Noise-Induced Phase Space Transport in Two-Dimensional Hamiltonian Systems

First passage time experiments were used to explore the effects of low amplitude noise as a source of accelerated phase space diffusion in two-dimensional Hamiltonian systems, and these effects were then compared with the effects of periodic driving. The objective was to quantify and understand the manner in which ``sticky'' chaotic orbits that, in the absence of perturbations, are confined near regular islands for very long times, can become ``unstuck'' much more quickly when subjected to even very weak perturbations. For both noise and periodic driving, the typical escape time scales logarithmically with the amplitude of the perturbation. For white noise, the details seem unimportant: Additive and multiplicative noise typically have very similar effects, and the presence or absence of a friction related to the noise by a Fluctuation-Dissipation Theorem is also largely irrelevant. Allowing for colored noise can significantly decrease the efficacy of the perturbation, but only when the autocorrelation time becomes so large that there is little power at frequencies comparable to the natural frequencies of the unperturbed orbit. Similarly, periodic driving is relatively inefficient when the driving frequency is not comparable to these natural frequencies. This suggests strongly that noise-induced extrinsic diffusion, like modulational diffusion associated with periodic driving, is a resonance phenomenon. The logarithmic dependence of the escape time on amplitude reflects the fact that the time required for perturbed and unperturbed orbits to diverge a given distance scales logarithmically in the amplitude of the perturbation.Comment: 15 pages, including 13 Figures and 1 Table, uses Phys. Rev. macro

Regulation of cell survival by sphingosine-1-phosphate receptor S1P1 via reciprocal ERK-dependent suppression of bim and PI-3-kinase/protein kinase C-mediated upregulation of Mcl-1

Although the ability of bioactive lipid sphingosine-1-phosphate (S1P) to positively regulate anti-apoptotic/pro-survival responses by binding to S1P1 is well known, the molecular mechanisms remain unclear. Here we demonstrate that expression of S1P1 renders CCL39 lung fibroblasts resistant to apoptosis following growth factor withdrawal. Resistance to apoptosis was associated with attenuated accumulation of pro-apoptotic BH3-only protein Bim. However, although blockade of extracellular signal-regulated kinase (ERK) activation could reverse S1P1-mediated suppression of Bim accumulation, inhibition of caspase-3 cleavage was unaffected. Instead S1P1-mediated inhibition of caspase-3 cleavage was reversed by inhibition of phosphatidylinositol-3-kinase (PI3K) and protein kinase C (PKC), which had no effect on S1P1 regulation of Bim. However, S1P1 suppression of caspase-3 was associated with increased expression of anti-apoptotic protein Mcl-1, the expression of which was also reduced by inhibition of PI3K and PKC. A role for the induction of Mcl-1 in regulating endogenous S1P receptor-dependent pro-survival responses in human umbilical vein endothelial cells was confirmed using S1P receptor agonist FTY720-phosphate (FTY720P). FTY720P induced a transient accumulation of Mcl-1 that was associated with a delayed onset of caspase-3 cleavage following growth factor withdrawal, whereas Mcl-1 knockdown was sufficient to enhance caspase-3 cleavage even in the presence of FTY720P. Consistent with a pro-survival role of S1P1 in disease, analysis of tissue microarrays from ER+ breast cancer patients revealed a significant correlation between S1P1 expression and tumour cell survival. In these tumours, S1P1 expression and cancer cell survival were correlated with increased activation of ERK, but not the PI3K/PKB pathway. In summary, pro-survival/anti-apoptotic signalling from S1P1 is intimately linked to its ability to promote the accumulation of pro-survival protein Mcl-1 and downregulation of pro-apoptotic BH3-only protein Bim via distinct signalling pathways. However, the functional importance of each pathway is dependent on the specific cellular context

Chaos and the continuum limit in the gravitational N-body problem II. Nonintegrable potentials

This paper continues a numerical investigation of orbits evolved in `frozen,' time-independent N-body realisations of smooth time-independent density distributions corresponding to both integrable and nonintegrable potentials, allowing for N as large as 300,000. The principal focus is on distinguishing between, and quantifying, the effects of graininess on initial conditions corresponding, in the continuum limit, to regular and chaotic orbits. Ordinary Lyapunov exponents X do not provide a useful diagnostic for distinguishing between regular and chaotic behaviour. Frozen-N orbits corresponding in the continuum limit to both regular and chaotic characteristics have large positive X even though, for large N, the `regular' frozen-N orbits closely resemble regular characteristics in the smooth potential. Viewed macroscopically both `regular' and `chaotic' frozen-N orbits diverge as a power law in time from smooth orbits with the same initial condition. There is, however, an important difference between `regular' and `chaotic' frozen-N orbits: For regular orbits, the time scale associated with this divergence t_G ~ N^{1/2}t_D, with t_D a characteristic dynamical time; for chaotic orbits t_G ~ (ln N) t_D. At least for N>1000 or so, clear distinctions exist between phase mixing of initially localised orbit ensembles which, in the continuum limit, exhibit regular versus chaotic behaviour. For both regular and chaotic ensembles, finite-N effects are well mimicked, both qualitatively and quantitatively, by energy-conserving white noise with amplitude ~ 1/N. This suggests strongly that earlier investigations of the effects of low amplitude noise on phase space transport in smooth potentials are directly relevant to real physical systems.Comment: 20 pages, including 21 FIGURES, uses RevTeX macro

Protein kinase Cδ expression in breast cancer as measured by real-time PCR, western blotting and ELISA

The protein kinase C (PKC) family of genes encode serine/threonine kinases that regulate proliferation, apoptosis, cell survival and migration. Multiple isoforms of PKC have been described, one of which is PKCδ. Currently, it is unclear whether PKCδ is involved in promoting or inhibiting cancer formation/progression. The aim of this study was therefore to investigate the expression of PKCδ in human breast cancer and relate its levels to multiple parameters of tumour progression. Protein kinase Cδ expression at the mRNA level was measured using real-time PCR (n=208) and at protein level by both immunoblotting (n=94) and ELISA (n=98). Following immunoblotting, two proteins were identified, migrating with molecular masses of 78 and 160 kDa. The 78 kDa protein is likely to be the mature form of PKCδ but the identity of the 160 kDa form is unknown. Levels of both these proteins correlated weakly but significantly with PKCδ concentrations determined by ELISA (for the 78 kDa form, r=0.444, P<0.005, n=91 and for the 160 kDa form, r=0.237, P=0.023, n=91) and with PKCδ mRNA levels (for the 78 kDa form, r=0.351, P=0.001, n=94 and for the 160 kDa form, r=0.216, P=0.037, n=94). Protein kinase Cδ mRNA expression was significantly higher in oestrogen receptor (ER)-positive compared with ER-negative tumours (P=0.007, Mann–Whitney U-test). Increasing concentrations of PKCδ mRNA were associated with reduced overall patient survival (P=0.004). Our results are consistent with a role for PKCδ in breast cancer progression

Day and night surgery: is there any influence in the patient postoperative period of urgent colorectal intervention?

Background Medical activity performed outside regular work hours may increase risk for patients and professionals. There is few data with respect to urgent colorectal surgery. The aim of this work was to evaluate the impact of daytime versus nighttime surgery on postoperative period of patients with acute colorectal disease. Methods A retrospective study was conducted in a sample of patients with acute colorectal disease who underwent urgent surgery at the General Surgery Unit of Braga Hospital, between January 2005 and March 2013. Patients were stratified by operative time of day into a daytime group (surgery between 8:00 and 20:59) and the nighttime group (21:00–7:59) and compared for clinical and surgical parameters. A questionnaire was distributed to surgeons, covering aspects related to the practice of urgent colorectal surgery and fatigue. Results A total of 330 patients were included, with 214 (64.8 %) in the daytime group and 116 (35.2 %) in the nighttime group. Colorectal cancer was the most frequent pathology. Waiting time (p?<?0.001) and total length of hospital stay (p?=?0.008) were significantly longer in the daytime group. There were no significant differences with respect to early or late complications. However, 100 % of surgeons reported that they are less proficient during nighttime. Conclusions Among patients with acute colorectal disease subjected to urgent surgery, there was no significant association between nighttime surgery and the presence of postoperative medical and surgical morbidities. Patients who were subjected to daytime surgery had longer length of stay at the hospital