Differential Temporal and Spatial Progerin Expression during Closure of the Ductus Arteriosus in Neonates

Closure of the ductus arteriosus (DA) at birth is essential for the transition from fetal to postnatal life. Before birth the DA bypasses the uninflated lungs by shunting blood from the pulmonary trunk into the systemic circulation. The molecular mechanism underlying DA closure and degeneration has not been fully elucidated, but is associated with apoptosis and cytolytic necrosis in the inner media and intima. We detected features of histology during DA degeneration that are comparable to Hutchinson Gilford Progeria syndrome and ageing. Immunohistochemistry on human fetal and neonatal DA, and aorta showed that lamin A/C was expressed in all layers of the vessel wall. As a novel finding we report that progerin, a splicing variant of lamin A/C was expressed almost selectively in the normal closing neonatal DA, from which we hypothesized that progerin is involved in DA closure. Progerin was detected in 16.2%±7.2 cells of the DA. Progerin-expressing cells were predominantly located in intima and inner media where cytolytic necrosis accompanied by apoptosis will develop. Concomitantly we found loss of α-smooth muscle actin as well as reduced lamin A/C expression compared to the fetal and non-closing DA. In cells of the adjacent aorta, that remains patent, progerin expression was only sporadically detected in 2.5%±1.5 of the cells. Data were substantiated by the detection of mRNA of progerin in the neonatal DA but not in the aorta, by PCR and sequencing analysis. The fetal DA and the non-closing persistent DA did not present with progerin expressing cells. Our analysis revealed that the spatiotemporal expression of lamin A/C and progerin in the neonatal DA was mutually exclusive. We suggest that activation of LMNA alternative splicing is involved in vascular remodeling in the circulatory system during normal neonatal DA closure

Analysis of arterial intimal hyperplasia: review and hypothesis

which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background: Despite a prodigious investment of funds, we cannot treat or prevent arteriosclerosis and restenosis, particularly its major pathology, arterial intimal hyperplasia. A cornerstone question lies behind all approaches to the disease: what causes the pathology? Hypothesis: I argue that the question itself is misplaced because it implies that intimal hyperplasia is a novel pathological phenomenon caused by new mechanisms. A simple inquiry into arterial morphology shows the opposite is true. The normal multi-layer cellular organization of the tunica intima is identical to that of diseased hyperplasia; it is the standard arterial system design in all placentals at least as large as rabbits, including humans. Formed initially as one-layer endothelium lining, this phenotype can either be maintained or differentiate into a normal multi-layer cellular lining, so striking in its resemblance to diseased hyperplasia that we have to name it "benign intimal hyperplasia". However, normal or "benign " intimal hyperplasia, although microscopically identical to pathology, is a controllable phenotype that rarely compromises blood supply. It is remarkable that each human heart has coronary arteries in which a single-layer endothelium differentiates earl

Does the Committee Peer Review Select the Best Applicants for Funding? An Investigation of the Selection Process for Two European Molecular Biology Organization Programmes

Does peer review fulfill its declared objective of identifying the best science and the best scientists? In order to answer this question we analyzed the Long-Term Fellowship and the Young Investigator programmes of the European Molecular Biology Organization. Both programmes aim to identify and support the best post doctoral fellows and young group leaders in the life sciences. We checked the association between the selection decisions and the scientific performance of the applicants. Our study involved publication and citation data for 668 applicants to the Long-Term Fellowship programme from the year 1998 (130 approved, 538 rejected) and 297 applicants to the Young Investigator programme (39 approved and 258 rejected applicants) from the years 2001 and 2002. If quantity and impact of research publications are used as a criterion for scientific achievement, the results of (zero-truncated) negative binomial models show that the peer review process indeed selects scientists who perform on a higher level than the rejected ones subsequent to application. We determined the extent of errors due to over-estimation (type I errors) and under-estimation (type 2 errors) of future scientific performance. Our statistical analyses point out that between 26% and 48% of the decisions made to award or reject an application show one of both error types. Even though for a part of the applicants, the selection committee did not correctly estimate the applicant's future performance, the results show a statistically significant association between selection decisions and the applicants' scientific achievements, if quantity and impact of research publications are used as a criterion for scientific achievement