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Concept: Variable

173

Libraries based on an isolated human immunoglobulin G1 (IgG1) constant domain 2 (CH2) have been previously diversified by random mutagenesis. However, native isolated CH2 is not very stable and the generation of many mutations could lead to an increase in immunogenicity. Recently, we demonstrated that engineering an additional disulfide bond and removing seven N-terminal residues results in an engineered antibody domain (eAd) (m01s) with highly increased stability and enhanced binding to human neonatal Fc receptor (FcRn) (Gong et al, JBC, 2009 and 2011). We and others have also previously shown that grafting of the heavy chain complementarity region 3 (CDR-H3 (H3)) onto cognate positions of the variable domain leads to highly diversified libraries from which a number of binders to various antigens have been selected. However, grafting of H3s to non-cognate positions in constant domains results in additional residues at the junctions of H3s and the CH2 framework. Here we describe a new method based on multi-step PCR that allows the precise replacement of loop FG (no changes in its flanking sequences) by human H3s from another library. Using this method and limited mutagenesis of loops BC and DE we generated an eAd phage-displayed library. Panning of this library against an HIV-1 gp41 MPER peptide resulted in selection of a binder, m2a1, which neutralized HIV-1 isolates from different clades with modest activity and retained the m01s capability of binding to FcRn. This result provides a proof of concept that CH2-based antigen binders that also mimic to certain extent other functions of full-size antibodies (binding to FcRn) can be generated; we have previously hypothesized that such binders can be made and coined the term nanoantibodies (nAbs). Further studies in animal models and in humans will show how useful nAbs could be as therapeutics and diagnostics.

Concepts: Immune system, Antibody, Protein, Fc receptor, Antigen, Epitope, Variable, Binder

91

The current study examined the adaptive response to both endurance (END) and sprint interval training (SIT) in a group of twenty-one recreationally active adults. All participants completed three weeks (four days/ week) of both END (30 minutes at ~65% VO2peak work rate (WR) and SIT (eight, 20-second intervals at ~170% VO2peak WR separated by 10 seconds of active rest) following a randomized crossover study design with a three-month washout period between training interventions. While a main effect of training was observed for VO2peak, lactate threshold, and submaximal heart rate (HR), considerable variability was observed in the individual responses to both END and SIT. No significant positive relationships were observed between END and SIT for individual changes in any variable. Non-responses were determined using two times the typical error (TE) of measurement for VO2peak (0.107 L/min), lactate threshold (15.7 W), and submaximal HR (10.7bpm). Non-responders in VO2peak, lactate threshold, and submaximal HR were observed following both END and SIT, however, the individual patterns of response differed following END and SIT. Interestingly, all individuals responded in at least one variable when exposed to both END and SIT. These results suggest that the individual response to exercise training is highly variable following different training protocols and that the incidence of non-response to exercise training may be reduced by changing the training stimulus for non-responders to three weeks of END or SIT.

Concepts: Crossover study, Exercise, Adaptive immune system, Variable, Running, Interval training, Renaissance music, Adaptive response

28

Purpose:Single-nucleotide polymorphism (SNP) microarrays are capable of detecting regions of homozygosity (ROH) that can suggest parental consanguinity or incest. This study was designed to describe the variable reporting practices of clinical laboratories in the United States regarding ROH found on SNP microarray tests, to discuss the follow-up practices of laboratory personnel when findings of ROH indicate consanguinity or incest, and to highlight the legal and ethical dilemmas faced by workers who have discovered these incidental findings.Methods:A 20-question survey was administered to microarray experts at 18 laboratories offering clinical SNP microarray tests. The results are presented using descriptive statistics.Results:There was variability in laboratory SNP microarray reporting practices with respect to information and interpretation of ROH findings. All the laboratories agreed that they have a duty to inform the ordering physician about results suggesting consanguinity or incest, but the follow-through practices varied among laboratories.Conclusions:This study discovered variability in reporting practices and follow-up procedures for microarray results that suggest parental consanguinity or incest. Our findings highlight the need for laboratory guidelines to standardize reporting practices for SNP microarray and other tests that are capable of detecting ROH.Genet Med 2012:14(12):971-976.

Concepts: Marriage, United States, Laboratory, Microarray, Microarrays, Variable, Consanguinity, Incest

28

Children demonstrate lower force production capacities compared to adults, whichhas often been attributed to ‘neuromuscular immaturity’. However, tendon stiffness, which influences both the electro-mechanical delay (EMD) and rate of force development (RFD) in adults, is lower in children and may influence rapid force production. PURPOSE: The aims of this study were to: 1) document EMD and RFD variation as a function of age, 2) determine the relationships between tendon stiffness and parameters relating to rapid force production in children and adults, and 3) estimate the relative neural and mechanical contributions to age-related changes in force production by examining the effects of tendon stiffness and muscle activation rate (rate of EMG increase; REI) on RFD. METHODS: Achilles tendon stiffness, EMD, RFD and REI were measured duringplantar flexion contractions in 47prepubertal children (5-12 yrs) and 19 adults. Relationships were determined between: 1) stiffness and EMD, 2) stiffness and RFD, and 3) REI and RFD. The relative contributions of age, stiffness and REI on RFD were determined using a multiple regression analysis. Age-related differences in tendon stiffness, EMD, RFD and REI were also examined according to chronological age (5-6, 7-8 and 9-10 years) and compared to adults. RESULTS: Increases in tendon stiffness with age were negatively correlated with EMD (r<-0.83). Stiffness and REI could account for up to 35% and 30% of RFD variability in children, respectively, which increased to 58% when these variables were combined. CONCLUSIONS: Both neural and mechanical factors influence rapid force production in prepubertal children. Children's longer EMD and slower RFD indicate a less effective development and transfer of muscular forces, which may have implications for complex movement performance.

Concepts: Regression analysis, Linear regression, Muscle, Childhood, Classical mechanics, Variable, Tendon, Achilles tendon

27

Suicide is not only an individual phenomenon, but it is also influenced by social and environmental factors. With the high suicide rate and the abundance of social media data in South Korea, we have studied the potential of this new medium for predicting completed suicide at the population level. We tested two social media variables (suicide-related and dysphoria-related weblog entries) along with classical social, economic and meteorological variables as predictors of suicide over 3 years (2008 through 2010). Both social media variables were powerfully associated with suicide frequency. The suicide variable displayed high variability and was reactive to celebrity suicide events, while the dysphoria variable showed longer secular trends, with lower variability. We interpret these as reflections of social affect and social mood, respectively. In the final multivariate model, the two social media variables, especially the dysphoria variable, displaced two classical economic predictors - consumer price index and unemployment rate. The prediction model developed with the 2-year training data set (2008 through 2009) was validated in the data for 2010 and was robust in a sensitivity analysis controlling for celebrity suicide effects. These results indicate that social media data may be of value in national suicide forecasting and prevention.

Concepts: Prediction, Future, Sociology, Variable, Forecasting, Unemployment, Inflation, Consumer price index

26

Mast-seeding species exhibit not only a large inter-annual variability in seed production but also considerable variability among individuals within the same year. However, very little is known about the causes and consequences for population dynamics of this potentially large between-individual variability. Here, we quantified seed production over ten consecutive years in two Mediterranean oak species - the deciduous Quercus canariensis and the evergreen Q. suber - that coexist in forests of southern Spain. First, we calibrated likelihood models to identify which abiotic and biotic variables best explain the magnitude (hereafter seed productivity) and temporal variation of seed production at the individual level (hereafter CVi), and infer whether reproductive effort results from the available soil resources for the plant or is primarily determined by selectively favoured strategies. Second, we explored the contribution of between-individual variability in seed production as a potential mechanism of satiation for predispersal seed predators. We found that Q. canariensis trees inhabiting moister and more fertile soils were more productive than those growing in more resource-limited sites. Regarding temporal variation, individuals of the two studied oak species inhabiting these resource-rich environments also exhibited larger values of CVi. Interestingly, we detected a satiating effect on granivorous insects at the tree level in Q. suber, which was evident in those years where between-individual variability in acorn production was higher. These findings suggest that individual seed production (both in terms of seed productivity and inter-annual variability) is strongly dependent on soil resource heterogeneity (at least for one of the two studied oak species) with potential repercussions for recruitment and population dynamics. However, other external factors (such as soil heterogeneity in pathogen abundance) or certain inherent characteristics of the tree might be also involved in this process.

Concepts: Plant, Demography, Variable, Nut, Oak, Quercus, Acorn, Deciduous

24

Global land cover is an essential climate variable and a key biophysical driver for earth system models. While remote sensing technology, particularly satellites, have played a key role in providing land cover datasets, large discrepancies have been noted among the available products. Global land use is typically more difficult to map and in many cases cannot be remotely sensed. In-situ or ground-based data and high resolution imagery are thus an important requirement for producing accurate land cover and land use datasets and this is precisely what is lacking. Here we describe the global land cover and land use reference data derived from the Geo-Wiki crowdsourcing platform via four campaigns. These global datasets provide information on human impact, land cover disagreement, wilderness and land cover and land use. Hence, they are relevant for the scientific community that requires reference data for global satellite-derived products, as well as those interested in monitoring global terrestrial ecosystems in general.

Concepts: Earth, Data set, Variable, Remote sensing, Land use, Land cover, Perl, Crowdsourcing

22

To what extent the lineage decisions of activated CD4(+) T cells are determined by the quality of T cell receptor (TCR) ligation is incompletely understood. Here, we show that individual T cells expressing identical TCRs take highly variable fate decisions despite binding the same ligand. We identify a mathematical model that correctly captures this probabilistic behavior and allows one to formalize changes in TCR signal quality-due to cognate versus altered peptide ligation-as changes of lineage-specific proliferation and differentiation rates. We show that recall responses also adhere to this probabilistic framework requiring recruitment of multiple memory clones to provide reliable differentiation patterns. By extending our framework to simulate hypothetical TCRs of distinct binding strength, we reconstruct primary and secondary response patterns emerging from a polyclonal TCR repertoire in silico. Collectively, these data suggest that individual T cells harboring distinct TCRs generate overlapping primary differentiation patterns that segregate only upon repetitive immunization.

Concepts: Protein, Mathematics, Receptor, Cell culture, Simulation, Operations research, Variable, Mathematical model

21

The links between increased participation in Physical Activity (PA) and improvements in health are well established. As this body of evidence has grown, so too has the search for measures of PA with high levels of methodological effectiveness (i.e. validity, reliability and responsiveness to change). The aim of this “review of reviews” was to provide a comprehensive overview of the methodological effectiveness of currently employed measures of PA, to aid researchers in their selection of an appropriate tool. A total of 63 review articles were included in this review, and the original articles cited by these reviews were included in order to extract detailed information on methodological effectiveness.Self-report measures of PA have been most frequently examined for methodological effectiveness, with highly variable findings identified across a broad range of behaviours. The evidence-base for the methodological effectiveness of objective monitors, particularly accelerometers/activity monitors, is increasing, with lower levels of variability observed for validity and reliability when compared to subjective measures. Unfortunately, responsiveness to change across all measures and behaviours remains under-researched, with limited information available.Other criteria beyond methodological effectiveness often influence tool selection, including cost and feasibility. However, researchers must be aware of the methodological effectiveness of any measure selected for use when examining PA. Although no “perfect” tool for the examination of PA in adults exists, it is suggested that researchers aim to incorporate appropriate objective measures, specific to the behaviours of interests, when examining PA in free-living environments.

Concepts: Scientific method, Systematic review, Measurement, Academic publishing, Psychometrics, Reliability, Review, Variable

17

In this study we produce a standardised dataset for benthic macrofauna and sediments through integration of data (33,198 samples) from 777 grab surveys. The resulting dataset is used to identify spatial and temporal patterns in faunal distribution around the UK, and the role of sediment composition and other explanatory variables in determining such patterns. We show how insight into natural variability afforded by the dataset can be used to improve the sustainability of activities which affect sediment composition, by identifying conditions which should remain favourable for faunal recolonisation. Other big data applications and uses of the dataset are discussed.

Concepts: Biodiversity, Mathematics, Lake, Sediment, United Kingdom, Sustainability, Variable, Identification