Disturbed Placental Imprinting in Preeclampsia Leads to Altered Expression of DLX5, a Human-Specific Early Trophoblast Marker.

Background -Preeclampsia (PE) is a complex and common human-specific pregnancy syndrome associated with placental pathology. The human-specificity provides both intellectual and methodological challenges, lacking a robust model system. Given the role of imprinted genes in human placentation and the vulnerability of imprinted genes to loss of imprinting changes, there has been extensive speculation, but no robust evidence, that imprinted genes are involved in PE. Our study aims at investigating whether disturbed imprinting contributes to PE. Methods -We first aimed at confirming that PE is a disease of the placenta by generating and analysing genome-wide molecular data on well-characterized patient material. We performed high-throughput transcriptome analyses of multiple placenta samples from normal and PE patients. Next, we identified differentially expressed genes (DEGs) in PE placenta, and intersected them with the list of human imprinted genes. We employed bioinformatics/statistical analyses to confirm association between imprinting and PE, and to predict biological processes affected in PE. Validation included epigenetic and cellular assays. Regarding human-specificity, we established an in vitro invasion-differentiation trophoblast model. Our comparative phylogenetic analysis involved single-cell transcriptome data of human, macaque and mouse preimplantation embryogenesis. Results -We found disturbed placental imprinting in PE and revealed potential candidates, including GATA3 and DLX5, with poorly explored imprinted status and no prior association with PE. Due to loss of imprinting DLX5 was upregulated in 69% of PE placentas. Levels of DLX5 correlated with classical PE marker. DLX5 is expressed in human, but not in murine trophoblast. The DLX5(high) phenotype resulted in reduced proliferation, increased metabolism and ER stress-response activation in trophoblasts in vitro The transcriptional profile of such cells mimics the transcriptome of PE placentas. Pan-mammalian comparative analysis identified DLX5 as a part of the human-specific regulatory network of trophoblast differentiation. Conclusions -Our analysis provides evidence of a true association between disturbed imprinting, gene expression and PE. Due to disturbed imprinting, the upregulated DLX5 affects trophoblast proliferation. Our in vitro model might fill a vital niche in PE research. Human-specific regulatory circuitry of DLX5 might help to explain certain aspects of PE

Beyond a Dichotomy of Perspectives: Understanding Religion on the Basis of Paul Natorp’s Logic of Boundary

Based on Paul Natorp’s (1854–1924) late post-Neo-Kantian “Logic of Boundary” (German: “Grenzlogik”) I will offer a methodically controlled, non-reductionist and equally anti-essentialist reconstruction of the notion of religion. The pre-eminent objective of this reconstructive work is to overcome the well-known epistemological as well as methodological problem of a dichotomy between inside and outside perspectives on the subject of religion. Differently put, the objective consists in an attempt to demonstrate that there actually is “reason in religion” that is intellectually accessible for academic knowledge production. Following Natorp’s splendid formulation I will argue that religion operates neither ‘within’ nor ‘beyond’ the ‘boundary of humanity’ but exactly on [or ‘in’] this boundary. More precisely, I will explicate that religious praxis (including its specific production of knowledge) from Natorp’s standpoint can be understood as the performative realization, and habitual embodiment of the (contextually concrete) boundary of humanity or human reason itself. Due to its principial self-referentiality this boundary carries the crucial sense of a first and last positive and, therefore, both in theoretical terms definitive and in practical terms eminently instructive notion of boundary with no outside. This paradoxically all-enclosing, positive boundary, while explicitly including life’s inevitable negativity but, nonetheless, able to ideally sublate it, is the reason why the practice of religion, as empirical evidence unmistakably documents, can provide an incommensurably fulfilling, significant and meaningful closure with regards to the innermost self-perception of its practitioners (concerning their self-determination or agency)

Volume and outcomes relationship in laparoscopic diaphragmatic hernia repair

BackgroundThere is no published data regarding the relationship between hospital volume and outcomes in patients undergoing laparoscopic diaphragmatic hernia repair. We hypothesize that hospitals performing high case volume have improved outcomes compared to low-volume hospitals.Materials and methodsWe reviewed the National Inpatient Sample (NIS) database between 2008 and 2012 for adults with the diagnosis of diaphragmatic hernia who underwent elective laparoscopic repair of diaphragmatic Hernia and/or Nissen fundoplication. Pediatric, emergent, and open cases were excluded. Main outcome measures included logistic regression analysis of factors predictive of in-hospital mortality and outcomes according to annual hospital case volume.ResultsA total of 31,228 laparoscopic diaphragmatic hernia operations were analyzed. The overall in-hospital mortality was 0.14%. Risk factors for higher in-hospital mortality included renal failure (AOR: 6.26; 95% CI: 2.48-15.78; p < 0.001), age>60 years (AOR: 5.06; 95% CI: 2.38-10.76; p < 0.001), and CHF (AOR: 3.80; 95% CI: 1.39-10.38; p = 0.009) while an incremental increase in volume of 10 cases/year (AOR: 0.89; 95% CI: 0.81-0.98; p = 0.019) and diabetes (AOR: 0.34; 95% CI: 0.12-0.93; p = 0.036) decreases mortality. There was a small but significant inverse relationship between hospital case volume and mortality with a 10% reduction in adjusted odds of in-hospital mortality for every increase in 10 cases per year. Using 10 cases per year as the volume threshold, low-volume hospitals (≤10 cases/year) had almost a twofold higher mortality compared to high-volume hospitals (0.23 vs. 0.12%, respectively, p = 0.02).ConclusionsThere was a small but significant inverse relationship between the hospitals' case volume and mortality in laparoscopic diaphragmatic hernia repair

Management control systems in innovation companies: A literature based framework

Past research has traditionally argued that management control systems (MCSs) may present a hindrance to the creativity of innovation companies. This theoretical paper surveys the literature to focus an investigation on the MCSs of innovation companies. Within the object of control paradigm the paper develops and presents a theoretical model of the impact of eleven external, organisational and innovation related contingency factors on the MCSs in companies that engage in innovation activities. We also suggest measures for further empirical research. By formulating hypotheses on 43 potential interactions the model predicts contradictory influences on two direct control categories, results and action control, but stresses the importance of two indirect categories, personnel and cultural control. More specifically, the high levels of technological complexity and innovation capability in this type of company are expected to be negatively associated with the application of results and action control, whereas personnel and cultural seem to be more appropriate. Furthermore, important sources of finance, venture capital and public funding, are both hypothesised to be positively associated with the application of results, action and personnel control; whereas only public funding is predicted to be positively related to the application of cultural control. The principal contribution of this paper lies in synthesising the literature to provide a model of the impact of a unique set of eleven contingency factors for innovation companies on a broad scope of controls. In addition, the contingency model, if empirically validated, would add value by inferring the particular forms of management control which would be beneficial in innovative company settings. © 2014 Springer-Verlag Berlin Heidelberg