The Transfer of Evolved Artificial Immune System Behaviours between Small and Large Scale Robotic Platforms

This paper demonstrates that a set of behaviours evolved in simulation on a miniature robot (epuck) can be transferred to a much larger scale platform (a virtual Pioneer P3-DX) that also differs in shape, sensor type, sensor configuration and programming interface. The chosen architecture uses a reinforcement learning-assisted genetic algorithm to evolve the epuck behaviours, which are encoded as a genetic sequence. This sequence is then used by the Pioneers as part of an adaptive, idiotypic artificial immune system (AIS) control architecture. Testing in three different simulated worlds shows that the Pioneer can use these behaviours to navigate and solve object-tracking tasks successfully, as long as its adaptive AIS mechanism is in place.Comment: 12 pages, 3 figures, 2 tables, 9th International Conference on Artificial Evolution (EA 09)

A new efficient trial design for assessing reliability of ankle-brachial index measures by three different observer groups

BACKGROUND: The usual method of assessing the variability of a measure such as the ankle brachial index (ABI) as a function of different observer groups is to obtain repeated measurements. Because the number of possible observer-subject combinations is impractically large, only a few small studies on inter- and intraobserver variability of ABI measures have been carried out to date. The present study proposes a new and efficient study design. This paper describes the study methodology. METHODS: Using a partially balanced incomplete block design, six angiologists, six primary-care physicians and six trained medical office assistants performed two ABI measurements each on six individuals from a group of 36 unselected subjects aged 65–70 years. Each test subject is measured by one observer from each of the three observer groups, and each observer measures exactly six of the 36 subjects in the group. Each possible combination of two observers occurs exactly once per patient and is not repeated on a second subject. The study involved four groups of 36 subjects (144), plus standbys. RESULTS: The 192 volunteers present at the study day were similar in terms of demographic characteristics and vascular risk factors: mean age 68.6 ± 1.7; mean BMI 29.1 ± 4.6; mean waist-hip ratio 0.92 ± 0.09; active smokers 12%; hypertension 60.9%; hypercholesterolemia 53.4%; diabetic 17.2%. A complete set of ABI measurements (three observers performing two Doppler measurements each) was obtained from 108 subjects. From all other subjects at least one ABI measurement was obtained. The mean ABI was 1.08 (± 0.13), 15 (7.9%) volunteers had an ABI <0.9, and none had an ABI >1.4, i.e. a ratio that may be associated with increased stiffening of the arterial walls. CONCLUSION: This is the first large-scale study investigating the components of variability and thus reliability in ABI measurements. The advantage of the new study design introduced here is that only one sixth of the number of theoretically possible measurements is required to obtain information about measurement errors. Bland-Altman plots show that there are only small differences and no systematic bias between the observers from three occupational groups with different training backgrounds

Modulation of the conductance of a 2,2′-bipyridine-functionalized peptidic ion channel by Ni2+

An α-helical amphipathic peptide with the sequence H2N-(LSSLLSL)3-CONH2 was obtained by solid phase synthesis and a 2,2′-bipyridine was coupled to its N-terminus, which allows complexation of Ni2+. Complexation of the 2,2′-bipyridine residues was proven by UV/Vis spectroscopy. The peptide helices were inserted into lipid bilayers (nano black lipid membranes, nano-BLMs) that suspend the pores of porous alumina substrates with a pore diameter of 60 nm by applying a potential difference. From single channel recordings, we were able to distinguish four distinct conductance states, which we attribute to an increasing number of peptide helices participating in the conducting helix bundle. Addition of Ni2+ in micromolar concentrations altered the conductance behaviour of the formed ion channels in nano-BLMs considerably. The first two conductance states appear much more prominent demonstrating that the complexation of bipyridine by Ni2+ results in a considerable confinement of the observed multiple conductance states. However, the conductance levels were independent of the presence of Ni2+. Moreover, from a detailed analysis of the open lifetimes of the channels, we conclude that the complexation of Ni2+ diminishes the frequency of channel events with larger open times

Semi-automated non-target processing in GC × GC–MS metabolomics analysis: applicability for biomedical studies

Due to the complexity of typical metabolomics samples and the many steps required to obtain quantitative data in GC × GC–MS consisting of deconvolution, peak picking, peak merging, and integration, the unbiased non-target quantification of GC × GC–MS data still poses a major challenge in metabolomics analysis. The feasibility of using commercially available software for non-target processing of GC × GC–MS data was assessed. For this purpose a set of mouse liver samples (24 study samples and five quality control (QC) samples prepared from the study samples) were measured with GC × GC–MS and GC–MS to study the development and progression of insulin resistance, a primary characteristic of diabetes type 2. A total of 170 and 691 peaks were quantified in, respectively, the GC–MS and GC × GC–MS data for all study and QC samples. The quantitative results for the QC samples were compared to assess the quality of semi-automated GC × GC–MS processing compared to targeted GC–MS processing which involved time-consuming manual correction of all wrongly integrated metabolites and was considered as golden standard. The relative standard deviations (RSDs) obtained with GC × GC–MS were somewhat higher than with GC–MS, due to less accurate processing. Still, the biological information in the study samples was preserved and the added value of GC × GC–MS was demonstrated; many additional candidate biomarkers were found with GC × GC–MS compared to GC–MS

Control of Canalization and Evolvability by Hsp90

Partial reduction of Hsp90 increases expression of morphological novelty in qualitative traits of Drosophila and Arabidopsis, but the extent to which the Hsp90 chaperone also controls smaller and more likely adaptive changes in natural quantitative traits has been unclear. To determine the effect of Hsp90 on quantitative trait variability we deconstructed genetic, stochastic and environmental components of variation in Drosophila wing and bristle traits of genetically matched flies, differing only by Hsp90 loss-of-function or wild-type alleles. Unexpectedly, Hsp90 buffering was remarkably specific to certain normally invariant and highly discrete quantitative traits. Like the qualitative trait phenotypes controlled by Hsp90, highly discrete quantitative traits such as scutellor and thoracic bristle number are threshold traits. When tested across genotypes sampled from a wild population or in laboratory strains, the sensitivity of these traits to many types of variation was coordinately controlled, while continuously variable bristle types and wing size, and critically invariant left-right wing asymmetry, remained relatively unaffected. Although increased environmental variation and developmental noise would impede many types of selection response, in replicate populations in which Hsp90 was specifically impaired, heritability and ‘extrinsic evolvability’, the expected response to selection, were also markedly increased. However, despite the overall buffering effect of Hsp90 on variation in populations, for any particular individual or genotype in which Hsp90 was impaired, the size and direction of its effects were unpredictable. The trait and genetic-background dependence of Hsp90 effects and its remarkable bias toward invariant or canalized traits support the idea that traits evolve independent and trait-specific mechanisms of canalization and evolvability through their evolution of non-linearity and thresholds. Highly non-linear responses would buffer variation in Hsp90-dependent signaling over a wide range, while over a narrow range of signaling near trait thresholds become more variable with increasing probability of triggering all-or-none developmental responses

Functional dissection of the Drosophila Kallmann's syndrome protein DmKal-1

BACKGROUND: Anosmin-1, the protein implicated in the X-linked Kallmann's syndrome, plays a role in axon outgrowth and branching but also in epithelial morphogenesis. The molecular mechanism of its action is, however, widely unknown. Anosmin-1 is an extracellular protein which contains a cysteine-rich region, a whey acidic protein (WAP) domain homologous to some serine protease inhibitors, and four fibronectin-like type III (FnIII) repeats. Drosophila melanogaster Kal-1 (DmKal-1) has the same protein structure with minor differences, the most important of which is the presence of only two FnIII repeats and a C-terminal region showing a low similarity with the third and the fourth human FnIII repeats. We present a structure-function analysis of the different DmKal-1 domains, including a predicted heparan-sulfate binding site. RESULTS: This study was performed overexpressing wild type DmKal-1 and a series of deletion and point mutation proteins in two different tissues: the cephalopharyngeal skeleton of the embryo and the wing disc. The overexpression of DmKal-1 in the cephalopharyngeal skeleton induced dosage-sensitive structural defects, and we used these phenotypes to perform a structure-function dissection of the protein domains. The reproduction of two deletions found in Kallmann's Syndrome patients determined a complete loss of function, whereas point mutations induced only minor alterations in the activity of the protein. Overexpression of the mutant proteins in the wing disc reveals that the functional relevance of the different DmKal-1 domains is dependent on the extracellular context. CONCLUSION: We suggest that the role played by the various protein domains differs in different extracellular contexts. This might explain why the same mutation analyzed in different tissues or in different cell culture lines often gives opposite phenotypes. These analyses also suggest that the FnIII repeats have a main and specific role, while the WAP domain might have only a modulator role, strictly connected to that of the fibronectins

Screen or not to screen for peripheral arterial disease: Guidance from a decision model

__Abstract__ Background: Asymptomatic Peripheral Arterial Disease (PAD) is associated with greater risk of acute cardiovascular events. This study aims to determine the cost-effectiveness of one time only PAD screening using Ankle Brachial Index (ABI) test and subsequent anti platelet preventive treatment (low dose aspirin or clopidogrel) in individuals at high risk for acute cardiovascular events compared to no screening and no treatment using decision analytic modelling. Methods. A probabilistic Markov model was developed to evaluate the life time cost-effectiveness of the strategy of selective PAD screening and consequent preventive treatment compared to no screening and no preventive treatment. The analysis was conducted from the Dutch societal perspective and to address decision uncertainty, probabilistic sensitivity analysis was performed. Results were based on average values of 1000 Monte Carlo simulations and using discount rates of 1.5% and 4% for effects and costs respectively. One way sensitivity analyses were performed to identify the two most influential model parameters affecting model outputs. Then, a two way sensitivity analysis was conducted for combinations of values tested for these two most influential parameters. Results: For the PAD screening strategy, life years and quality adjusted life years gained were 21.79 and 15.66 respectively at a lifetime cost of 26,548 Euros. Compared to no screening and treatment (20.69 life years, 15.58 Quality Adjusted Life Ye

Genetic Ancestry, Self-Reported Race and Ethnicity in African Americans and European Americans in the PCaP Cohort

Family history and African-American race are important risk factors for both prostate cancer (CaP) incidence and aggressiveness. When studying complex diseases such as CaP that have a heritable component, chances of finding true disease susceptibility alleles can be increased by accounting for genetic ancestry within the population investigated. Race, ethnicity and ancestry were studied in a geographically diverse cohort of men with newly diagnosed CaP.Individual ancestry (IA) was estimated in the population-based North Carolina and Louisiana Prostate Cancer Project (PCaP), a cohort of 2,106 incident CaP cases (2063 with complete ethnicity information) comprising roughly equal numbers of research subjects reporting as Black/African American (AA) or European American/Caucasian/Caucasian American/White (EA) from North Carolina or Louisiana. Mean genome wide individual ancestry estimates of percent African, European and Asian were obtained and tested for differences by state and ethnicity (Cajun and/or Creole and Hispanic/Latino) using multivariate analysis of variance models. Principal components (PC) were compared to assess differences in genetic composition by self-reported race and ethnicity between and within states.Mean individual ancestries differed by state for self-reporting AA (p = 0.03) and EA (p = 0.001). This geographic difference attenuated for AAs who answered "no" to all ethnicity membership questions (non-ethnic research subjects; p = 0.78) but not EA research subjects, p = 0.002. Mean ancestry estimates of self-identified AA Louisiana research subjects for each ethnic group; Cajun only, Creole only and both Cajun and Creole differed significantly from self-identified non-ethnic AA Louisiana research subjects. These ethnicity differences were not seen in those who self-identified as EA.Mean IA differed by race between states, elucidating a potential contributing factor to these differences in AA research participants: self-reported ethnicity. Accurately accounting for genetic admixture in this cohort is essential for future analyses of the genetic and environmental contributions to CaP

Peripheral artery disease assessed by ankle-brachial index in patients with established cardiovascular disease or at least one risk factor for atherothrombosis - CAREFUL Study: A national, multi-center, cross-sectional observational study

<p>Abstract</p> <p>Background</p> <p>To investigate the presence of peripheral artery disease (PAD) via the ankle brachial index (ABI) in patients with known cardiovascular and/or cerebrovascular diseases or with at least one risk factor for atherothrombosis.</p> <p>Methods</p> <p>Patients with a history of atherothrombotic events, or aged 50-69 years with at least one cardiovascular risk factor, or > = 70 years of age were included in this multicenter, cross-sectional, non-interventional study (DIREGL04074). Demographics, medical history, physical examination findings, and physician awareness of PAD were analyzed. The number of patients with low ABI (< = 0.90) was analyzed.</p> <p>Results</p> <p>A total of 530 patients (mean age, 63.4 ± 8.7 years; 50.2% female) were enrolled. Hypertension and dyslipidemia were present in 88.7% and 65.5% of patients, respectively. PAD-related symptoms were evident in about one-third of the patients, and at least one of the pedal pulses was negative in 6.5% of patients. The frequency of low ABI was 20.0% in the whole study population and 30% for patients older than 70 years. Older age, greater number of total risk factors, and presence of PAD-related physical findings were associated with increased likelihood of low ABI (<it>p </it>< 0.001). There was no gender difference in the prevalence of low ABI, PAD symptoms, or total number of risk factors. Exercise (33.6%) was the most common non-pharmacological option recommended by physicians, and acetylsalicylic acid (ASA) (45.4%) was the most frequently prescribed medication for PAD.</p> <p>Conclusion</p> <p>Our results indicate that advanced age, greater number of total risk factors and presence of PAD-related physical findings were associated with increased likelihood of low ABI. These findings are similar to those reported in similar studies of different populations, and document a fairly high prevalence of PAD in a Mediterranean country.</p

Triple Combination Antiviral Drug (TCAD) Composed of Amantadine, Oseltamivir, and Ribavirin Impedes the Selection of Drug-Resistant Influenza A Virus

Widespread resistance among circulating influenza A strains to at least one of the anti-influenza drugs is a major public health concern. A triple combination antiviral drug (TCAD) regimen comprised of amantadine, oseltamivir, and ribavirin has been shown to have synergistic and broad spectrum activity against influenza A strains, including drug resistant strains. Here, we used mathematical modeling along with three different experimental approaches to understand the effects of single agents, double combinations, and the TCAD regimen on resistance in influenza in vitro, including: 1) serial passage at constant drug concentrations, 2) serial passage at escalating drug concentrations, and 3) evaluation of the contribution of each component of the TCAD regimen to the suppression of resistance. Consistent with the modeling which demonstrated that three drugs were required to suppress the emergence of resistance in influenza A, treatment with the TCAD regimen resulted in the sustained suppression of drug resistant viruses, whereas treatment with amantadine alone or the amantadine-oseltamivir double combination led to the rapid selection of resistant variants which comprised ∼100% of the population. Furthermore, the TCAD regimen imposed a high genetic barrier to resistance, requiring multiple mutations in order to escape the effects of all the drugs in the regimen. Finally, we demonstrate that each drug in the TCAD regimen made a significant contribution to the suppression of virus breakthrough and resistance at clinically achievable concentrations. Taken together, these data demonstrate that the TCAD regimen was superior to double combinations and single agents at suppressing resistance, and that three drugs at a minimum were required to impede the selection of drug resistant variants in influenza A virus. The use of mathematical modeling with multiple experimental designs and molecular readouts to evaluate and optimize combination drug regimens for the suppression of resistance may be broadly applicable to other infectious diseases