Differential regulation of RasGAPs in cancer

Ever since their discovery as cellular counterparts of viral oncogenes more than 25 years ago, much progress has been made in understanding the complex networks of signal transduction pathways activated by oncogenic Ras mutations in human cancers. The activity of Ras is regulated by nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs), and much emphasis has been put into the biochemical and structural analysis of the Ras/GAP complex. The mechanisms by which GAPs catalyze Ras-GTP hydrolysis have been clarified and revealed that oncogenic Ras mutations confer resistance to GAPs and remain constitutively active. However, it is yet unclear how cells coordinate the large and divergent GAP protein family to promote Ras inactivation and ensure a certain biological response. Different domain arrangements in GAPs to create differential protein-protein and protein-lipid interactions are probably key factors determining the inactivation of the 3 Ras isoforms H-, K-, and N-Ras and their effector pathways. In recent years, in vitro as well as cell- and animal-based studies examining GAP activity, localization, interaction partners, and expression profiles have provided further insights into Ras inactivation and revealed characteristics of several GAPs to exert specific and distinct functions. This review aims to summarize knowledge on the cell biology of RasGAP proteins that potentially contributes to differential regulation of spatiotemporal Ras signaling.

Psychometric characteristics of the Spanish version of instruments to measure neck pain disability

Background: The NDI, COM and NPQ are evaluation instruments for disability due to NP. There was no Spanish version of NDI or COM for which psychometric characteristics were known. The objectives of this study were to translate and culturally adapt the Spanish version of the Neck Disability Index Questionnaire (NDI), and the Core Outcome Measure (COM), to validate its use in Spanish speaking patients with non-specific neck pain (NP), and to compare their psychometric characteristics with those of the Spanish version of the Northwick Pain Questionnaire (NPQ).Methods: Translation/re-translation of the English versions of the NDI and the COM was done blindly and independently by a multidisciplinary team. The study was done in 9 primary care Centers and 12 specialty services from 9 regions in Spain, with 221 acute, subacute and chronic patients who visited their physician for NP: 54 in the pilot phase and 167 in the validation phase. Neck pain (VAS), referred pain (VAS), disability (NDI, COM and NPQ), catastrophizing (CSQ) and quality of life (SF-12) were measured on their first visit and 14 days later. Patients' self-assessment was used as the external criterion for pain and disability. In the pilot phase, patients' understanding of each item in the NDI and COM was assessed, and on day 1 test-retest reliability was estimated by giving a second NDI and COM in which the name of the questionnaires and the order of the items had been changed.Results: Comprehensibility of NDI and COM were good. Minutes needed to fill out the questionnaires [median, (P25, P75)]: NDI. 4 (2.2, 10.0), COM: 2.1 (1.0, 4.9). Reliability: [ICC, (95%CI)]: NDI: 0.88 (0.80, 0.93). COM: 0.85 (0.75,0.91). Sensitivity to change: Effect size for patients having worsened, not changed and improved between days 1 and 15, according to the external criterion for disability: NDI: -0.24, 0.15, 0.66; NPQ: -0.14, 0.06, 0.67; COM: 0.05, 0.19, 0.92. Validity: Results of NDI, NPQ and COM were consistent with the external criterion for disability, whereas only those from NDI were consistent with the one for pain. Correlations with VAS, CSQ and SF-12 were similar for NDI and NPQ (absolute values between 0.36 and 0.50 on day 1, between 0.38 and 0.70 on day 15), and slightly lower for COM (between 0.36 and 0.48 on day 1, and between 0.33 and 0.61 on day 15). Correlation between NDI and NPQ: r = 0.84 on day 1, r = 0.91 on day 15. Correlation between COM and NPQ: r = 0.63 on day 1, r = 0.71 on day 15.Conclusion: Although most psychometric characteristics of NDI, NPQ and COM are similar, those from the latter one are worse and its use may lead to patients' evolution seeming more positive than it actually is. NDI seems to be the best instrument for measuring NP-related disability, since its results are the most consistent with patient's assessment of their own clinical status and evolution. It takes two more minutes to answer the NDI than to answer the COM, but it can be reliably filled out by the patient without assistance.

Brownian motion of spiral waves driven by spatiotemporal structured noise

Spiral chemical waves subjected to a spatiotemporal random excitability are experimentally and numerically investigated in relation to the light-sensitive Belousov-Zhabotinsky reaction. Brownian motion is identified and characterized by an effective diffusion coefficient which shows a rather complex dependence on the time and length scales of the noise relative to those of the spiral. A kinematically based model is proposed whose results are in good qualitative agreement with experiments and numerics.

Dynamics of turing patterns under spatiotemporal forcing

We study, both theoretically and experimentally, the dynamical response of Turing patterns to a spatiotemporal forcing in the form of a traveling-wave modulation of a control parameter. We show that from strictly spatial resonance, it is possible to induce new, generic dynamical behaviors, including temporally modulated traveling waves and localized traveling solitonlike solutions. The latter make contact with the soliton solutions of Coullet [Phys. Rev. Lett. 56, 724 (1986)] and generalize them. The stability diagram for the different propagating modes in the Lengyel-Epstein model is determined numerically. Direct observations of the predicted solutions in experiments carried out with light modulations in the photosensitive chlorine dioxide-iodine-malonic acid reaction are also reported.

Spatiotemporal order out of noise

Experimental observations of self-organized behavior arising out of noise are also described, and details on the numerical algorithms needed in the computer simulation of these problems are given.

Self-sustained spatiotemporal oscillations induced by membrane-bulk coupling

We propose a novel mechanism leading to spatiotemporal oscillations in extended systems that does not rely on local bulk instabilities. Instead, oscillations arise from the interaction of two subsystems of different spatial dimensionality. Specifically, we show that coupling a passive diffusive bulk of dimension d with an excitable membrane of dimension d-1 produces a self-sustained oscillatory behavior. An analytical explanation of the phenomenon is provided for d=1. Moreover, in-phase and antiphase synchronization of oscillations are found numerically in one and two dimensions. This novel dynamic instability could be used by biological systems such as cells, where the dynamics on the cellular membrane is necessarily different from that of the cytoplasmic bulk.

Excitability transitions and wave dynamics under spatiotemporal structured noise

We present an analytic and numerical study of the effects of external fluctuations in active media. Our analytical methodology transforms the initial stochastic partial differential equations into an effective set of deterministic reaction-diffusion equations. As a result we are able to explain and make quantitative predictions on the systematic and constructive effects of the noise, for example, target patterns created out of noise and traveling or spiral waves sustained by noise. Our study includes the case of realistic noises with temporal and spatial structures.

Generation of spatiotemporal colored noise

We develop an algorithm to simulate a Gaussian stochastic process that is non-¿-correlated in both space and time coordinates. The colored noise obeys a linear reaction-diffusion Langevin equation with Gaussian white noise. This equation is exactly simulated in a discrete Fourier space.

Spatiotemporal stochastic resonance in the Swift-Hohenberg equation

We show the appearance of spatiotemporal stochastic resonance in the Swift-Hohenberg equation. This phenomenon emerges when a control parameter varies periodically in time around the bifurcation point. By using general scaling arguments and by taking into account the common features occurring in a bifurcation, we outline possible manifestations of the phenomenon in other pattern-forming systems.

Expression cloning of a rat hepatic reduced glutathione transporter with canalicular characteristics

Using the Xenopus oocyte expression system, we have previously identified an approximately 4-kb fraction of mRNA from rat liver that expresses sulfobromophthalein-glutathione (BSP-GSH)-insensitive reduced glutathione (GSH) transport (Fernandez-Checa, J., J. R. Yi, C. Garcia-Ruiz, Z. Knezic, S. Tahara, and N. Kaplowitz. 1993. J. Biol. Chem. 268:2324-2328). Starting with a cDNA library constructed from this fraction, we have now isolated a single clone that expresses GSH transporter activity. The cDNA for the rat canalicular GSH transporter (RcGshT) is 4.05 kb with an open reading frame of 2,505 nucleotides encoding for a polypeptide of 835 amino acids (95,785 daltons). No identifiable homologies were found in searching various databases. An approximately 96-kD protein is generated in in vitro translation of cRNA for RcGshT. Northern blot analysis reveals a single 4-kb transcript in liver, kidney, intestine, lung, and brain. The abundance of mRNA for RcGshT in rat liver increased 3, 6, and 12 h after a single dose of phenobarbital. Insensitivity to BSP-GSH and induction by phenobarbital, unique characteristics of canalicular GSH secretion, suggest that RcGshT encodes for the canalicular GSH transporter.

Excitability transitions and wave dynamics under spatiotemporal structured noise

We present an analytic and numerical study of the effects of external fluctuations in active media. Our analytical methodology transforms the initial stochastic partial differential equations into an effective set of deterministic reaction-diffusion equations. As a result we are able to explain and make quantitative predictions on the systematic and constructive effects of the noise, for example, target patterns created out of noise and traveling or spiral waves sustained by noise. Our study includes the case of realistic noises with temporal and spatial structures.

Dynamics of turing patterns under spatiotemporal forcing

We study, both theoretically and experimentally, the dynamical response of Turing patterns to a spatiotemporal forcing in the form of a traveling-wave modulation of a control parameter. We show that from strictly spatial resonance, it is possible to induce new, generic dynamical behaviors, including temporally modulated traveling waves and localized traveling solitonlike solutions. The latter make contact with the soliton solutions of Coullet [Phys. Rev. Lett. 56, 724 (1986)] and generalize them. The stability diagram for the different propagating modes in the Lengyel-Epstein model is determined numerically. Direct observations of the predicted solutions in experiments carried out with light modulations in the photosensitive chlorine dioxide-iodine-malonic acid reaction are also reported.

Spatiotemporal order out of noise

Experimental observations of self-organized behavior arising out of noise are also described, and details on the numerical algorithms needed in the computer simulation of these problems are given.