Präkallikrein (PK), Faktor XI und Faktor XII) identifiziert. Außerdem untersuchten wir ihre Assoziationen mit Phänotypen von vaskulären Erkrankungen in einer Fall-Kontroll-Studie. Zusätzlich zur Replikation bekannter Assoziationen zwischen einzelnen genetischen Varianten und den Spiegeln der Gerinnungsfaktoren identifizierten wir zwei neue Genloci: einen für den PK-Antigenspiegel (KLKB1 rs4253243; βadjustiert=-12,38; 95% Konfidenzintervall (KI): -20,07 bis -4,69) und einen für den HMWK-Antigenspiegel (KNG1 rs5029980; βadjustiert=5,86; 95%KI, 2,40 bis 9,32). Des Weiteren schätzten wir die Effekte von hohen Faktor-XI-, Faktor-XII- und Faktor-VIII-Aktivitätsspiegeln auf Langzeit-Outcomes in einer Kohorte von 576 Patient*innen mit ischämischem Schlaganfall. Im Vergleich zu niedrigen oder normalen Werten hatten Schlaganfallpatient*innen mit einer hohen FXI-Aktivität (>75. Perzentil) ein höheres Risiko für den kombinierten Endpunkt (rezidivierender Schlaganfall, Myokardinfarkt oder Gesamtmortalität) innerhalb von drei Jahren (HR=1,80; 95%KI: 1,09 bis 2,98) nach Confounding-Adjustierung. Eine hohe FVIII-Aktivität war ebenfalls mit einem schlechteren Outcome verbunden (HR=2,05; 95%KI: 1,28 bis 3,29), eine hohe FXII-Aktivität hingegen nicht (HR=0,86; 95%KI: 0,49 bis 1,51). Schließlich fanden wir in einer Allgemeinbevölkerungskohorte älterer Personen keine Hinweise auf einen relevanten Beitrag des Faktor-VIII-Aktivitätsspiegels zur Präsenz von White Matter Hyperintensities oder verminderten kognitiven Funktionen und deren Verschlechterung im Zeitverlauf. Meine Arbeit schließt mit praktischen und methodischen Vorschlägen für zukünftige Forschung zu Gerinnungsfaktoren, insbesondere im Kontext des ischämischen Schlaganfalls, basierend auf den Erkenntnissen aus der Synthese und kritischen Bewertung meiner Ergebnisse

Praenomen Petronii: the date and author of the Satyricon reconsidered

This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.Peer Reviewe