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]

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

Impact of COPD and anemia on motor and cognitive performance in the general older population: results from the English longitudinal study of ageing

Background: Cognitive and motor-performance decline with age and the process is accelerated by decline in general health. In this study, we aimed to estimate the effects of COPD and HB levels on cognitive and motor performance in the general older population and assess potential interaction. Methods: The English Longitudinal Study of Aging is a population-based cohort study including measurements of lung-function and HB levels together with cognitive and motor performance testing. Data were collected from 5709 participants including three measurement time over eight years. COPD was defined using lung-function-parameters and clinical symptoms. HB was assessed continuously and low HB was defined using clinical anemia cutoffs. Linear mixed-effects regression models were used to quantify the associations of COPD and HB with outcome measures, both individually and in combination. Results: Participants with both low HB and COPD demonstrated worse motor performance compared to individuals with only one exposure, resulting in up to 1 s (95%CI, 0.04–1.8) longer time needed to complete the five times sit to stand task than what would be expected based on purely additive effects. Additionally in individuals with COPD, the time to complete the motor-performance task per unit decrease in continuous HB levels was longer than in participants without COPD after full adjustment for confounding (up to 1.38 s/unit HB level, 95% CI: 0.65–2.11). Conclusion: In persons with COPD low HB levels may contribute to low motor-performance in a supra additive fashion. Further studies should re-evaluate whether earlier treatment of lower HB in these individuals might be beneficial

The Statistics of Natural Shapes in Modern Coral Reef Landscapes

Spatial heterogeneity is a fundamental characteristic of modern and ancient depositional settings, and the scaling of many carbonate environments has been shown to follow power function distributions. The difficulty in obtaining information on the horizontal persistence of sedimentary lithotopes at the basin scale has, however, hampered evaluation of this fact over larger geographic areas. In recent years, large‐scale maps of reef facies derived from remotely sensed data have become widely available, allowing for an analysis of reef‐scale map products from 26 sites spread through four reef provinces, covering \u3e7000 km2 of shallow‐water habitat in the U.S. territorial Pacific. For each site, facies maps were decomposed to polygons describing the perimeter of patches of differing sedimentologic/benthic character. A suite of geospatial metrics quantifying unit shape, fractal dimension, and frequency‐area relations was applied to investigate the intra‐ and intersite variability. The spatial architecture of these reef sites displays robust fractal properties over an extended range of scales with remarkable consistency between provinces. These results indicate the possibility of extrapolating information from large to small scales in various depositional environments

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

Examining the Roots of Political Discontent: The “Left Behind” Theory in the Context of the 2016 U.S. Presidential Election

The growing popularity of anti-establishment parties and politicians among voters in Western democracies since the mid-2010s has led to a number of explanations. One widely accepted approach, both in journalistic and academic circles, is the theory that the "left behind" voters are primarily responsible for this development. Despite the popularity of this theory, it has two central problems: firstly, a clear definition of what “left behind” means and secondly, a lack of empirical testing. This dissertation addresses these problems using the 2016 U.S. presidential election as an example. Based on an examination of media and academic discourse, an empirically testable definition of the theory is distilled, operationalized, and then empirically tested at the county level through two regression models. The results of the analysis show that the chosen operationalization of the theory can explain approximately two-thirds of the variance in the vote share for Donald Trump. In order to understand the proportion of unexplained variance, counties in which Trump's share of the vote as predicted by the statistical models deviates significantly from the actual vote are then examined in descriptive analysis in exploratory form. It becomes clear that the reasons for the strong deviations lie less in the selection of the chosen variables, but probably in their lack of weighting, as well as in other factors such as voter turnout and historical loyalty to a party. The dissertation places this empirical research in a broader context by viewing Trump's election as a symptom of a transitional phase between two political paradigms. Both by adopting this perspective and through the empirical aspects of the work, this dissertation contributes to a better understanding of the origins of Trump's electoral success and opens up new ways to address them

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

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