Analysis of the effects of an oncogenic stress on the cell cycle in human tumoral cells

Although differing only for the last 24 aminoacids, the three major isoforms of p21 Ras (Ha-, Ki- and N \u2013Ras) can trigger alternative pathways of signal transduction, at least in part as a consequence of different post-translational modifications and subcellular localization. Ras mutations are a common event in tumorigenesis. In colorectal carcinomas (CRCs) the mutations affect almost exclusively Ki-Ras, while Ha-Ras mutations are mostly found in bladder carcinomas and N-Ras mutations in leukemia cells. In almost all cases, the genetic alteration is a point mutation in codons 12 or 13, and less frequently in codon 61. By affecting the GTPase activity of the protein, they always lead to a constitutively active protein. However, data obtained in different experimental systems or by analysis of primary and metastatic tumors show that not only mutations of different isoforms of Ras, but also mutations in different codons or different mutations in the same codon of the same isoform of Ras may have diverse biological consequences. To shed more light on the molecular mechanisms responsible for the different effects of Ras mutations, we have obtained stable clones of HT-29 (a human colorectal adenocarcinoma cell line in which the endogenous Ras genes are wild type) transfected with cDNAs codifying Ha-RasG12V, Ki-RasG12V and Ki-RasG13D, under the control of an hormone-inducible promoter. We found that the expression of each of these mutated Ras isoforms induces specific, different effects on cell morphology and growth rate. FACS analysis shows also a differential effect on the cell cycle. H-RasG12V expression, in addition, induces apoptosis, through caspase activation mediated by p53 independent, MEK-1 dependent expression of the CDK inhibitor p21

Slowly, slowly in the wind: 3D hydrodynamical simulations of wind mass transfer and angular-momentum loss in AGB binary systems

Wind mass transfer in binary systems with AGB donor stars plays a fundamental role in the formation of a variety of objects, including barium stars and CEMP stars. We carry out a comprehensive set of SPH simulations of wind-losing AGB stars in binaries, for a variety of binary mass ratios, orbital separations, initial wind velocities and rotation rates of the donor star. The initial parameters of the simulated systems are chosen to match the expected progenitors of CEMP stars. We find that the strength of interaction between the wind and the stars depends on both the wind-velocity-to-orbital-velocity ratio ($v_\infty/v_\mathrm{orb}$) and the binary mass ratio. Strong interaction occurs for close systems and comparable mass ratios, and gives rise to a complex morphology of the outflow and substantial angular-momentum loss, which leads to a shrinking of the orbit. As the orbital separation increases and the mass of the companion star decreases, the morphology of the outflow, as well as the angular-momentum loss, become more similar to the spherically symmetric wind case. We also explore the effects of tidal interaction and find that for orbital separations up to 7-10 AU, depending on mass ratio, spin-orbit coupling of the donor star occurs at some point during the AGB phase. If the initial wind velocity is relatively low, we find that corotation of the donor star results in a modified outflow morphology that resembles wind Roche-lobe overflow. In this case the mass-accretion efficiency and angular-momentum loss differ from those found for a non-rotating donor. Finally, we provide a relation for both the mass-accretion efficiency and angular-momentum loss as a function of $v_\infty/v_\mathrm{orb}$ and the binary mass ratio that can be easily implemented in a population synthesis code to study populations of barium stars, CEMP stars and other products of interaction in AGB binaries.Comment: Accepted for publication in A&A, 20 pages, 12 figures, 4 tables. Abstract abridged due to arXiv requirement

Gone with the wind: the impact of wind mass transfer on the orbital evolution of AGB binary systems

In low-mass binary systems, mass transfer is likely to occur via a slow and dense stellar wind when one of the stars is in the AGB phase. Observations show that many binaries that have undergone AGB mass transfer have orbital periods of 1-10 yr, at odds with the predictions of binary population synthesis models. We investigate the mass-accretion efficiency and angular-momentum loss via wind mass transfer in AGB binary systems. We use these quantities to predict the evolution of the orbit. We perform 3D hydrodynamical simulations of the stellar wind lost by an AGB star using the AMUSE framework. We approximate the thermal evolution of the gas by imposing a simple effective cooling balance and we vary the orbital separation and the velocity of the stellar wind. We find that for wind velocities $v_{\infty}$ larger than the relative orbital velocity of the system $v_\mathrm{orb}$ the flow is described by the Bondi-Hoyle-Lyttleton approximation and the angular-momentum loss is modest, leading to an expansion of the orbit. For low wind velocities an accretion disk is formed around the companion and the accretion efficiency as well as the angular-momentum loss are enhanced, implying that the orbit will shrink. We find that the transfer of angular momentum from the orbit to the outflowing gas occurs within a few orbital separations from the center of mass of the binary. Our results suggest that the orbital evolution of AGB binaries can be predicted as a function of the ratio $v_{\infty}/v_\mathrm{orb}$. Our results can provide insight into the puzzling orbital periods of post-AGB binaries and suggest that the number of stars entering into the common-envelope phase will increase. The latter can have significant implications for the expected formation rates of the end products of low-mass binary evolution, such as cataclysmic binaries, type Ia supernova and double white-dwarf mergers. [ABRIDGED]Comment: Accepted for publication in A&A, 17 pages, 11 figures, 3 tables. Abstract abridged due to arXiv requirement

The origin of life: chemical evolution of a metabolic system in a mineral honeycomb?

For the RNA-world hypothesis to be ecologically feasible, selection mechanisms acting on replicator communities need to be invoked and the corresponding scenarios of molecular evolution specified. Complementing our previous models of chemical evolution on mineral surfaces, in which selection was the consequence of the limited mobility of macromolecules attached to the surface, here we offer an alternative realization of prebiotic group-level selection: the physical encapsulation of local replicator communities into the pores of the mineral substrate. Based on cellular automaton simulations we argue that the effect of group selection in a mineral honeycomb could have been efficient enough to keep prebiotic ribozymes of different specificities and replication rates coexistent, and their metabolic cooperation protected from extensive molecular parasitism. We suggest that mutants of the mild parasites persistent in the metabolic system can acquire useful functions such as replicase activity or the production of membrane components, thus opening the way for the evolution of the first autonomous protocells on Earth

Fusion imaging for intra-operative ultrasound-based navigation in neurosurgery

The major shortcoming of image-guided navigation systems is the use of presurgically acquired image data, which does not account for intra-operative changes such as brain shift, tissue deformation and tissue removal occurring during the surgical procedure. Intra-operative ultrasound (iUS) is becoming widely used in neurosurgery but they lack orientation and panoramic view. In this article, we describe our procedure for US-based real-time neuro-navigation during surgery. We used fusion imaging between preoperative magnetic resonance imaging (MRI) and iUS for brain lesion removal in 67 patients so far. Surgical planning is based on preoperative MRI only. iUS images obtained during surgery are fused with the preoperative MRI. Surgery is performed under intra-operative US control. Relying on US imaging, it is possible to recalibrate navigated MRI imaging, adjusting distortion due to brain shift and tissue resection, continuously updating the two modalities. Ultrasound imaging provides excellent visualization of targets, their margins and surrounding structures. The use of navigated MRI is helpful in better understanding cerebral ultrasound images, providing orientation and panoramic view. Intraoperative US-guided neuro-navigation adjustments are very accurate and helpful in the event of brain shift. The use of this integrated system allows for a true real-time feedback during surgery

Tracking with heavily irradiated silicon detectors operated at cryogenic temperatures

In this work we show that a heavily irradiated double-sided silicon microstrip detector recovers its performance when operated at cryogenic temperatures. A DELPHI microstrip detector, irradiated to a fluence of $\sim\,4\times 10^{14}$ p/cm$^2$, no longer operational at room temperature, cannot be distinguished from a non-irradiated one when operated at $T<120$~K. Besides confirming the previously observed `Lazarus effect' in single diodes, these results establish for the first time, the possibility of using standard silicon detectors for tracking applications in extremely demanding radiation environments

Cardiac risk stratification in elective non-cardiac surgery: role of NT-proBNP

AIM: The aim of the study was to investigate the utility of NT-proBNP measurement for the stratification of presurgical cardiac risk. METHODS: Cardiac risk before elective non-cardiac surgery was evaluated in 82 consecutive patients. From each patient a venous blood sample was drawn to determinate NT-proBNP levels. Patients were followed up over three months in order to detect the occurrence of cardiac adverse events. RESULTS: NT-proBNP was positively correlated (P<0.0001) with age, days of hospitalization (P=0.001) and ASA class (P=0.001). High surgical risk (P<0.0001), diabetes (P=0.004), dyslipidemia (P=0.006) and elevated levels of NT-proBNP (P<0.0001) were significantly correlated with events. Using a logistic regression analysis we found an independent association between pre-operative elevated NT-proBNP and postoperative cardiac events (OR 1.2, 95% CI 1.0-1.4, P=0.01). CONCLUSION: Measuring NT-proBNP before non cardiac surgery in clinical practice could be useful to better stratify patients' risk

Strangeness enhancement at mid-rapidity in Pb-Pb collisions at 158 GeV/c

$K^{0}_{s}$, $\Lambda$, $\Xi$, $\Omega$ and negative particle yields and transverse mass spectra have been measured at central rapidity in Pb-Pb and p-Pb collisions at 158 $A$ GeV/$c$. The yields in Pb-Pb interactions % are presented as a function of the collision centrality and compared with those obtained from p-Pb collisions. Strangeness enhancement in Pb-Pb relative to p-Pb collisions increases with the strangeness content of the particle. Going from p-Pb to Pb-Pb, the strange particle yields increase faster than linearly with the number of participants $N_{part}$ up to $N_{part} \approx 100$, thereafter the increase becomes %linear with $N_{part}$. Yields are studied as a function of the number of nucleons participating in the collision $N_{part}$, which is estimated with the Glauber model. From p-Pb to Pb-Pb collisions the particle yields per participant increase substantially. The enhancement is more pronounced for multistrange particles, and exceeds an order of magnitude for the $\Omega$. For a number of participants, $N_{part}$, greater than $100$, however, all yields per participant appear to be constant

Protein CoAlation and antioxidant function of Coenzyme A in prokaryotic cells

In all living organisms, Coenzyme A (CoA) is an essential cofactor with a unique design allowing it to function as an acyl group carrier and a carbonyl-activating group in diverse biochemical reactions. It is synthesized in a highly conserved process in prokaryotes and eukaryotes that requires pantothenic acid (vitamin B5), cysteine and ATP. CoA and its thioester derivatives are involved in major metabolic pathways, allosteric interactions and the regulation of gene expression. A novel unconventional function of CoA in redox regulation has been recently discovered in mammalian cells and termed protein CoAlation. Here, we report for the first time that protein CoAlation occurs at a background level in exponentially growing bacteria and is strongly induced in response to oxidizing agents and metabolic stress. Over 12% ofS. aureusgene products were shown to be CoAlated in response to diamide-induced stress. In vitroCoAlation ofS. aureusglyceraldehyde-3-phosphate dehydrogenase (SaGAPDH) was found to inhibit its enzymatic activity and to protect the catalytic cysteine 151 from overoxidation by hydrogen peroxide (H2O2). These findings suggest that in exponentially growing bacteria CoA functions to generate metabolically active thioesters, while it also has the potential to act as a low molecular weight antioxidant in response to oxidative and metabolic stress