Signal processing at the Ras circuit: what shapes Ras activation patterns?

A systems biology approach is applied to gain a quantitative understanding of the integration of signalling by the small GTPase Ras. The Ras protein acts as a critical switch in response to signals that determine the cell's fate. In unstimulated cells, Ras switching between an inactive GDP-binding and active GTP-binding state is controlled by the intrinsic catalytic activities of Ras. The calculated high sensitivity of the basal Ras-GTP fraction to changes in the rate constant of GTP-hydrolysis by Ras can account for the carcinogenic potential of Ras mutants with decreased GTPase activities. Extracelluar stimuli initiate Ras interactions with GDP/GTP exchange factors such as SOS, and GTP-hydrolysis activating proteins such as RasGAP. Our data on freshly isolated hepatocytes stimulated with epidermal growth factor (EGF) show transient SOS activation and sustained Ras-GTP patterns. We demonstrate that these dose-response data can only be explained by transient RasGAP activitation, and not by merely switching off the SOS signal, e.g. by inhibitory phosphorylation of SOS. A transient RasGAP activity can be brought about by a number of mechanisms. A comprehensive kinetic model of the EGF receptor (EGFR) network was developed to explore feasible molecular scenarios, including the receptor-mediated recruitment of SOS and RasGAP to the plasma membrane, phosphorylation of RasGAP and p190 RhoGAP by soluble tyrosine kinases, and RasGAP interactions with phosphoinositides and p190 RhoGAP. We show that a transient RasGAP association with EGFR followed by the capture of RasGAP through the formation of complexes with p190 RhoGAP can account for data on hepatocytes. In summary, our results demonstrate that a combination of experimental monitoring and integrated dynamic analysis is capable of dissecting regulatory mechanisms that govern cellular signal transduction.     

Kernel weight per spike: what contributes to it at the individual QTL level?

Spike length (SL), spikelet number (SPN) per spike, kernel number per spike (KNPS), and thousand-kernel weight (TKW) have strong genetic associations with kernel weight per spike (KWPS) in wheat. To investigate their genetic relationships at the individual quantitative trait locus (QTL) level, both unconditional and conditional QTL mapping for KWPS with respect to SL, SPN, KNPS, and TKW were conducted. Two related F_8:9 recombinant inbred line populations, comprising 485 and 229 lines, respectively, were used. The trait phenotypic performances of each population were evaluated in four different environments. Unconditional QTL mapping analysis identified 22 putative additive QTL for KWPS, five of which were stable QTL, and only QKwps-WJ-1B.2 showed significant additive-by-environment interaction effects. In comparison with unconditional QTL mapping analysis, conditional QTL mapping analysis indicated that, at the QTL level, KNPS and TKW contributed more to KWPS than did SL and SPN. Any unconditional QTL for KWPS detected in this study was associated with at least one of its four related traits. The present study will provide assistance in the understanding of the genetic relationships between KWPS and its related traits.     

Avoiding risk at what cost? Putting use of medicines for breastfeeding women into perspective

Breastfeeding women often need to take medicines, and therefore health professionals need to consider the effects of medication on lactation and the breastfed infant, and any associated risks. This commentary discusses the tragic case of a young woman with a history of mental illness who committed suicide in the postpartum period. She was determined to be a 'good mother' and breastfeed, and to avoid any potential adverse effects of medication on her breastfed infant. The final outcome was fatal for both mother and child. We argue that if women require medication during lactation, all risks need to be considered ?C the risk of not treating the maternal medical condition may greatly outweigh the potential risk to the breastfed infant.     

Debate: at what level of coronary heart disease risk should a statin be prescribed?

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are effective treatments for the primary and secondary prevention of coronary heart disease, but an outstanding issue is determining who should have such treatment. The benefit from treatment with statins appears to be proportional to the underlying risk of coronary heart disease and independent of the factors increasing risk. Most benefit will therefore be achieved by treating people at increased risk of coronary heart disease. Statins reduce coronary morbidity even when the risk of coronary heart disease is relatively low (6% over 10 years), but reduction in all-cause mortality, the true measure of safety has been shown only when the risk of a major coronary heart disease event is 15% over 10 years or greater. At this level of risk patients appear willing to take treatment to gain the benefit expected from statin treatment, and the cost effectiveness of statin treatment is within the range accepted for other treatments. The major impediments to the systematic introduction of statin treatment at this level of risk are the very high overall cost and the large workload in countries like Britain, where the population risk of coronary heart disease is high. For this reason, recent British guidelines correctly advise statin treatment for secondary prevention and primary prevention when the 10 year coronary heart disease risk is 30% or greater as the first priority, moving to a lower coronary heart disease threshold for primary prevention only when resources permit.     

People with disability and privacy in precision medicine research: what’s at stake?

Re-identification from data used in precision medicine research is presumed to create minimal risk but may disproportionately impact health disparity populations. We consider plausible privacy risks and the negative ramifications thereof for people with disabilities, the largest health disparity population in the USA, and suggest measures to address these concerns.     

The structures at the termini of chromosomes: what is there hidden under the cap ?

The telomeres are the nucleoproteic structures present at the ends of eukaryotic chromosomes. One can compare them to the protective ends of a shoelace; when the ends get eroded, the shoelace disintegrates and we dispose of it. The same thus applies to the chromosomes; when telomeres reach a critical threshold for function, the genome becomes unstable and the cell senesces. Therefore, telomeres, and particularly their terminal DNA structures, are critical for the integrity of the genome.     

Recording brain waves at the supermarket: what can we learn from a shopper's brain?

Communication and marketing campaigns have traditionally been divided into two lines: above the line (ATL) and below the line (BTL). ATL campaigns refer to communications such as TV, print, and outdoor displays that are intended to reach large audiences. The effects of ATL are inherently difficult to measure; we do not see the direct consequences of viewing an advertisement (i.e., a talking baby giving financial advice) and actual purchase of the product. ATL is intended to indirectly improve the impression of a brand. BTL campaigns refer to promotions and in-store displays and are designed to affect the point-of-purchase behavior. The effects of BTL are easier to measure; we see direct consequences of viewing a display (i.e., “Today Only, Two for the Price of One”) and eventual purchase of the product. BTL is intended to directly improve the impression of a brand. Neuroscience plays an important role in measuring the effects of marketing campaigns. Traditional methods of measurement (such as surveys and interviews) depend on the verbal ability of the consumer to articulate their motivations for purchasing a product. It is well known that participants are poor at introspective reasoning, leading to an eventual purchase that omits emotional elements. Recently, methods normally employed in cognitive neuroscience have been adapted for use in the evaluation of campaign effectiveness. These methods have increased our understanding of factors leading to economic decisions. The application of neuroscience in ATL campaigns is relatively straightforward. Participants view TV commercials, for example, seated in a comfortable setting with minimal movement while electroencephalogram (EEG) measures are monitored. These brain waves reveal cognitive events related to the media. Participants are exposed to a functional magnetic resonance imaging (fMRI) scanner to monitor changes in blood flow in various regions of the brain. Both of these methods are sensitive to underlying cognitive and emotional activity and are complimentary. EEG is more sensitive to time-locked events (i.e., story lines), whereas fMRI is more sensitive to the brain regions involved. The application of neuroscience in BTL campaigns is significantly more difficult to achieve. Participants move unconstrained in a shopping environment while EEG and eye movements are monitored. In this scenario, fMRI is not possible. fMRI can be used with virtual store mock-ups, but it is expensive and seldom used. We have developed a technology that allows for the measurement of EEG in an unobtrusive manner. The intent is to record the brain waves of participants during their day-to-day shopping experience. A miniaturized video recorder, EEG amplifiers, and eye-tracking systems are used. Digital signal processing is employed to remove the substantial artifact generated by eye movements and motion. Eye fixations identify specific viewings of products and displays, and they are used for synchronizing the behavior with EEG response. The location of EEG sources is determined by the use of a source reconstruction software.     

Cardiac adrenoceptors at low temperature: what is the experimental evidence for the adrenoceptor interconversion hypothesis?

Isolated heart preparations of frog and rat were used to test the validity of the adrenoceptor interconversion hypothesis. This hypothesis claims that low temperature converts the inotropic beta-adrenoceptors in isolated frog and rat heart to alpha-adrenoceptors. The present results do not support the adrenoceptor interconversion hypothesis. In the isolated frog ventricle, lowering the temperature from 24 C to 14 C did not significantly alter the inotropic potency of the sympathomimetic drugs isoprenaline, epinephrine, and phenylephrine and did not reduce the potency of the beta-adrenoceptor blocking drug propranolol as an epinephrine antagonist. In the isolated rat left atrium, lowering the temperature from 31 C to 17-19 C did not significantly change the inotropic potency of isoprenaline, norepinephrine and phenylephrine, did not diminish the potency of propranolol, and did not increase the potency of the alpha-adrenoceptor blocking drug phentolamine.--Benfey, B. G. Cardiac adrenoceptors at low temperature; what is the experimental evidence for the adrenoceptor interconversion hypothesis?     

Hatching date vs laying date: what should we look at to study avian optimal timing of reproduction?

Most research conducted on optimal timing of reproduction in birds has traditionally considered laying date of the first egg as the event that needs to be related to the time of maximum food availability. However, what (most) birds need to time with the seasonal peak of food availability is the moment of maximum food demand of their nestlings, which is more tightly related with hatching date than with laying date. After initiating egg laying, birds still have some opportunities to adjust the time of highest food demand, as during the several days elapsed between laying of the first egg until hatching, more precise cues will become available to birds in order to make a more accurate match with food availability. I provide an overview of the suite of mechanisms available to birds for shortening or enlarging the interval between laying and hatching date, which include laying gaps, adjustment of clutch size, variation in onset and intensity of incubation, and differential investment on eggs. Then I illustrate with an example the extent to which birds can adjust hatching dates after egg laying. I argue that birds should more accurately time hatching date rather than laying date to maximum food availability on the basis of available cues. Therefore, I suggest that researchers should target on hatching date rather than laying date to better study optimal timing of reproduction in birds. Exploration of responses other than adjusting laying date to changing environmental conditions will surely uncover key aspects of avian reproductive biology and behaviour that have been ignored until now. This is a necessary step towards a better understanding of capacities of organisms to adapt to a changing world in particular, and of fitness consequences of timing of reproduction in general.     

Statin therapy and stroke prevention: what was known, what is new and what is next?

PURPOSE OF REVIEW: Randomized trials have shown that statins may reduce the risk of primary stroke. There is no evidence however that statins can reduce recurrent stroke incidence. RECENT FINDINGS: In the SPARCL trial, patients with a recent stroke or transient ischemic attack randomized to atorvastatin 80 mg/day had a significant 16% relative risk reduction of stroke, and a 35% reduction in major coronary events compared with placebo. This was obtained despite 25% of the placebo arm patients receiving a commercially-available statin outside of the trial. Post-hoc analysis used blinded LDL-cholesterol measurements as a marker of adherence to lipid-lowering therapy. Compared with the group with no change or an increase in LDL-cholesterol (the group adherent to placebo or not taking a statin), the group with over 50% reduction in LDL-cholesterol had a significant 31% reduction in stroke. The next step is to define whether achieving LDL-cholesterol below 70 mg/dl is better than a standard dose of statin (LDL around 100-110 mg/dl) in the secondary prevention of stroke. SUMMARY: Statins are effective in reducing both first-ever and recurrent stroke, and this effect seems driven by the extent of LDL-cholesterol lowering.     

Actin in the nucleus: what form and what for?

Actin is an abundant protein in most nonmuscle cells. It has often been observed in isolated nuclei, yet cytoplasmic contamination was of course initially regarded as the most plausible origin. Numerous studies on nuclear actin appeared in the 1970s and 1980s, but the picture remained rather muddy. The viewpoint at that time was that actin-shown to move freely between cytoplasm and nucleus-was a mere "thermodynamic wanderer," transiently occupying the nucleus. More recently, evidence has been mounting that actin's presence in the nucleus is not simply governed by the laws of diffusion. The same holds true for the finding of various actin-related proteins in the nucleus, and the case for nuclear myosin, specifically myosin I, is now quite convincing. Moreover, the first intimations of functional roles of nuclear actin are now emerging. Here we examine the overall subject from cell biological and chemical perspectives. The major issue is no longer the presence of actin in the nucleus but rather its supramolecular organization, intranuclear locations, and, of course, functions. These issues interface with recent findings that reveal a surprisingly diverse repertoire of actin conformations and oligomer and polymer forms beyond monomeric G-actin and polymeric F-actin. We present ideas for advancing the nuclear actin field and call for a renewed attack on this major problem in cell biology.     

Community‐level effects of herbicide‐based restoration treatments: structural benefits but at what cost?

Invasive species alter ecosystem structure, impact biodiversity, and have significant economic costs. In Oregon's Willamette Valley, invasive grasses Arrhenatherum elatius and Schedonorus arundinaceus alter the dynamics of the phenologically paired interaction between an endangered butterfly, Icaricia icarioides fenderi (Fender's blue), and its larval host plant, Lupinus oreganus (Kincaid's lupine). To test methods to restore this interaction, we established a 3‐year experiment where a post‐emergent grass‐specific herbicide, fluazifop‐p‐butyl, was applied to Fender's blue habitat. Plant community data were recorded throughout the growing season at eight paired plots for 1 year prior to treatment and 3 years during treatment. We asked whether annual application of herbicide could reduce the height of invasive grasses to levels at or beneath the height of Kincaid's lupine racemes throughout the Fender's blue flight season. We hypothesized that native forb species, which are critical nectar sources for Fender's blue, would increase in cover and frequency following the release from competitive dominance of invasive grasses. Grass‐specific herbicide reduced grass height during the flight season of Fender's blue, but with several costs. We found no change in nectar and a suppression of lupine growth in plots in response to experimental herbicide treatment. Each study site had multiple secondary invaders; the long‐term impact of these new invaders is unknown. We suggest that herbicide application results in a net negative effect in the context of Fender's blue habitat restoration. That is, the costs to primary resources for Fender's blue and the influx of secondary invaders may be as problematic as the primary invasion by non‐native grasses.     

Was what ail’d ya what kill’d ya?

Making use of those Union Army veterans for whom death certificates are available, we compare the conditions with which they were diagnosed by Civil War pension surgeons to the causes of death on the certificates. We divide the data between those veterans who entered the pension system early because of war injuries and those who entered the pension system after the 1890 reform that made it available to many more veterans. We examine the correlation between specific medical conditions rated by the surgeons and death causes to gauge support for the hypothesis that death is attributable to something specific. We also examine the correlation between the accumulation of rated conditions to the length of time until death to gauge support for the “insult hypothesis.” In general, we find support for both hypotheses. Examining the hazard ratios for dying of a specific condition, there is support for the idea that what ail’d ya’ is what kill’d ya’.     

Statin pharmacogenomics: what have we learned, and what remains unanswered?

PURPOSE OF REVIEW: Statins are widely prescribed and are established as first-line therapy for the primary and secondary prevention of coronary heart disease. Response to treatment varies considerably from person to person; however, inherited traits (genetic variability) may play a central role in this inter-individual variation. The purpose of this review is to summarize recent progress in the research for exploring genetic determinants of clinical efficacy and safety of statin therapy. RECENT FINDINGS: In addition to 41 previous studies of 19 genes, the results of 17 pharmacogenomic studies investigating the relationship between common genetic variants and response to statin therapy in terms of lipid responses, clinical outcomes, and adverse events have been reported since January 2004 - 15 candidate genes related to pharmacodynamics and three to pharmacokinetics of statins. These reported data suggest that genetic variations influencing intestinal cholesterol absorption, cholesterol production, and lipoprotein catabolism may all play a role in modulating responsiveness, as well as genes involved in drug metabolism of statins. They also suggest that combined analysis of multiple variants in several genes, all of which have possible functional relations, is more likely to give significant results, especially when being performed with a larger number of participants. SUMMARY: Pharmacogenomic studies of statin therapy will provide a better picture as to who is most likely and least likely to benefit from treatment, which results in more individualized management of coronary artery disease.