Effects of 5-fluorouracil on morphology, cell cycle, proliferation, apoptosis, autophagy and ros production in endothelial cells and cardiomyocytes

Antimetabolites are a class of effective anticancer drugs interfering in essential biochemical processes. 5-Fluorouracil (5-FU) and its prodrug Capecitabine are widely used in the treatment of several solid tumors (gastro-intestinal, gynecological, head and neck, breast carcinomas). Therapy with fluoropyrimidines is associated with a wide range of adverse effects, including diarrhea, dehydration, abdominal pain, nausea, stomatitis, and hand-foot syndrome. Among the 5-FU side effects, increasing attention is given to cardiovascular toxicities induced at different levels and intensities. Since the mechanisms related to 5-FU-induced cardiotoxicity are still unclear, we examined the effects of 5-FU on primary cell cultures of human cardiomyocytes and endothelial cells, which represent two key components of the cardiovascular system. We analyzed at the cellular and molecular level 5-FU effects on cell proliferation, cell cycle, survival and induction of apoptosis, in an experimental cardioncology approach. We observed autophagic features at the ultrastructural and molecular levels, in particular in 5-FU exposed cardiomyocytes. Reactive oxygen species (ROS) elevation characterized the endothelial response. These responses were prevented by a ROS scavenger. We found induction of a senescent phenotype on both cell types treated with 5-FU. In vivo, in a xenograft model of colon cancer, we showed that 5-FU treatment induced ultrastructural changes in the endothelium of various organs. Taken together, our data suggest that 5-FU can affect, both at the cellular and molecular levels, two key cell types of the cardiovascular system, potentially explaining some manifestations of 5-FU-induced cardiovascular toxicity

Scaling of Self-Avoiding Walks in High Dimensions

We examine self-avoiding walks in dimensions 4 to 8 using high-precision Monte-Carlo simulations up to length N=16384, providing the first such results in dimensions $d > 4$ on which we concentrate our analysis. We analyse the scaling behaviour of the partition function and the statistics of nearest-neighbour contacts, as well as the average geometric size of the walks, and compare our results to $1/d$-expansions and to excellent rigorous bounds that exist. In particular, we obtain precise values for the connective constants, $\mu_5=8.838544(3)$, $\mu_6=10.878094(4)$, $\mu_7=12.902817(3)$, $\mu_8=14.919257(2)$ and give a revised estimate of $\mu_4=6.774043(5)$. All of these are by at least one order of magnitude more accurate than those previously given (from other approaches in $d>4$ and all approaches in $d=4$). Our results are consistent with most theoretical predictions, though in $d=5$ we find clear evidence of anomalous $N^{-1/2}$-corrections for the scaling of the geometric size of the walks, which we understand as a non-analytic correction to scaling of the general form $N^{(4-d)/2}$ (not present in pure Gaussian random walks).Comment: 14 pages, 2 figure

Against strong pluralism

Strong pluralists hold that not even permanent material coincidence is enough for identity. Strong pluralism entails the possibility of purely material objects -- even if not coincident -- alike in all general respects, categorial and dispositional, relational and non-relational, past, present and future, at the microphysical level, but differing in some general modal, counterfactual or dispositional repscts at the macrophysical level. It is objectionable because it thus deprives us of the explanatory resources to explain why evident absurdities are absurd. A second objection is to the suggestion that cases involving artefacts can illustrate strong pluralism. This offends against the principle that gien a complex intrinsic microphysical property instantiated in some regiion, the number of material things possessing it in that region cannot depend on the existence and nature of intentional activity taking place outside it

A Characterisation of Strong Wave Tails in Curved Space-Times

A characterisation of when wave tails are strong is proposed. The existence of a curvature induced tail (i.e. a Green's function term whose support includes the interior of the light-cone) is commonly understood to cause backscattering of the field governed by the relevant wave equation. Strong tails are characterised as those for which the purely radiative part of the field is backscattered. With this definition, it is shown that electromagnetic waves in asymptotically flat space-times and fields governed by tail-free propagation have weak tails, but minimally coupled scalar fields in a cosmological scenario have strong tails.Comment: 17 pages, Revtex, to appear in Classical and Quantum Gravit

The aorta can act as a site of naïve CD4+ T-cell priming

Aims: Aortic adaptive immunity plays a role in atherosclerosis; however, the precise mechanisms leading to T-cell activation in the arterial wall remain poorly understood. Methods and results: Here, we have identified naïve T cells in the aorta of wild-Type and T-cell receptor transgenic mice and we demonstrate that naïve T cells can be primed directly in the vessel wall with both kinetics and frequency of T-cell activation found to be similar to splenic and lymphoid T cells. Aortic homing of naïve T cells is regulated at least in part by the P-selectin glycosylated ligand-1 receptor. In experimental atherosclerosis the aorta supports CD4+ T-cell activation selectively driving Th1 polarization. By contrast, secondary lymphoid organs display Treg expansion. Conclusion: Our results demonstrate that the aorta can support T-cell priming and that naïve T cells traffic between the circulation and vessel wall. These data underpin the paradigm that local priming of T cells specific for plaque antigens contributes to atherosclerosis progression

A dynastic elite in monumental Neolithic society

The nature and distribution of political power in Europe during the Neolithic era remains poorly understood. During this period, many societies began to invest heavily in building monuments, which suggests an increase in social organization. The scale and sophistication of megalithic architecture along the Atlantic seaboard, culminating in the great passage tomb complexes, is particularly impressive. Although co-operative ideology has often been emphasised as a driver of megalith construction, the human expenditure required to erect the largest monuments has led some researchers to emphasize hierarchy—of which the most extreme case is a small elite marshalling the labour of the masses. Here we present evidence that a social stratum of this type was established during the Neolithic period in Ireland. We sampled 44 whole genomes, among which we identify the adult son of a first-degree incestuous union from remains that were discovered within the most elaborate recess of the Newgrange passage tomb. Socially sanctioned matings of this nature are very rare, and are documented almost exclusively among politico-religious elites—specifically within polygynous and patrilineal royal families that are headed by god-kings. We identify relatives of this individual within two other major complexes of passage tombs 150 km to the west of Newgrange, as well as dietary differences and fine-scale haplotypic structure (which is unprecedented in resolution for a prehistoric population) between passage tomb samples and the larger dataset, which together imply hierarchy. This elite emerged against a backdrop of rapid maritime colonization that displaced a unique Mesolithic isolate population, although we also detected rare Irish hunter-gatherer introgression within the Neolithic population

Dnmt3a regulates emotional behavior and spine plasticity in the nucleus accumbens.

Despite abundant expression of DNA methyltransferases (Dnmts) in brain, the regulation and behavioral role of DNA methylation remain poorly understood. We found that Dnmt3a expression was regulated in mouse nucleus accumbens (NAc) by chronic cocaine use and chronic social defeat stress. Moreover, NAc-specific manipulations that block DNA methylation potentiated cocaine reward and exerted antidepressant-like effects, whereas NAc-specific Dnmt3a overexpression attenuated cocaine reward and was pro-depressant. On a cellular level, we found that chronic cocaine use selectively increased thin dendritic spines on NAc neurons and that DNA methylation was both necessary and sufficient to mediate these effects. These data establish the importance of Dnmt3a in the NAc in regulating cellular and behavioral plasticity to emotional stimuli

Noonan syndrome and related disorders: Alterations in growth and puberty

Noonan syndrome is a relatively common multiple malformation syndrome with characteristic facies, short stature and congenital heart disease, most commonly pulmonary stenosis (Noonan, Clin Pediatr, 33:548–555, 1994). Recently, a mutation in the PTPN11 gene (Tartaglia, Mehler, Goldberg, Zampino, Brunner, Kremer et al., Nat Genet, 29:465–468, 2001) was found to be present in about 50% of individuals with Noonan syndrome. The phenotype noted in Noonan syndrome is also found in a number of other syndromes which include LEOPARD (Gorlin, Anderson, Blaw, Am J Dis Child, 17:652–662, 1969), Cardio-facio-cutaneous syndrome (Reynolds, Neri, Hermann, Blumberg, Coldwell, Miles et al., Am J Med Genet, 28:413–427, 1986) and Costello syndrome (Hennekam, Am J Med Genet, 117C(1):42–48, 2003). All three of these syndromes share similar cardiac defects and all have postnatal short stature. Very recently, HRAS mutations (Aoki, Niihori, Kawame, Kurosawa, Ohashi, Tanaka et al., Nat Genet, 37:1038–1040, 2005) have been found in the Costello syndrome and germline mutations in KRAS and BRAF genes (Rodriguez-Viciana, Tetsu, Tidyman, Estep, Conger, Santa Cruz et al., Nat Genet,2006; Niihori, Aoki, Narumi, Neri, Cave, Verloes et al., Nat Genet, 38:294–296, 2006) in the Cardio-facio-cutaneous syndrome. Phenotypic overlap between these genetic disorders can now be explained since each is caused by germline mutations that are major components of the RAS-MAPK pathway. This pathway plays an important role in growth factor and cytokine signaling as well as cancer pathogenesis

Increased FGF23 protects against detrimental cardio-renal consequences during elevated blood phosphate in CKD

The phosphaturic hormone FGF23 is elevated in chronic kidney disease (CKD). The risk of premature death is substantially higher in the CKD patient population, with cardiovascular disease (CVD) as the leading mortality cause at all stages of CKD. Elevated FGF23 in CKD has been associated with increased odds for all-cause mortality; however, whether FGF23 is associated with positive adaptation in CKD is unknown. To test the role of FGF23 in CKD phenotypes, a late osteoblast/osteocyte conditional flox-Fgf23 mouse (Fgf23fl/fl/Dmp1-Cre+/-) was placed on an adenine-containing diet to induce CKD. Serum analysis showed casein-fed Cre+ mice had significantly higher serum phosphate and blood urea nitrogen (BUN) versus casein diet and Cre- genotype controls. Adenine significantly induced serum intact FGF23 in the Cre- mice over casein-fed mice, whereas Cre+ mice on adenine had 90% reduction in serum intact FGF23 and C-terminal FGF23 as well as bone Fgf23 mRNA. Parathyroid hormone was significantly elevated in mice fed adenine diet regardless of genotype, which significantly enhanced midshaft cortical porosity. Echocardiographs of the adenine-fed Cre+ hearts revealed profound aortic calcification and cardiac hypertrophy versus diet and genotype controls. Thus, these studies demonstrate that increased bone FGF23, although associated with poor outcomes in CKD, is necessary to protect against the cardio-renal consequences of elevated tissue phosphate

Women and Illegal Activities: Gender Differences and Women's Willingness to Comply Over Time

In recent years the topics of illegal activities such as corruption or tax evasion have attracted a great deal of attention. However, there is still a lack of substantial empirical evidence about the determinants of compliance. The aim of this paper is to investigate empirically whether women are more willing to be compliant than men and whether we observe (among women and in general) differences in attitudes among similar age groups in different time periods (cohort effect) or changing attitudes of the same cohorts over time (age effect) using data from eight Western European countries from the World Values Survey and the European Values Survey that span the period from 1981 to 1999. The results reveal higher willingness to comply among women and an age rather than a cohort effect. Working Paper 06-5