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‘What might peer review look like in 2030’ examines how peer review can be improved for future generations of academics and offers key recommendations to the academic community. The report is based on the lively and progressive sessions at the SpotOn London conference held at Wellcome Collection Conference centre in November 2016It includes a collection of reflections on the history of peer review, current issues such as sustainability and ethics, while also casting a look into the future including advances such as preprint servers and AI applications. The contributions cover perspectives from the researcher, a librarian, publishers and others.

The metadata in the HTML format of these original articles (Eppard et al., 2017; Decristoforo & Patt, 2017; Domnanich et al., 2017; Chan et al., 2017; Jovalekic et al., 2017; Zhang & Villalobos, 2017; Meckel et al., 2017; Li et al., 2017; Colin et al., 2017; Koziorowski et al., 2017; Ooms et al., 2017; Elsinga, 2017; Seemann et al., 2017; Müller et al., 2017; Luurtsema et al., 2017) were published with an incorrect cover date. The correct cover date is December 2016. This does not alter the text of the original articles.

Following publication of these three articles [1–3], it was flagged that the articles have an incorrect issue copyright year of 2017, because of an xml-related error. Please be advised, therefore, that the correct issue copyright year of these articles [1–3] is 2016.

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Field potential (FP) recording is an accessible means to capture the shifts in the activity of neuron populations. However, the spatial and composite nature of these signals has largely been ignored, at least until it became technically possible to separate activities from co-activated sources in different structures or those that overlap in a volume. The pathway-specificity of mesoscopic sources has provided an anatomical reference that facilitates transcending from theoretical analysis to the exploration of real brain structures. We review computational and experimental findings that indicate how prioritizing the spatial geometry and density of sources, as opposed to the distance to the recording site, better defines the amplitudes and spatial reach of FPs. The role of geometry is enhanced by considering that zones of the active populations that act as sources or sinks of current may arrange differently respect to each other, and have different geometry and densities. Thus, observations that seem counterintuitive in the scheme of distance-based logic alone can now be explained. For example, geometric factors explain why some structures produce FPs and others do not, why different FP motifs generated in the same structure extend far while others remain local, why factors like the size of an active population or the strong synchronicity of its neurons may fail to affect FPs, or why the rate of FP decay varies in different directions. These considerations are exemplified in large structures like the cortex and hippocampus, in which the role of geometrical elements and regional activation in shaping well-known FP oscillations generally go unnoticed. Discovering the geometry of the sources in play will decrease the risk of population or pathway misassignments based solely on the FP amplitude or temporal pattern., We thank Mark Sefton (BiomedRed) for editorial support. This work was supported by the Spanish Ministerio de Ciencia e Innovación (MICIN) grant PID2019-111587RB-I00, and the Agencia Estatal de Evaluación, Next Generation EU grant PDC2021-121103-I00 to O.H. Present addresses: D.T.: Instituto de Neurociencias de Alicante, UMH-CSIC, Sant Joan d'Alacant, Spain.

Background Wood represents the majority of the biomass on land and constitutes a renewable source of biofuels and other bioproducts. However, wood is recalcitrant to bioconversion, raising a need for feedstock improvement in production of, for instance, biofuels. We investigated the properties of wood that affect bioconversion, as well as the underlying genetics, to help identify superior tree feedstocks for biorefining. Results We recorded 65 wood-related and growth traits in a population of 113 natural aspen genotypes from Sweden (https://doi.org/10.5061/dryad.gtht76hrd). These traits included three growth and field performance traits, 20 traits for wood chemical composition, 17 traits for wood anatomy and structure, and 25 wood saccharification traits as indicators of bioconversion potential. Glucose release after saccharification with acidic pretreatment correlated positively with tree stem height and diameter and the carbohydrate content of the wood, and negatively with the content of lignin and the hemicellulose sugar units. Most of these traits displayed extensive natural variation within the aspen population and high broad-sense heritability, supporting their potential in genetic improvement of feedstocks towards improved bioconversion. Finally, a genome-wide association study (GWAS) revealed 13 genetic loci for saccharification yield (on a whole-tree-biomass basis), with six of them intersecting with associations for either height or stem diameter of the trees. Conclusions The simple growth traits of stem height and diameter were identified as good predictors of wood saccharification yield in aspen trees. GWAS elucidated the underlying genetics, revealing putative genetic markers for bioconversion of bioenergy tree feedstocks.

Background Recent evidence indicates that elevating plasma nitrites through dietary nitrates (NO3 −) supplementation is associated with enhanced muscle efficiency, fatigue resistance and performance. Beetroot (in various forms) is the dominant source of dietary NO3 − primarily due to its vast availability and the simple form of preparation suitable for final consumption. After a few years of research and experimentation, our scientific team identified alternative source rich with dietary NO3 − as possible nitric oxide precursor, amaranth (Amaranthus hypochondriacus) with a standardized concentration 9–11% of NO3 −. This study aimed to evaluate the effect of single-dose (±400 mg of dietary NO3 −) and long-term (6 days) supplementation of amaranth concentrate derived dietary NO3 − on aerobic capacity in physically active young people. Methods We conducted a randomized, double-blind, placebo-controlled human study. Thirteen healthy and physically active young male participants were randomized into experimental and placebo groups. The aerobic capacity was tested during increasing cycling exercise (ICE) with pulmonary gas exchange recording and analysis. Results The peak power of the ICE, the maximum oxygen consumption and the first ventilatory threshold were significantly increased after long-term consumption of dietary amaranth (from 4.44 ± 0.50 to 4.55 ± 0.43 W/kg; from 37.7 ± 2.7 to 41.2 ± 5.4 mL/kg/min and from 178.6 ± 30.3 to 188.6 ± 35.2 W, p

Background Recursive movement patterns have been used to detect behavioral structure within individual movement trajectories in the context of foraging ecology, home-ranging behavior, and predator avoidance. Some animals exhibit movement recursions to locations that are tied to reproductive functions, including nests and dens; while existing literature recognizes that, no method is currently available to explicitly target different types of revisited locations. Moreover, the temporal persistence of recursive movements to a breeding location can carry information regarding the fate of breeding attempts, but it has never been used as a metric to quantify recursive movement patterns. Here, we introduce a method to locate breeding attempts and estimate their fate from GPS-tracking data of central place foragers. We tested the performance of our method in three bird species differing in breeding ecology (wood stork (Mycteria americana), lesser kestrel (Falco naumanni), Mediterranean gull (Ichthyaetus melanocephalus)) and implemented it in the R package ‘nestR’. Methods We identified breeding sites based on the analysis of recursive movements within individual tracks. Using trajectories with known breeding attempts, we estimated a set of species-specific criteria for the identification of nest sites, which we further validated using non-reproductive individuals as controls. We then estimated individual nest survival as a binary measure of reproductive fate (success, corresponding to fledging of at least one chick, or failure) from nest-site revisitation histories during breeding attempts, using a Bayesian hierarchical modeling approach that accounted for temporally variable revisitation patterns, probability of visit detection, and missing data. Results Across the three species, positive predictive value of the nest-site detection algorithm varied between 87 and 100% and sensitivity between 88 and 92%, and we correctly estimated the fate of 86–100% breeding attempts. Conclusions By providing a method to formally distinguish among revisited locations that serve different ecological functions and introducing a probabilistic framework to quantify temporal persistence of movement recursions, we demonstrated how the analysis of recursive movement patterns can be applied to estimate reproduction in central place foragers. Beyond avian species, the principles of our method can be applied to other central place foraging breeders such as denning mammals. Our method estimates a component of individual fitness from movement data and will help bridge the gap between movement behavior, environmental factors, and their fitness consequences.

Background Understanding the factors that influence the foraging behavior and perception of habitat quality by animals has long been the focus in ecology. Due to the direct effect resource acquisition has on an individual’s fitness and species’ survival, predation risk is considered widely to be a major driver of foraging decision. The objectives of this study were to investigate how predation risk is perceived by granivorous bird species with respect to different habitat and microhabitat types, time of day and food types in Amurum Forest Reserve, Nigeria, with a view to direct future conservation planning. Methods For 3 months, we conducted field experiments to measure giving-up densities (GUD, the amount of food left behind in artificial patches after birds cease to forage in it) and how it differs with habitat types, microhabitats, times of day, and food types. General linear mixed-effect models (GLMMs) were fitted to investigate the differences in GUD with respect to the aforementioned variables. Model selection was done based on the Akaike’s Information Criterion (AIC). Results There was no significant difference in GUDs across habitats. However, there was a significant difference in GUDs between microhabitats. Higher food remnants were recorded in the open than in cover microhabitats, as birds exploited food patches in the cover more. Time of day influenced foraging behavior in the birds. They foraged more in the morning than afternoon across all three habitats except for the gallery forest where birds foraged less in the morning. Higher GUDs were recorded in open than cover microhabitats both in the morning and the afternoon. Birds had a preference for rice, millet, and groundnut respectively. Conclusion The differences in GUDs were very indicative of differences in foraging behavior and perception of resource availability in response to perceived predation risk. Therefore, this study suggests that the understanding of foraging decisions can be a veritable method for assessing habitat quality as perceived by animals.

Background Endophytic microorganisms are a rich source of bioactive natural products. They are considered as promising biofertilizers and biocontrol agents due to their growth-promoting interactions with the host plants and their bioactive secondary metabolites that can help manage plant pathogens. Identification of new endophytes may lead to the discovery of novel molecules or provide new strains for production of valuable compounds. Results In this study, we isolated an endophytic bacterium from the leaves of Taxus chinensis, which was identified as Pseudomonas sp. 102515 based on the 16S rRNA gene sequence and physiological characteristics. Analysis of its secondary metabolites revealed that this endophytic strain produces a major product zeaxanthin diglucoside, a promising antioxidant natural product that belongs to the family of carotenoids. A carotenoid (Pscrt) biosynthetic gene cluster was amplified from this strain, and the functions of PsCrtI and PsCrtY in the biosynthesis of zeaxanthin diglucoside were characterized in Escherichia coli BL21(DE3). The entire Pscrt biosynthetic gene cluster was successfully reconstituted in E. coli BL21(DE3) and Pseudomonas putida KT2440. The production of zeaxanthin diglucoside in Pseudomonas sp. 102515 was improved through the optimization of fermentation conditions such as medium, cultivation temperature and culture time. The highest yield under the optimized conditions reached 206 mg/L. The engineered strain of P. putida KT2440 produced zeaxanthin diglucoside at 121 mg/L in SOC medium supplemented with 0.5% glycerol at 18 °C, while the yield of zeaxanthin diglucoside in E. coli BL21(DE3) was only 2 mg/L. To further enhance the production, we introduced an expression plasmid harboring the Pscrt biosynthetic gene cluster into Pseudomonas sp. 102515. The yield in this engineered strain reached 380 mg/L, 85% higher than the wild type. Through PCR, we also discovered the presence of a turnerbactin biosynthetic gene cluster in Pseudomonas sp. 102515. Because turnerbactin is involved in nitrogen fixation, this endophytic strain might have a role in promoting growth of the host plant. Conclusions We isolated and identified an endophytic strain of Pseudomonas from T. chinensis. A zeaxanthin diglucoside biosynthetic gene cluster was discovered and characterized in this bacterium. Through fermentation and genetic engineering, the engineered strain produced zeaxanthin diglucoside at 380 ± 12 mg/L, representing a promising strain for the production of this antioxidant natural product. Additionally, Pseudomonas sp. 102515 might also be utilized as a plant-promoting strain for agricultural applications.

Background In Brazil, members of the sand fly species complex Lutzomyia longipalpis transmit Leishmania infantum, a protist parasite that causes visceral leishmaniasis. Male Lu. longipalpis produce a sex pheromone that is attractive to both females and males. During a cluster randomised trial, to determine the combined effect of synthetic sex-aggregation pheromone and insecticide on Le. infantum transmission Lu. longipalpis had been continuously exposed to insecticide for 30 months. The objective of this study was to determine the effect of continuous exposure to the insecticides used in the trial on the susceptibility of Lu. longipalpis population. Methods During the trial the sand flies had been exposed to either lambda-cyhalothrin [pheromone + residual insecticide spray (PI)], deltamethrin [dog collars (DC)] or no insecticide [control (C)], for 30 months (November 2012 to April 2015). The insecticide treatment regime was kept in place for an additional 12 months (May 2015-April 2016) during this susceptibility study. Sand flies collected from the field were exposed to WHO insecticide-impregnated papers cyhalothrin (0.05%), deltamethrin (0.5%) and control (silicone oil) in a modified WHO insecticide exposure trial to determine their susceptibility. Results We collected 788 Lu. longipalpis using CDC-light traps in 31 municipalities across the three trial arms. Probit analysis showed that the knockdown times (KDTs) of Lu. longipalpis collected from the lambda-cyhalothrin exposed PI-arm [KDT50: 31.1 min, confidence interval (CI): 29.6–32.6 and KDT90: 44.2 min, CI: 42.1–46.7] were longer than the KDTs from the non-insecticide-treated C-arm (KDT50: 26.3 min, CI: 25.1–27.6 and KDT90: 38.2, CI: 36.5–40.2) (no-overlapping 95% CIs). KDTs of Lu. longipalpis collected from the deltamethrin exposed DC-arm had similar values (KDT50: 13.7 min, CI: 10.1–16.2 and KDT90: 26.7 min, CI: 21.8–30.6) to those for the C-arm (KDT50: 13.5 min; CI: 12.2–14.8 and KDT90: 23.2 min, CI: 21.4–25.4) (overlapping CIs). The wild-caught unexposed Lu. longipalpis (C-arm), took approximately twice as long to knock down as laboratory-colonised specimens for both insecticides. Conclusions Our study reveals slight changes in KDT, in sand flies after prolonged exposure to lambda-cyhalothrin in the presence of pheromone. These changes are not considered to have reached the reference levels indicative of resistance in sand flies suggesting that pheromone and insecticide treatment at the level indicated in this study do not constitute a significant risk of increased insecticide resistance. Prolonged exposure to deltamethrin in dog collars did not result in changes to KDT. Electronic supplementary material The online version of this article (10.1186/s13071-019-3364-4) contains supplementary material, which is available to authorized users.

Background The Grooved Pegboard Test (GPT) is widely adopted to evaluate manual dexterity, it presents normative data but the test is influenced by different factors. The influence of time spent on smartphones has not been considered before, for this reason, the objective of this study was to evaluate if smartphone use influences the time to complete the GPT. A total of 38 (21 women; 17 men) young adults 20.7 (1.5) years participated in the study. The time spent on the smartphones during the last seven days was recorded through the device itself and the GPT performance was measured. A correlation analysis between the time spent on the smartphone and GPT was performed while the t-test was adopted to evaluate gender differences. Results No statistically significant differences were detected between men and women in the time to complete the GPT (p = 0.20) and in the time spent on the smartphone (p = 0.87). The GPT and the time spent using the smartphone were not correlated (r = 0.044, p = 0.78). Conclusion The time spent on the smartphone by young adults does not influence the time to complete the GPT, indicating that smartphone use does not influence measures of manual dexterity.

BackgroundA better understanding of sea turtle spatial ecology is critical for the continued conservation of imperiled sea turtles and their habitats. For resource managers to develop the most effective conservation strategies, it is especially important to examine how turtles use and select for habitats within their developmental foraging grounds. Here, we examine the space use and relative habitat selection of immature green turtles (Chelonia mydas) using acoustic telemetry within the marine protected area, Buck Island Reef National Monument (BIRNM), St. Croix, United States Virgin Islands.ResultsSpace use by turtles was concentrated on the southern side of Buck Island, but also extended to the northeast and northwest areas of the island, as indicated by minimum convex polygons (MCPs) and 99%, 95%, and 50% kernel density estimations (KDEs). On average space use for all categories was 2with mean KDE area overlap ranging from 41.9 to 67.7%. Cumulative monthly MCPs and their proportions to full MCPs began to stabilize 3 to 6 detection months after release, respectively. Resource selection functions (RSFs) were implemented using a generalized linear mixed effects model with turtle ID as the random effect. After model selection, the accuracy of the top model was 77.3% and showed relative habitat selection values were highest at shallow depths, for areas in close proximity to seagrass, and in reef zones for both day and night, and within lagoon zones at night. The top model was also extended to predict across BIRNM at both day and night.ConclusionMore traditional acoustic telemetry analyses in combination with RSFs provide novel insights into animal space use and relative resource selection. Here, we demonstrated immature green turtles within the BIRNM have small, specific home ranges and core use areas with temporally varying relative selection strengths across habitat types. We conclude the BIRNM marine protected area is providing sufficient protection for immature green turtles, however, habitat protection could be focused in both areas of high space use and in locations where high relative selection values were determined. Ultimately, the methodologies and results presented here may help to design strategies to expand habitat protection for immature green turtles across their greater distribution.

Background Prescription drug abuse (PDA) disorders continue to contribute to the current American opioid crisis. Within this context, our study seeks to improve understanding about stigma associated with, and symptom recognition of, prescription drug abuse. Aims Model the stigma and symptom recognition of PDA in the general population. Methods A randomized, nation-wide, online, vignette-focused survey of the general public (N = 631) was implemented with an oversample for rural counties. Logit estimation was used for analysis, with regional and county-level sociodemographic variables as controls. Results Individual respondents that self-identify as having or having had “a prescription drug abuse issue” were less likely to correctly identify the condition and were 4 times more likely to exhibit stigma. Male respondents were approximately half as likely to correctly identify PDA as female respondents while older respondents (55+) were more likely to correctly identify PDA, relative to those aged 35–54. Being both male and younger was associated with slightly more stigma, in that they were less likely to disagree with the stigma statement. Conclusions In light of the continued risks that individuals with PDA behaviors face in potentially transitioning to illicit opioid use, the findings of this survey suggested a continued need for public education and outreach. Of particular note is the perspective of those who have self-identified with the condition, as this population faces the largest risks of adverse health outcomes from illicit drug use within the survey respondents.

Background In food animal agriculture, there is a need to identify the mechanisms that can improve the efficiency of muscle growth and protein accretion. Callipyge sheep provide excellent machinery since the up-regulation of DLK1 and RTL1 results in extreme postnatal muscle hypertrophy in distinct muscles. The aim of this study is to distinguish the genes that directly respond to DLK1 and RTL1 signaling from the genes that change as the result of muscle specific effects. Results The quantitative PCR results indicated that DLK1 expression was significantly increased in hypertrophied muscles but not in non-hypertrophied muscles. However, RTL1 was up-regulated in both hypertrophied and non-hypertrophied muscles. Five genes, including PARK7, DNTTIP1, SLC22A3, METTL21E and PDE4D, were consistently co-expressed with DLK1, and therefore were possible transcriptional target genes responding to DLK1 signaling. Treatment of myoblast and myotubes with DLK1 protein induced an average of 1.6-fold and 1.4-fold increase in Dnttip1 and Pde4d expression respectively. Myh4 expression was significantly elevated in DLK1-treated myotubes, whereas the expression of Mettl21e was significantly increased in the DLK1-treated myoblasts but reduced in DLK1-treated myotubes. DLK1 treatment had no impact on Park7 expression. In addition, Park7 and Dnttip1 increased Myh4 and decreased Myh7 promoter activity, resemble to the effects of Dlk1. In contrast, expression of Mettl21e increased Myh7 and decreased Myh4 luciferase activity. Conclusion The study provided additional supports that RTL1 alone was insufficient to induce muscle hypertrophy and concluded that DLK1 was likely the primary effector of the hypertrophy phenotype. The results also suggested that DNTTIP1 and PDE4D were secondary effector genes responding to DLK1 signaling resulting in muscle fiber switch and muscular hypertrophy in callipyge lamb. Electronic supplementary material The online version of this article (10.1186/s12864-018-4682-1) contains supplementary material, which is available to authorized users.

Background Choroidal neovascularization (CNV) is a major cause of blindness in patients with age-related macular degeneration. CNV is characterized by new blood vessel growth and subretinal fluid accumulation, which results in mechanical pressure on retinal pigment epithelial (RPE) cells. The overexpression of RPE-derived angiogenic factors plays an important role in inducing CNV. In this work, we investigated the effect of mechanical stress on the expression of angiogenic factors in porcine RPE cells and determined the impact of conditioned medium on in-vitro angiogenesis. Results The goal of this study was to determine whether low levels of acute mechanical stress during early CNV can induce the expression of angiogenic factors in RPE cells and accelerate angiogenesis. Using a novel device, acute mechanical stress was applied to primary porcine RPE cells and the resulting changes in the expression of major angiogenic factors, VEGF, ANG2, HIF-1α, IL6, IL8 and TNF-α, were examined using immunocytochemistry, qRT-PCR, and ELISA. An in vitro tube formation assay was used to determine the effect of secreted angiogenic proteins due to mechanical stress on endothelial tube formation by human umbilical vein endothelial cells (HUVECs). Our results showed an increase in the expression of VEGF, ANG2, IL-6 and IL-8 in response to mechanical stress, resulting in increased in vitro angiogenesis. Abnormal epithelial-mesenchymal transition (EMT) in RPE cells is also associated with CNV and further retinal degeneration. Our qRT-PCR results verified an increase in the expression of EMT genes, CDH2, VIM and FN1, in RPE cells. Conclusions In conclusion, we showed that acute mechanical stress induces the expression of major angiogenic and EMT factors and promotes in vitro angiogenesis, suggesting that mechanical stress plays a role in promoting aberrant angiogenesis in AMD.

Background Six Sarcocystis species are known to use cattle (Bos taurus) as the intermediate host, two of which, S. hominis and S. heydorni, are zoonotic. There is a need for a method that will enable rapid identification of the Sarcocystis species in cattle. Methods The diaphragm muscles of 102 cattle from Lithuania were examined for the presence of Sarcocystis spp., using two different methods for species identification. Individual sarcocysts were isolated from squash preparations of the diaphragm muscle under the light microscope, followed by genetic characterisation of excised cysts using sequence analysis of the 18S rRNA (18S rRNA) and cytochrome c oxidase subunit I (cox1) genes. The same cattle muscle samples were digested and species-specific PCR analyses targeting cox1 were developed to identify the Sarcocystis isolates to the species level. Results Under the light microscope, sarcocysts were detected in 87.3% of animals, and Sarcocystis infection was verified in all digested samples. Three species, namely S. cruzi (n = 20), S. bovifelis (n = 23) and S. hirsuta (n = 6), were identified by DNA sequence analysis of isolated sarcocysts. Based on sequence analysis of cox1, the level of genetic variability depended on Sarcocystis species and geographical location. Four Sarcocystis species, S. cruzi (96.1%), S. bovifelis (71.6%), S. hirsuta (30.4%) and S. hominis (13.7%), were confirmed in the digested samples. In individual samples, the most common finding was two species of Sarcocystis (44.1%), followed by three species (26.5%), a single species (24.5%) and four species (4.9%). Conclusions Although examination of tissue preparations under the light microscrope did not detect any sarcocysts belonging to S. hominis, this species was identified in the digested samples subjected to a cox1-specific PCR analysis. These results demonstrate the need for effective molecular diagnosis techniques to detect Sarcocystis spp., which may be present at a lower prevalence and not detectable among the limited number of sarcocysts identified individually under the light microscope. Graphical Abstract

Background: This paper discusses best practices for estimating fractions of mortality attributable to health exposures in survey data that are biased by observed confounders and unobserved endogenous selection. Extant research has shown that estimates of population attributable fractions (PAF) from the formula using the proportion of deceased that is exposed (PAFpd) can attend to confounders, whereas the formula using the proportion of the entire sample exposed (PAFpe) is biased by confounders. Research has not explored how PAFpd and PAFpe equations perform when both confounding and selection bias are present. Methods: We review equations for calculating PAF based on either the proportion of deceased (pd) or the proportion of the entire sample (pe) that receives the exposure. We explore how estimates from each equation are affected by confounding bias and selection bias using hypothetical data and real-world survey data from the National Health Interview Survey–Linked Mortality Files, 1987–2011. We examine the association between cigarette smoking and all-cause mortality risk in the US adult population as an example. Results: We show that both PAFpd and PAFpe calculate the true PAF in the presence of confounding bias if one uses the “weighted-sum” approach. We further show that both the PAFpd and PAFpe calculate biased PAFs in the presence of collider bias, but that the bias is more severe in the PAFpd formula. Conclusion: We recommend that researchers use the PAFpe formula with the weighted-sum approach when estimates of the exposure-outcome relationship are biased by endogenous selection.

MotivationMulticellular entities, such as mammalian tissues or microbial biofilms, typically exhibit complex spatial arrangements that are adapted to their specific functions or environments. These structures result from intercellular signaling as well as from the interaction with the environment that allow cells of the same genotype to differentiate into well-organized communities of diversified cells. Despite its importance, our understanding on how cell–cell and metabolic coupling produce functionally optimized structures is still limited.ResultsHere, we present a data-driven spatial framework to computationally investigate the development of one multicellular structure, yeast colonies. Using experimental growth data from homogeneous liquid media conditions, we develop and parameterize a dynamic cell state and growth model. We then use the resulting model in a coarse-grained spatial model, which we calibrate using experimental time-course data of colony growth. Throughout the model development process, we use state-of-the-art statistical techniques to handle the uncertainty of model structure and parameterization. Further, we validate the model predictions against independent experimental data and illustrate how metabolic coupling plays a central role in colony formation.AvailabilityExperimental data and a computational implementation to reproduce the results are available athttp://research.cs.aalto.fi/csb/software/multiscale/code.zip.Contactjukka.intosalmi@aalto.fi,alexander.skupin@uni.lu

Background Saffron crocus (Crocus sativus) is a valuable spice with medicinal uses in gynaecopathia and nervous system diseases. Identify flowering regulatory genes plays a vital role in increasing flower numbers, thereby resulting in high saffron yield. Results Two full length transcriptome gene sets of flowering and non-flowering saffron crocus were established separately using the single-molecule real-time (SMRT) sequencing method. A total of sixteen SMRT cells generated 22.85 GB data and 75,351 full-length saffron crocus unigenes on the PacBio RS II panel and further obtained 79,028 SSRs, 72,603 lncRNAs and 25,400 alternative splicing (AS) events. Using an Illumina RNA-seq platform, an additional fifteen corms with different flower numbers were sequenced. Many differential expression unigenes (DEGs) were screened separately between flowering and matched non-flowering top buds with cold treatment (1677), flowering top buds of 20 g corms and non-flowering top buds of 6 g corms (1086), and flowering and matched non-flowering lateral buds (267). A total of 62 putative flower-related genes that played important roles in vernalization (VRNs), gibberellins (G3OX, G2OX), photoperiod (PHYB, TEM1, PIF4), autonomous (FCA) and age (SPLs) pathways were identified and a schematic representation of the flowering gene regulatory network in saffron crocus was reported for the first time. After validation by real-time qPCR in 30 samples, two novel genes, PB.20221.2 (p = 0.004, r = 0.52) and PB.38952.1 (p = 0.023, r = 0.41), showed significantly higher expression levels in flowering plants. Tissue distribution showed specifically high expression in flower organs and time course expression analysis suggested that the transcripts increasingly accumulated during the flower development period. Conclusions Full-length transcriptomes of flowering and non-flowering saffron crocus were obtained using a combined NGS short-read and SMRT long-read sequencing approach. This report is the first to describe the flowering gene regulatory network of saffron crocus and establishes a reference full-length transcriptome for future studies on saffron crocus and other Iridaceae plants.

Background In postural stability evaluation, the dual-task concept is often adopted in order to create a more challenging situation. The dual-task consists of performing simultaneously two tasks, a primary static or dynamic motor task and an additional secondary cognitive task. Usually, a multitask condition leads to a reduction in the postural control performance, especially in older adults. Considering the wide spectrum of secondary task conditions existing in scientific literature, the present manuscript aims to write a peer-reviewed protocol that will be used in a systematic review and meta-analysis performed to identify the effects of different secondary tasks conditions in a population of older adults during static postural stability. Methods The study will follow the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and for this manuscript, the PRISMA Protocol. PICOS criteria (population, intervention, comparison, outcomes, study design) will be also followed. The population examined will be healthy older adults over 60 years of age and all quantitative, qualitative, and mixed methods study design will be included. Original articles will be also included if written in English, while no restriction criteria will be applied to the country of origin. Instead, reviews, meta-analysis, abstracts, citations, scientific conferences, opinion pieces, books, books reviews, statements, letters, editorials, non-peer reviewed journals articles, and commentaries will be excluded. The research of literature will be performed using PubMed, Web of Science, and Scopus with words related to the topic. From each included study, information previously agreed will be extracted and inserted into a spreadsheet and a narrative synthesis containing summary tables and graphs will describe the articles taken in examination. Furthermore, a meta-analysis will be performed to establish which DT condition has a greater effect following the Hedges and Olkin approach, extension of Glass’ method and Cohen’s d will be calculated. Discussion The present manuscript wants to provide the protocol that will be used in the systematic review and meta-analysis with the intent to inform the researchers and professionals about the dual-task condition effects. Such will lead future investigations in using the most appropriate dual-task condition. Systematic review registration PROSPERO CRD42018116597.

Background Although the black-white gap in life expectancy has narrowed in the U.S., there is considerable variability across states. In Wisconsin, the black-white gap exceeds 6 years, well above the national average. Reducing this disparity is an urgent public health priority, but there is limited understanding of what contributes to Wisconsin’s racial gap in longevity. Our investigation identifies causes of death that contribute most to Wisconsin’s black-white gap in life expectancy among males and females, and highlights specific ages where each cause of death contributes most to the gap. Methods Our study employs 1999–2016 restricted-use mortality data provided by the National Center for Health Statistics. After generating race- and sex-specific life tables for each 3-year period of observation (e.g., 1999–2001), we trace recent trends in the black-white life expectancy gap in Wisconsin. We subsequently conduct a series of analyses to decompose the black-white gap in three time periods into 13 separate causes and 19 different age groups. Results In 2014–16, Wisconsin’s black-white gap in life expectancy was 7.34 years for males (67% larger than the national gap), and 5.61 years for females (115% larger than the national gap). Among males, homicide was the single largest contributor, accounting for 1.56 years of the total gap. Heart disease and cancer followed, contributing 1.43 and 1.42 years, respectively. Among females, heart disease and cancer were the two leading contributors to the gap, accounting for 1.12 and 1.00 years, respectively. Whereas homicide contributed most to the racial gap in male longevity during late adolescence and early adulthood, heart disease and cancer exerted most of their influence between ages 50–70 for both males and females. Other notable contributors were unintentional injuries (males), diabetes and cerebrovascular disease (females), and perinatal conditions (males and females). Conclusions Our study identifies targets for future policy interventions that could substantially reduce Wisconsin’s racial gap in life expectancy. Concerted efforts to eliminate racial disparities in perinatal mortality and homicide early in the life course, and chronic conditions such as cancer and heart disease in later life, promise to help Wisconsin achieve the public health objective of racial parity in longevity. Electronic supplementary material The online version of this article (10.1186/s12889-019-7145-y) contains supplementary material, which is available to authorized users.

Background Gamma (γ)-Aminobutyric acid (GABA) as a bioactive compound is used extensively in functional foods, pharmaceuticals and agro-industry. It can be biosynthesized via decarboxylation of monosodium glutamate (MSG) or L-glutamic acid (L-Glu) by glutamate decarboxylase (GAD; EC4.1.1.15). GADs have been identified from a variety of microbial sources, such as Escherichia coli and lactic acid bacteria. However, no GADs from Streptomyces have been characterized. The present study is aimed to identify new GADs from Streptomyces strains and establish an efficient bioproduction platform for GABA in E. coli using these enzymes. Results By sequencing and analyzing the genomes of three Streptomycesstrains, three putative GADs were discovered, including StGAD from Streptomyces toxytricini NRRL 15443, SsGAD from Streptomyces sp.MJ654-NF4 and ScGAD from Streptomyces chromofuscus ATCC 49982. The corresponding genes were cloned from these strains and heterologously expressed in E. coli BL21(DE3). The purified GAD proteins showed a similar molecular mass to GadB from E. coliBL21(DE3). The optimal reaction temperature is 37 °C for all three enzymes, while the optimum pH values for StGAD, SsGAD and ScGAD are 5.2, 3.8 and 4.2, respectively. The kinetic parameters including Vmax, Km, kcat and kcat/Km values were investigated and calculated through in vitro reactions. SsGAD and ScGAD showed high biocatalytic efficiency with kcat/Km values of 0.62 and 1.21 mM− 1·s− 1, respectively. In addition, engineered E. coli strains harboring StGAD, SsGAD and ScGAD were used as whole-cell biocatalysts for production of GABA from L-Glu. E. coli/SsGAD showed the highest capability of GABA production. The cells were repeatedly used for 10 times, with an accumulated yield of 2.771 kg/L and an average molar conversion rate of 67% within 20 h. Conclusions Three new GADs have been functionally characterized from Streptomyces, among which two showed higher catalytic efficiency than previously reported GADs. Engineered E. coli harboring SsGAD provides a promising cost-effective bioconversion system for industrial production of GABA.

Background: Oil in the form of triacylglycerols (TAGs) is quantitatively the most important storage form of energy for eukaryotic cells. Diacylglycerol acyltransferase (DGAT) is considered the rate-limiting enzyme for TAG accumulation. Chlorella, a unicellular eukaryotic green alga, has attracted much attention as a potential feedstock for renewable energy production. However, the function of DGAT1 in Chlorella has not been reported. Results: A full-length cDNA encoding a putative diacylglycerol acyltransferase 1 (DGAT1, EC 2.3.1.20) was obtained from Chlorella ellipsoidea. The 2,142 bp open reading frame of this cDNA, designated CeDGAT1, encodes a protein of 713 amino acids showing no more than 40% identity with DGAT1s of higher plants. Transcript analysis showed that the expression level of CeDGAT1 markedly increased under nitrogen starvation, which led to significant triacylglycerol (TAG) accumulation. CeDGAT1 activity was confirmed in the yeast quadruple mutant strain H1246 by restoring its ability to produce TAG. Upon expression of CeDGAT1, the total fatty acid content in wild-type yeast (INVSc1) increased by 142%, significantly higher than that transformed with DGAT1s from higher plants, including even the oil crop soybean. The over-expression of CeDGAT1 under the NOS promoter in wild-type Arabidopsis thaliana and Brassica napus var. Westar significantly increased the oil content by 8–37% and 12–18% and the average 1,000-seed weight by 9–15% and 6–29%, respectively, but did not alter the fatty acid composition of the seed oil. The net increase in the 1,000-seed total lipid content was up to 25–50% in both transgenic Arabidopsis and B. napus. Conclusions: We identified a gene encoding DGAT1 in C. ellipsoidea and confirmed that it plays an important role in TAG accumulation. This is the first functional analysis of DGAT1 in Chlorella. This information is important for understanding lipid synthesis and accumulation in Chlorella and for genetic engineering to enhance oil production in microalgae and oil plants.

Background The configuration of necrotic areas within the retinal pigmented epithelium is an important element in the progression of age-related macular degeneration (AMD). In the exudative (wet) and non-exudative (dry) forms of the disease, retinal pigment epithelial (RPE) cells respond to adjacent atrophied regions by secreting vascular endothelial growth factor (VEGF) that in turn recruits new blood vessels which lead to a further reduction in retinal function and vision. In vitro models exist for studying VEGF expression in wet AMD (Vargis et al., Biomaterials 35(13):3999–4004, 2014), but are limited in the patterns of necrotic and intact RPE epithelium they can produce and in their ability to finely resolve VEGF expression dynamics. Results In this work, an in silico hybrid agent-based model was developed and validated using the results of this cell culture model of VEGF expression in AMD. The computational model was used to extend the cell culture investigation to explore the dynamics of VEGF expression in different sized patches of RPE cells and the role of negative feedback in VEGF expression. Results of the simulation and the cell culture studies were in excellent qualitative agreement, and close quantitative agreement. Conclusions The model indicated that the configuration of necrotic and RPE cell-containing regions have a major impact on VEGF expression dynamics and made precise predictions of VEGF expression dynamics by groups of RPE cells of various sizes and configurations. Coupled with biological studies, this model may give insights into key molecular mechanisms of AMD progression and open routes to more effective treatments.

Introduction Systematic reviews evaluating the impact of interventions to improve the quality of peer review for biomedical publications highlighted that interventions were limited and have little impact. This study aims to compare the accuracy of early career peer reviewers who use an innovative online tool to the usual peer reviewer process in evaluating the completeness of reporting and switched primary outcomes in completed reports. Methods and analysis This is a cross-sectional study of individual two-arm parallel-group randomised controlled trials (RCTs) published in the BioMed Central series medical journals, BMJ, BMJ Open and Annals of Emergency Medicine and indexed with the publication type ‘Randomised Controlled Trial’. First, we will develop an online tool and training module based (a) on the Consolidated Standards of Reporting Trials (CONSORT) 2010 checklist and the Explanation and Elaboration document that would be dedicated to junior peer reviewers for assessing the completeness of reporting of key items and (b) the Centre for Evidence-Based Medicine Outcome Monitoring Project process used to identify switched outcomes in completed reports of the primary results of RCTs when initially submitted. Then, we will compare the performance of early career peer reviewers who use the online tool to the usual peer review process in identifying inadequate reporting and switched outcomes in completed reports of RCTs at initial journal submission. The primary outcome will be the mean number of items accurately classified per manuscript. The secondary outcomes will be the mean number of items accurately classified per manuscript for the CONSORT items and the sensitivity, specificity and likelihood ratio to detect the item as adequately reported and to identify a switch in outcomes. We aim to include 120 RCTs and 120 early career peer reviewers. Ethics and dissemination The research protocol was approved by the ethics committee of the INSERM Institutional Review Board (21 January 2016). The study is based on voluntary participation and informed written consent. Trial registration number NCT03119376.

Introduction: Marathon race transiently elevates the probability of sudden death. Also during long-distance run may occur various gastrointestinal symptoms with range from mild nausea to hemorrhagic stool. However microcirculatory nature of this disturbances is not clear. Microcirculation of sublingual mucosa is part of interest, because it is easy and noninvasively accessible, changes have relation with mortality and it is part of the upper digestive tract. Here, we evaluate changes in sublingual microcirculation induced by a marathon race. Methods: Thirteen healthy male controls and 13 male marathon runners volunteered for the study. We performed sublingual microcirculation, using a Cytocam-IDF device (Braedius Medical, Huizen, The Netherlands), and systemic hemodynamic measurements four times on the marathon runners: 24 hours prior to their participation in the Kaunas Marathon (distance: 41.2 km), directly after finishing the marathon, 24 hours after the marathon and one week after the marathon. Results: The marathon runners exhibited a higher functional capillary density (FCD) and total vascular density of small vessels at the first visit compared with the controls. Overall, we did not find any changes in sublingual microcirculation in the marathon runners at any of the visits. However, in a subgroup of marathon runners with a decreased FCD after finishing the marathon race compared to increased FCD had shorter running time (190.37 ± 30.2 vs. 221.80 ± 23.4 min, p = 0.045), ingested less fluids (907 ± 615 vs. 1950 ± 488 ml, p = 0.007) during the race and lost much more weight (−2.4 ± 1.3 vs. -1.0 ± 0.8 kg, p = 0.041). Conclusions: Recreational marathon running is not associated with an alteration of sublingual microcirculation. However, faster running and dehydration may be crucial for further impairing microcirculation.

Background In the past two decades, rates of suicide mortality have declined among most OECD member states. Two notable exceptions are Japan and South Korea, where suicide mortality has increased by 20 % and 280 %, respectively. Methods Population and suicide mortality data were collected through national statistics organizations in Japan and South Korea for the period 1985 to 2010. Age, period of observation, and birth cohort membership were divided into five-year increments. We fitted a series of intrinsic estimator age-period-cohort models to estimate the effects of age-related processes, secular changes, and birth cohort dynamics on the rising rates of suicide mortality in the two neighboring countries. Results In Japan, elevated suicide rates are primarily driven by period effects, initiated during the Asian financial crisis of the late 1990s. In South Korea, multiple factors appear to be responsible for the stark increase in suicide mortality, including recent secular changes, elevated suicide risks at older ages in the context of an aging society, and strong cohort effects for those born between the Great Depression and the aftermath of the Korean War. Conclusion In spite of cultural, demographic and geographic similarities in Japan and South Korea, the underlying causes of increased suicide mortality differ across these societies—suggesting that public health responses should be tailored to fit each country’s unique situation.

Background: Insecticide resistance to synthetic chemical insecticides is a worldwide concern in phlebotomine sand flies (Diptera: Psychodidae), the vectors of Leishmania spp. parasites. The CDC bottle bioassay assesses resistance by testing populations against verified diagnostic doses and diagnostic times for an insecticide, but the assay has been used limitedly with sand flies. The objective of this study was to determine diagnostic doses and diagnostic times for laboratory Lutzomyia longipalpis (Lutz & Nieva) and Phlebotomus papatasi (Scopoli) to ten insecticides, including pyrethroids, organophosphates, carbamates, and DDT, that are used worldwide to control vectors. Methods: Bioassays were conducted in 1,000-ml glass bottles each containing 10–25 sand flies from laboratory colonies of L. longipalpis or P. papatasi. Four pyrethroids, three organophosphates, two carbamates and one organochlorine, were evaluated. A series of concentrations were tested for each insecticide, and four replicates were conducted for each concentration. Diagnostic doses were determined only during the exposure bioassay for the organophosphates and carbamates. For the pyrethroids and DDT, diagnostic doses were determined for both the exposure bioassay and after a 24-hour recovery period. Results: Both species are highly susceptible to the carbamates as their diagnostic doses are under 7.0 μg/ml. Both species are also highly susceptible to DDT during the exposure assay as their diagnostic doses are 7.5 μg/ml, yet their diagnostic doses for the 24-h recovery period are 650.0 μg/ml for Lu. longipalpis and 470.0 μg/ml for P. papatasi. Conclusions: Diagnostic doses and diagnostic times can now be incorporated into vector management programs that use the CDC bottle bioassay to assess insecticide resistance in field populations of Lu. longipalpis and P. papatasi. These findings provide initial starting points for determining diagnostic doses and diagnostic times for other sand fly vector species and wild populations using the CDC bottle bioassay.

Background: Caustic ingestions are rare but potentially life-threatening events requiring multidisciplinary emergency approaches. Although particularly respiratory functions may be impaired after caustic ingestions, studies involving acute emergency care are scarce. The goal of this study was to explore acute emergency care with respect to airway management and emergency department (ED) infrastructures. Methods: We retrospectively evaluated adult patients after caustic ingestions admitted to our university hospital over a 10-year period (2005–2014). Prognostic analysis included age, morbidity, ingested agent, airway management, interventions (endoscopy findings, computed tomography (CT), surgical procedures), intensive care unit (ICU) admission, length of stay in hospital and hospital mortality. Results: Twenty-eight patients with caustic ingestions were included in the analysis of which 18 (64 %) had suicidal intentions. Ingested agents were caustic alkalis (n = 22; 79 %) and acids (n = 6; 21 %). ICU admission was required in 20 patients (71 %). Fourteen patients (50 %) underwent tracheal intubation and mechanical ventilation, of which 3 (21 %) presented with difficult airways. Seven patients (25 %) underwent tracheotomy including one requiring awake tracheotomy due to progressive upper airway obstruction. Esophagogastroduodenoscopy (EGD) was performed in 21 patients (75 %) and 11 (39 %) underwent CT examination. Five patients (18 %) required emergency surgery with a mortality of 60 %. Overall hospital mortality was 18 % whereas the need for tracheal intubation (P = 0.012), CT-diagnostic (P = 0.001), higher EGD score (P = 0.006), tracheotomy (P = 0.048), and surgical interventions (P = 0.005) were significantly associated with mortality. Conclusions: Caustic ingestions in adult patients require an ED infrastructure providing 24/7-availability of expertise in establishing emergent airway safety, endoscopic examination (EGD and bronchoscopy), and CT diagnostic, intensive care and emergency esophageal surgery. We recommend that - even in patients with apparently stable clinical conditions - careful monitoring of respiratory functions should be considered as long as diagnostic work-up is completed.

Background: The specification of metadata in clinical and epidemiological study projects absorbs significant expense. The validity and quality of the collected data depend heavily on the precise and semantical correct representation of their metadata. In various research organizations, which are planning and coordinating studies, the required metadata are specified differently, depending on many conditions, e.g., on the used study management software. The latter does not always meet the needs of a particular research organization, e.g., with respect to the relevant metadata attributes and structuring possibilities. Methods: The objective of the research, set forth in this paper, is the development of a new approach for ontology-based representation and management of metadata. The basic features of this approach are demonstrated by the software tool OntoStudyEdit (OSE). The OSE is designed and developed according to the three ontology method. This method for developing software is based on the interactions of three different kinds of ontologies: a task ontology, a domain ontology and a top-level ontology. Results: The OSE can be easily adapted to different requirements, and it supports an ontologically founded representation and efficient management of metadata. The metadata specifications can by imported from various sources; they can be edited with the OSE, and they can be exported in/to several formats, which are used, e.g., by different study management software. Conclusions: Advantages of this approach are the adaptability of the OSE by integrating suitable domain ontologies, the ontological specification of mappings between the import/export formats and the DO, the specification of the study metadata in a uniform manner and its reuse in different research projects, and an intuitive data entry for non-expert users.

Introduction Zygomatic fractures form a major entity in craniomaxillofacial traumatology. Few studies have dealt with biomechanical basics and none with the role of the facial soft tissues. Therefore this study should investigate, whether facial soft tissue plays a protecting role in lateral midfacial trauma. Methods A head-to-head encounter was simulated by way of finite element analysis. In two scenarios this impact - with and without soft tissues - was investigated to demonstrate the potential protective effects. To achieve realism, a transient simulation was chosen, which considers temporal dynamics and realistic material parameters derived from CT grey values. Results The simulation results presented a typical zygomatic fracture with all relevant fracture lines. Including soft tissues did not change the maximum bony stress pattern, but increased the time period from impact to maximal stresses by 1.3 msec. Conclusions Although this could have clinical implications, facial soft tissues may be disregarded in biomechanical simulations of the lateral midface, if only the bony structures are to be investigated. Soft tissue seems to act as a temporal buffer only.

© Dhanasekaran et al. Background: Mass spectrometric analysis of microbial metabolism provides a long list of possible compounds. Restricting the identification of the possible compounds to those produced by the specific organism would benefit the identification process. Currently, identification of mass spectrometry (MS) data is commonly done using empirically derived compound databases. Unfortunately, most databases contain relatively few compounds, leaving long lists of unidentified molecules. Incorporating genome-encoded metabolism enables MS output identification that may not be included in databases. Using an organism's genome as a database restricts metabolite identification to only those compounds that the organism can produce. Results: To address the challenge of metabolomic analysis from MS data, a web-based application to directly search genome-constructed metabolic databases was developed. The user query returns a genome-restricted list of possible compound identifications along with the putative metabolic pathways based on the name, formula, SMILES structure, and the compound mass as defined by the user. Multiple queries can be done simultaneously by submitting a text file created by the user or obtained from the MS analysis software. The user can also provide parameters specific to the experiment's MS analysis conditions, such as mass deviation, adducts, and detection mode during the query so as to provide additional levels of evidence to produce the tentative identification. The query results are provided as an HTML page and downloadable text file of possible compounds that are restricted to a specific genome. Hyperlinks provided in the HTML file connect the user to the curated metabolic databases housed in ProCyc, a Pathway Tools platform, as well as the KEGG Pathway database for visualization and metabolic pathway analysis. Conclusions: Metabolome Searcher, a web-based tool, facilitates putative compound identification of MS output based on genome-restricted metabolic capability. This enables researchers to rapidly extend the possible identifications of large data sets for metabolites that are not in compound databases. Putative compound names with their associated metabolic pathways from metabolomics data sets are returned to the user for additional biological interpretation and visualization. This novel approach enables compound identification by restricting the possible masses to those encoded in the genome.

Background High-altitude inhabitants have cardiovascular and respiratory adaptations that are advantageous for high-altitude living, but they may have impaired cognitive function. This study evaluated the influence of altitude of residence on cognitive and psychomotor function upon acute exposure to very high altitude. Findings Ecuadorians (31 residing at 0–1,500 m [LOW], 78 from 1,501–3,000 m [MOD], and 23 living >3,000 m [HIGH]) were tested upon their arrival to a hut at 4,860 m on Mount Chimborazo. Cognitive/psychomotor measurements included a go-no-go test (responding to a non-visual stimulus), a verbal fluency test (verbalizing a series of words specific to a particular category), and a hand movement test (rapidly repeating a series of hand positions). Mean differences between the three altitude groups on these cognitive/psychomotor tests were evaluated with one-way ANOVA. There were no significant differences (p = 0.168) between LOW, MOD, and HIGH for the verbal fluency test. However, the go-no-go test was significantly lower (p

Background: Smartphones and related applications are increa singly gaining relevance in the healthcare domain. We previously assessed the demands and preferences of medical students towards an application accompanying them during a course on general practice. The current study aims to elucidate the factors associated with adop tion of such a technology. Therefore we provided students with a prototype of an application specifically related to their studies in general practice.

Background The clinical development of advanced therapy medicinal products (ATMPs), a new class of drugs, requires initial safety studies that deviate from standard non-clinical safety protocols. The study provides a strategy to address the safety aspects of biodistribution and tumorigenicity of ATMPs under good laboratory practice (GLP) conditions avoiding cell product manipulation. Moreover, the strategy was applied on a human ATMP for cartilage repair. Methods The testing strategy addresses biodistribution and tumorigenicity using a multi-step analysis without any cell manipulation to exclude changes of test item characteristics. As a safeguard measurement for meeting regulatory expectations, the project design and goals were discussed continuously with the regulatory authority using a staggered scientific advice concept. Subsequently, the strategy was applied to co.don chondrosphere® (huChon spheroid), a tissue-engineered matrix-free ATMP of human normal chondrocytes. In both the biodistribution and tumorigenicity studies, huChon spheroids were implanted subcutaneously into 40 immunodeficient mice. Biodistribution was studied 1 month after implantation. A skin disc containing the huChon spheroid, two surrounding skin rings and selected organs were analyzed by validated, gender-specific, highly-sensitive triplex qPCR and by immunohistochemistry (IHC). Results No human DNA was detected in distant skin rings and analyzed organs. IHC revealed no direct or indirect indications of cell migration. Tumorigenicity was assessed 6 months after huChon spheroid implantation by palpation, macroscopic inspection, histology and IHC. No mice from the huChon spheroid group developed a tumor at the implantation site. In two mice, benign tumors were detected that were negative for HLA-ABC, suggesting that they were of spontaneous murine origin. Conclusions In summary, the presented strategy using a multi-step analysis was confirmed to be suitable for safety studies of ATMPs. Electronic supplementary material The online version of this article (doi:10.1186/s12967-015-0517-x) contains supplementary material, which is available to authorized users.

Background: A large number of life science ontologies has been developed to support different application scenarios such as gene annotation or functional analysis. The continuous accumulation of new insights and knowledge affects specific portions in ontologies and thus leads to their adaptation. Therefore, it is valuable to study which ontology parts have been extensively modified or remained unchanged. Users can monitor the evolution of an ontology to improve its further development or apply the knowledge in their applications.

International audience; BMC Ecology showcases the winning entries from its second Ecology Image Competition. More than 300 individual images were submitted from an international array of research scientists, depicting life on every continent on earth. The journal’s Editorial Board and guest judge Caspar Henderson outline why their winning selections demonstrated high levels of technical skill and aesthetic sense in depicting the science of ecology, and we also highlight a small selection of highly commended images that we simply couldn’t let you miss out on.

Depression is common among persons with diabetes and associated with adverse health outcomes. To date, little is known about the causal mechanisms that lead to depression in diabetes. The aim of the present study was to examine to which extent functional and self-rated health mediate the association between physical health and depressive symptoms in diabetes. Data of n = 3222 individuals with type 2 diabetes were analyzed cross-sectionally and longitudinally at three measurement occasions using path analysis. Indicators of physical health were glycemic control, number of comorbid somatic diseases, BMI, and insulin dependence. Furthermore, functional health, self-rated health and depressive symptoms were assessed. The effects of physical health on depressive symptoms were largely mediated by functional health and self-rated health. There was only a weak indirect effect of physical health on depressive symptoms. In contrast, self-rated health was a strong direct predictor of depressive symptoms. Self-rated health in turn depended strongly on patients’ functional health. The way individuals perceive their health appears to have a stronger effect on their depressive symptoms than objective physical indicators of diabetes. Therefore practitioners should be trained to pay more attention to their patients’ subjective health perceptions.

Background: The effect of deep mineral water (DMW) with moderate mineralization on the recovery of physical performance after prolonged dehydrating aerobic exercise in the heat was studied in nine healthy, physically active (VO2max = 45.8 ± 8.4 mL kg �1 min �1 ) women aged 24.0 ± 3.7 years. Methods: We conducted a randomized, double-blind, placebo-controlled crossover human study to evaluate the effect of ingestion of natural mineral water extracted from a depth of 689 m on recovery from prolonged fatiguing aerobic running conducted at 30°C. Results: Mean body weight decreased by 2.6–2.8% following dehydrating exercise. VO2max was 9% higher after 4 h of recovery after rehydrating with DMW compared with plain water. Leg muscle power recovered better during the slow phase of recovery and was significantly higher after 48 h of recovery after rehydrating with DMW compared with plain water. Conclusions: DMW with moderate mineralization was more effective in inducing recovery of aerobic capacity and leg muscle power compared with plain water following prolonged dehydrating aerobic running exercise.

Backgroud: The Cancer Genome Atlas (TCGA) is a multidisciplinary, multi-institutional effort to catalogue genetic mutations responsible for cancer using genome analysis techniques. One of the aims of this project is to create a comprehensive and open repository of cancer related molecular analysis, to be exploited by bioinformaticians towards advancing cancer knowledge. However, devising bioinformatics applications to analyse such large dataset is still challenging, as it often requires downloading large archives and parsing the relevant text files. Therefore, it is making it difficult to enable virtual data integration in order to collect the critical co-variates necessary for analysis. Methods: We address these issues by transforming the TCGA data into the Semantic Web standard Resource Description Format (RDF), link it to relevant datasets in the Linked Open Data (LOD) cloud and further propose an efficient data distribution strategy to host the resulting 20.4 billion triples data via several SPARQL endpoints. Having the TCGA data distributed across multiple SPARQL endpoints, we enable biomedical scientists to query and retrieve information from these SPARQL endpoints by proposing a TCGA tailored federated SPARQL query processing engine named TopFed. Results: We compare TopFed with a well established federation engine FedX in terms of source selection and query execution time by using 10 different federated SPARQL queries with varying requirements. Our evaluation results show that TopFed selects on average less than half of the sources (with 100% recall) with query execution time equal to one third to that of FedX. Conclusion: With TopFed, we aim to offer biomedical scientists a single-point-of-access through which distributed TCGA data can be accessed in unison. We believe the proposed system can greatly help researchers in the biomedical domain to carry out their research effectively with TCGA as the amount and diversity of data exceeds the ability of local resources to handle its retrieval and parsing.

Background Hedgehog signaling plays an important role in embryonic development, organogenesis and cancer. In the adult liver, Hedgehog signaling in non-parenchymal cells has been found to play a role in certain disease states such as fibrosis and cirrhosis. However, whether the Hedgehog pathway is active in mature healthy hepatocytes and is of significance to liver function are controversial. Findings Two types of mice with distinct conditional hepatic deletion of the Smoothened gene, an essential co-receptor protein of the Hedgehog pathway, were generated for investigating the role of Hedgehog signaling in mature hepatocytes. The knockout animals (KO) were inconspicuous and healthy with no changes in serum transaminases, but showed a slower weight gain. The liver was smaller, but presented a normal architecture and cellular composition. By quantitative RT-PCR the downregulation of the expression of Indian hedgehog (Ihh) and the Gli3 transcription factor could be demonstrated in healthy mature hepatocytes from these mice, whereas Patched1 was upregulated. Strong alterations in gene expression were also observed for the IGF axis. While expression of Igf1 was downregulated, that of Igfbp1 was upregulated in the livers of both genders. Corresponding changes in the serum levels of both proteins could be detected by ELISA. By activating and inhibiting the transcriptional output of Hedgehog signaling in cultured hepatocytes through siRNAs against Ptch1 and Gli3, respectively, in combination with a ChIP assay evidence was collected indicating that Igf1 expression is directly dependent on the activator function of Gli3. In contrast, the mRNA level of Igfbp1 appears to be controlled through the repressor function of Gli3, while that of Igfbp2 and Igfbp3 did not change. Interestingly, body weight of the transgenic mice correlated well with IGF-I levels in both genders and also with IGFBP-1 levels in females, whereas it did not correlate with serum growth hormone levels. Conclusions Our results demonstrate for the first time that Hedgehog signaling is active in healthy mature mouse hepatocytes and that it has considerable importance for IGF-I homeostasis in the circulation. These findings may have various implications for mouse physiology including the regulation of body weight and size, glucose homeostasis and reproductive capacity.

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Background In recent years liver resection has increasingly been performed. Bleeding and hepatic acute failure, secondary to vascular inflow occlusion (Pringle’s manoeuvre), remain significant complications; these problems seem to be higher in older patients and in those with cirrhosis. Several surgical tools such as CUSA, Harmonic scalpel, Bipolar scissors, Ligasure diathermy, have been developed to decrease blood loss. Another device, based on radiofrequency, was proposed by Habib.1 The aim of our study was to evaluate Habib’s procedure and its influence in the outcomes of patients.

Background Data from the National Health Interview Survey (NHIS) show a larger-than-expected increase in mean BMI between 1996 and 1997. Proxy-reports of height and weight were discontinued as part of the 1997 NHIS redesign, suggesting that the sharp increase between 1996 and 1997 may be artifactual. Methods We merged NHIS data from 1976–2002 into a single database consisting of approximately 1.7 million adults aged 18 and over. The analysis consisted of two parts: First, we estimated the magnitude of BMI differences by reporting status (i.e., self-reported versus proxy-reported height and weight). Second, we developed a procedure to correct biases in BMI introduced by reporting status. Results Our analyses confirmed that proxy-reports of weight tended to be biased downward, with the degree of bias varying by race, sex, and other characteristics. We developed a correction procedure to minimize BMI underestimation associated with proxy-reporting, substantially reducing the larger-than-expected increase found in NHIS data between 1996 and 1997. Conclusion It is imperative that researchers who use reported estimates of height and weight think carefully about flaws in their data and how existing correction procedures might fail to account for them. The development of this particular correction procedure represents an important step toward improving the quality of BMI estimates in a widely used source of epidemiologic data.

RNA viruses replicate with a very high error rate and give rise to heterogeneous, highly plastic populations able to adapt very rapidly to changing environments. Viral diseases are thus difficult to control because of the appearance of drug-resistant mutants, and it becomes essential to seek mechanisms able to force the extinction of the quasispecies before adaptation emerges. An alternative to the use of conventional drugs consists in increasing the replication error rate through the use of mutagens. Here, we report about persistent infections of lymphocytic choriomeningitis virus treated with fluorouracil, where a progressive debilitation of infectivity leading to eventual extinction occurs. The transition to extinction is accompanied by the production of large amounts of RNA, indicating that the replicative ability of the quasispecies is not strongly impaired by the mutagen. By means of experimental and theoretical approaches, we propose that a fraction of the RNA molecules synthesized can behave as a defective subpopulation able to drive the viable class extinct. Our results lead to the identification of two extinction pathways, one at high amounts of mutagen, where the quasispecies completely loses its ability to infect and replicate, and a second one, at lower amounts of mutagen, where replication continues while the infective class gets extinct because of the action of defectors. The results bear on a potential application of increased mutagenesis as an antiviral strategy in that low doses of a mutagenic agent may suffice to drive persistent virus to extinction, This work was supported by a Sir Henry Welcome Award for Innovative Research, The Wellcome Trust (P.L. and E.D.), an International Research Collaboration grant from The Wellcome Trust, the British Heart Foundation, and the National Health Service research and development levy. Work in Madrid was supported by BioMed Central, Comunidad Autónoma de Madrid, and Fundación Ramón Areces grants (to E.D.). A.G.-P. was supported by Consejería de Educación (Comunidad Autónoma de Madrid). A.G.-P. and S.C.M. were supported by Ramón y Cajal contracts from the Ministerio de Ciencia y Tecnología. Work at Centro de Astrobiología was supported by the Instituto Nacional de Técnica Aeroespacial