Recent advances in lamellarin alkaloids: isolation, synthesis and activity

Lamellarins are a large family of marine alkaloids with potential anticancer activity that have been isolated from diverse marine organisms, mainly ascidians and sponges. All lamellarins feature a 3,4-diarylpyrrole system. Pentacyclic lamellarins, whose polyheterocyclic system has a pyrrole core, are the most active compounds. Some of these alkaloids are potently cytotoxic to various tumor cell lines. To date, Lam-D and Lam-H have been identified as lead compounds for the inhibition of topoisomerase I and HIV-1 integrase, respectively nuclear enzymes which are over-expressed in deregulation disorders. Moreover,these compounds have been reported for their efficacy in treatment of multi-drug resistant (MDR) tumors cells without mediated drug efflux, as well as their immunomodulatory activity and selectivity towards melanoma cell lines. This article is an overview of recent literature on lamellarins, encompassing their isolation, recent synthetic strategies for their total synthesis, the preparation of their analogs, studies on their mechanisms of action, and their structure-activity relationships (SAR).

Potential of local bio-geoengineering to mitigate dangerous temperature increases in a global warming scenario

Crops and forests are already responding to rising atmospheric carbon dioxide and air temperatures. Increasing atmospheric CO2 concentrations are expected to enhance plant photosynthesis. Nevertheless, after long-term exposure, plants acclimate and show a reduction in photosynthetic activity (i.e. down-regulation). If in the future the Earth"s temperature is allowed to rise further, plant ecosystems and food security will both face significant threats. The scientific community has recognized that an increase in global temperatures should remain below 2°C in order to combat climate change. All this evidence suggests that, in parallel with reductions in CO2 emissions, a more direct approach to mitigate global warming should be considered. We propose here that global warming could be partially mitigated directly through local bio-geoengineering approaches. For example, this could be done through the management of solar radiation at surface level, i.e. by increasing global albedo. Such an effect has been documented in the south-eastern part of Spain, where a significant surface air temperature trend of -0.3°C per decade has been observed due to a dramatic expansion of greenhouse horticulture.

Potential of local bio-geoengineering to mitigate dangerous temperature increases in a global warming scenario

Crops and forests are already responding to rising atmospheric carbon dioxide and air temperatures. Increasing atmospheric CO2 concentrations are expected to enhance plant photosynthesis. Nevertheless, after long-term exposure, plants acclimate and show a reduction in photosynthetic activity (i.e. down-regulation). If in the future the Earth"s temperature is allowed to rise further, plant ecosystems and food security will both face significant threats. The scientific community has recognized that an increase in global temperatures should remain below 2°C in order to combat climate change. All this evidence suggests that, in parallel with reductions in CO2 emissions, a more direct approach to mitigate global warming should be considered. We propose here that global warming could be partially mitigated directly through local bio-geoengineering approaches. For example, this could be done through the management of solar radiation at surface level, i.e. by increasing global albedo. Such an effect has been documented in the south-eastern part of Spain, where a significant surface air temperature trend of -0.3°C per decade has been observed due to a dramatic expansion of greenhouse horticulture.

Predicting the potential for lightning activity in mediterranean storms based on the WRF model dynamic and microphysical fields

A new parameter is introduced: the lightning potential index (LPI), which is a measure of the potential for charge generation and separation that leads to lightning flashes in convective thunderstorms. The LPI is calculated within the charge separation region of clouds between 0 C and 20 C, where the noninductive mechanism involving collisions of ice and graupel particles in the presence of supercooled water is most effective. As shown in several case studies using the Weather Research and Forecasting (WRF) model with explicit microphysics, the LPI is highly correlated with observed lightning. It is suggested that the LPI may be a useful parameter for predicting lightning as well as a tool for improving weather forecasting of convective storms and heavy rainfall.

Feedback-related Brain Potential Activity Complies with Basic Assumptions of Associative Learning Theory

Feedback-related negativity (FRN) is an ERP component that distinguishes positive from negative feedback. FRN has been hypothesized to be the product of an error signal that may be used to adjust future behavior. In addition, associative learning models assume that the trial-to-trial learning of cueoutcome mappings involves the minimization of an error term. This study evaluated whether FRN is a possible electrophysiological correlate of this error term in a predictive learning task where human subjects were asked to learn different cueoutcome relationships. Specifically, we evaluated the sensitivity of the FRN to the course of learning when different stimuli interact or compete to become a predictor of certain outcomes. Importantly, some of these cues were blocked by more informative or predictive cues (i.e., the blocking effect). Interestingly, the present results show that both learning and blocking affect the amplitude of the FRN component. Furthermore, independent analyses of positive and negative feedback event-related signals showed that the learning effect was restricted to the ERP component elicited by positive feedback. The blocking test showed differences in the FRN magnitude between a predictive and a blocked cue. Overall, the present results show that ERPs that are related to feedback processing correspond to the main predictions of associative learning models. ■

Identification of potential small molecule binding pockets on Rho family GTPases

Rho GTPases are conformational switches that control a wide variety of signaling pathways critical for eukaryotic cell development and proliferation. They represent attractive targets for drug design as their aberrant function and deregulated activity is associated with many human diseases including cancer. Extensive high-resolution structures (.100) and recent mutagenesis studies have laid the foundation for the design of new structure-based chemotherapeutic strategies. Although the inhibition of Rho signaling with drug-like compounds is an active area of current research, very little attention has been devoted to directly inhibiting Rho by targeting potential allosteric non-nucleotide binding sites. By avoiding the nucleotide binding site, compounds may minimize the potential for undesirable off-target interactions with other ubiquitous GTP and ATP binding proteins. Here we describe the application of molecular dynamics simulations, principal component analysis, sequence conservation analysis, and ensemble small-molecule fragment mapping to provide an extensive mapping of potential small-molecule binding pockets on Rho family members. Characterized sites include novel pockets in the vicinity of the conformationaly responsive switch regions as well as distal sites that appear to be related to the conformations of the nucleotide binding region. Furthermore the use of accelerated molecular dynamics simulation, an advanced sampling method that extends the accessible time-scale of conventional simulations, is found to enhance the characterization of novel binding sites when conformational changes are important for the protein mechanism.

Nanomotors: new strategies of (bio)sensing based on motion

Nanomotors are nanoscale devices capable of converting energy into movement and forces. Among them, self-propelled nanomotors offer considerable promise for developing new and novel bioanalytical and biosensing strategies based on the direct isolation of target biomolecules or changes in their movement in the presence of target analytes. The mainachievements of this project consists on the development of receptor-functionalized nanomotors that offer direct and rapid target detection, isolation and transport from raw biological samples without preparatory and washing steps. For example, microtube engines functionalized with aptamer, antibody, lectin and enzymes receptors were used for the direct isolation of analytes of biomedical interest, including proteins and whole cells, among others. A target protein was also isolated from a complex sample by using an antigen-functionalized microengine navigating into the reservoirs of a lab-on-a-chip device. The new nanomotorbased target biomarkers detection strategy not only offers highly sensitive, rapid, simple and low cost alternative for the isolation and transport of target molecules, but also represents a new dimension of analytical information based on motion. The recognition events can be easily visualized by optical microscope (without any sophisticated analytical instrument) to reveal the target presence and concentration. The use of artificial nanomachines has shown not only to be useful for (bio)recognition and (bio)transport but also for detection of environmental contamination and remediation. In this context, micromotors modified with superhydrophobic layer demonstrated that effectively interacted, captured, transported and removed oil droplets from oil contaminated samples. Finally, a unique micromotor-based strategy for water-quality testing, that mimics live-fish water-quality testing, based on changes in the propulsion behavior of artificial biocatalytic microswimmers in the presence of aquatic pollutants was also developed. The attractive features of the new micromachine-based target isolation and signal transduction protocols developed in this project offer numerous potential applications in biomedical diagnostics, environmental monitoring, and forensic analysis.

Changes in leisure time and occupational physical activity over 8 years: The Cornellà health Interview Survey Follow-Up Study

Aim: To describe changes in leisure time and occupational physical activity status in an urban Mediterranean population-based cohort, and to evaluate sociodemographic, health-related and lifestyle correlates of such changes. Methods: Data for this study come from the Cornellè Health Interview Survey Follow-Up Study, a prospective cohort study of a representative sample (n¿=¿2500) of the population. Participants in the analysis reported here include 1246 subjects (567 men and 679 women) who had complete data on physical activity at the 1994 baseline survey and at the 2002 follow-up. We fitted Breslow-Cox regression models to assess the association between correlates of interest and changes in physical activity. Results: Regarding leisure time physical activity, 61.6% of cohort members with ¿sedentary¿ habits in 1994 changed their status to ¿light/moderate¿ physical activity in 2002, and 70% who had ¿light/moderate¿ habits in 1994 did not change their activity level. Regarding occupational physical activity, 74.4% of cohort members who were ¿active¿ did not change their level of activity, and 64.3% of participants with ¿sedentary¿ habits in 1994 changed to ¿active¿ occupational physical activity. No clear correlates of change in physical activity were identified in multivariate analyses. Conclusion: While changes in physical activity are evident in this population-based cohort, no clear determinants of such changes were recognised. Further longitudinal studies including other potential individual and contextual determinants are needed to better understand determinants of changes in physical activity at the population level.

Membrane-destabilizing activity of pH-responsive cationic lysine-based surfactants: role of charge position and alkyl chain length

Many strategies for treating diseases require the delivery of drugs into the cell cytoplasm following internalization within endosomal vesicles. Thus, compounds triggered by low pH to disrupt membranes and release endosomal contents into the cytosol are of particular interest. Here, we report novel cationic lysine-based surfactants (hydrochloride salts of N¿- and N¿-acyl lysine methyl ester) that differ in the position of the positive charge and the length of the alkyl chain. Amino acid-based surfactants could be promising novel biomaterials in drug delivery systems, given their biocompatible properties and low cytotoxic potential. We examined their ability to disrupt the cell membrane in a range of pH values, concentrations and incubation times, using a standard hemolysis assay as a model of endosomal membranes. Furthermore, we addressed the mechanism of surfactant-mediated membrane destabilization, including the effects of each surfactant on erythrocyte morphology as a function of pH. We found that only surfactants with the positive charge on the ¿-amino group of lysine showed pH-sensitive hemolytic activity and improved kinetics within the endosomal pH range, indicating that the positive charge position is critical for pH-responsive behavior. Moreover, our results showed that an increase in the alkyl chain length from 14 to 16 carbon atoms was associated with a lower ability to disrupt cell membranes. Knowledge on modulating surfactant-lipid bilayer interactions may help us to develop more efficient biocompatible amino acid-based drug delivery devices.

Antimicrobial Activity of Iberian macroalgae

The antibacterial and antifungal activity of 82 marine macroalgae (18 Chlorophyceae, 25 Phaeophyceae and 39 Rhodophyceae) was studied to evaluate their potential for being used as natural preservatives in the cosmetic industry. The bioactivity was analysed from crude extracts of fresh and lyophilised samples against three Gram-positive bacteria, two Gram-negative bacteria and one yeast using the agar diffusion technique. The samples were collected seasonally from Mediterranean and Atlantic coasts of the Iberian Peninsula. Of the macroalgae analysed, 67% were active against at least one of the six test microorganisms. The highest percentage of active taxa was found in Phaeophyceae (84%), followed by Rhodophyceae (67%) and Chlorophyceae (44%). Nevertheless, red algae had both the highest values and the broadest spectrum of bioactivity. In particular, Bonnemaisonia asparagoides, Bonnemaisonia hamifera, Asparagopsis armata and Falkenbergia rufolanosa (Bonnemaisoniales) were the most active taxa. Bacillus cereus was the most sensitive test microorganism and Pseudomonas aeruginosa was the most resistant. The highest percentages of active taxa from Phaeophyceae and Rhodophyceae were found in autumn, whereas they were found in summer for Chlorophyceae.

Self reported physical activity, public health, and perceived environment: results from a comparative European study

The focus of physical activity promotion is moving from methods for increasing health enhancing physical activity on the individual level to higher level strategies including environmental and policy approaches. Scientific inquiry, traditionally related to individual-based strategies, requires adaptation and refinement when environmental and policy changes become more relevant. The objective of this study is to investigate the significance for behaviour and health of community-based environments that encourage physical activity. DESIGN AND SETTING The article presents data and results from a cross sectional comparative survey of the general population in six European countries (Belgium, Finland, Germany (East and West), Netherlands, Spain, Switzerland). Specifically, the relation between perceived community-based opportunities for physical activity, self reported physical activity, and self rated health status is investigated. PARTICIPANTS Representative samples of general populations (adults 18 years or older). Overall response rate: 53.5%. Sample sizes realised: Belgium: n=389; Finland: n=400; Germany (East): n = 913; Germany (West): n=489; Netherlands: n=366; Spain: n=380; Switzerland: n=406. MAIN RESULTS Analyses show that best opportunities are reported by people who are lightly to moderately physically active. People's self rated health is moderately, but significantly associated with both perceived opportunities, and physical activity itself. These predictors interact in that especially for women, the health impact of physical activity is more pronounced in case of good opportunities. CONCLUSIONS The paper shows the potential of opportunities within residential and community environments with regard to physical activity, both for behaviour and health. Opportunities may enable the population, especially women, to develop an active lifestyle, and thus improve their health. Future studies with objective indicators for physical activity related environments should test the findings that are based on perceptions.

Do walking strategies to increase physical activity reduce reported sitting in workplaces: a randomized control trial

Background: Interventions designed to increase workplace physical activity may not automatically reduce high volumes of sitting, a behaviour independently linked to chronic diseases such as obesity and type II diabetes. This study compared the impact two different walking strategies had on step counts and reported sitting times. Methods: Participants were white-collar university employees (n = 179; age 41.3 ± 10.1 years; 141 women), who volunteered and undertook a standardised ten-week intervention at three sites. Preintervention step counts (Yamax SW-200) and self-reported sitting times were measured over five consecutive workdays. Using pre-intervention step counts, employees at each site were randomly allocated to a control group (n = 60; maintain normal behaviour), a route-based walking group (n = 60; at least 10 minutes sustained walking each workday) or an incidental walking group (n = 59; walking in workday tasks). Workday step counts and reported sitting times were re-assessed at the beginning, mid- and endpoint of intervention and group mean± SD steps/day and reported sitting times for pre-intervention and intervention measurement points compared using a mixed factorial ANOVA; paired sample-t-tests were used for follow-up, simple effect analyses. Results: A significant interactive effect (F = 3.5; p < 0.003) was found between group and step counts. Daily steps for controls decreased over the intervention period (-391 steps/day) and increased for route (968 steps/day; t = 3.9, p < 0.000) and incidental (699 steps/day; t = 2.5, p < 0.014) groups. There were no significant changes for reported sitting times, but average values did decrease relative to the control (routes group = 7 minutes/day; incidental group = 15 minutes/day). Reductions were most evident for the incidental group in the first week of intervention, where reported sitting decreased by an average of 21 minutes/day (t = 1.9; p < 0.057). Conclusion: Compared to controls, both route and incidental walking increased physical activity in white-collar employees. Our data suggests that workplace walking, particularly through incidental movement, also has the potential to decrease employee sitting times, but there is a need for on-going research using concurrent and objective measures of sitting, standing and walking.

Differential pharmacologic properties of the two C75 enantiomers: (+)-C75 is a strong anorectic drug. (-)-C75 has antitumour activity

C75 is a synthetic compound described as having antitumoral properties. It produces hypophagia and weight loss in rodents, limiting its use in cancer therapy but identify- ing it as a potential anti-obesity drug. C75 is a fatty acid synthase (FAS) inhibitor and, through its coenzyme A (CoA) derivative, it acts as a carnitine palmitoyltransferase (CPT) 1 inhibitor. Racemic mixtures of C75 have been used in all the previous studies; however, the potential dif- ferent biological activities of C75 enantiomers have not been examined yet. To address this question we synthesized the two C75 enantiomers separately. Our results showed that ( )- C75 inhibits FAS activity in vitro and has a cytotoxic effect on tumor cell lines, without affecting food consumption. (+)-C75 inhibits CPT1 and its administration produces anorexia, suggesting that central inhibition of CPT1 is essential for the anorectic effect of C75. The differential activity of C75 enantiomers may lead to the development of potential new specific drugs for cancer and obesity.

Differential pharmacologic properties of the two C75 enantiomers: (+)-C75 is a strong anorectic drug. (-)-C75 has antitumour activity

C75 is a synthetic compound described as having antitumoral properties. It produces hypophagia and weight loss in rodents, limiting its use in cancer therapy but identify- ing it as a potential anti-obesity drug. C75 is a fatty acid synthase (FAS) inhibitor and, through its coenzyme A (CoA) derivative, it acts as a carnitine palmitoyltransferase (CPT) 1 inhibitor. Racemic mixtures of C75 have been used in all the previous studies; however, the potential dif- ferent biological activities of C75 enantiomers have not been examined yet. To address this question we synthesized the two C75 enantiomers separately. Our results showed that ( )- C75 inhibits FAS activity in vitro and has a cytotoxic effect on tumor cell lines, without affecting food consumption. (+)-C75 inhibits CPT1 and its administration produces anorexia, suggesting that central inhibition of CPT1 is essential for the anorectic effect of C75. The differential activity of C75 enantiomers may lead to the development of potential new specific drugs for cancer and obesity.

Prognostic value of cortically induced motor evoked activity by TMS in chronic stroke: caveats from a very revealing single clinical case

Background: We report the case of a chronic stroke patient (62 months after injury) showing total absence of motor activity evoked by transcranial magnetic stimulation (TMS) of spared regions of the left motor cortex, but near-to-complete recovery of motor abilities in the affected hand. Case presentation: Multimodal investigations included detailed TMS based motor mapping, motor evoked potentials (MEP), and Cortical Silent period (CSP) as well as functional magnetic resonance imaging (fMRI) of motor activity, MRI based lesion analysis and Diffusion Tensor Imaging (DTI) Tractography of corticospinal tract (CST). Anatomical analysis revealed a left hemisphere subinsular lesion interrupting the descending left CST at the level of the internal capsule. The absence of MEPs after intense TMS pulses to the ipsilesional M1, and the reversible suppression of ongoing electromyographic (EMG) activity (indexed by CSP) demonstrate a weak modulation of subcortical systems by the ipsilesional left frontal cortex, but an inability to induce efficient descending volleys from those cortical locations to right hand and forearm muscles. Functional MRI recordings under grasping and finger tapping patterns involving the affected hand showed slight signs of subcortical recruitment, as compared to the unaffected hand and hemisphere, as well as the expected cortical activations. Conclusions: The potential sources of motor voluntary activity for the affected hand in absence of MEPs are discussed. We conclude that multimodal analysis may contribute to a more accurate prognosis of stroke patients.