bluuebunny/crossref_metadata_2025 huggingface dataset:
NATF (Native And Tissue-specific Fluorescence): A strategy for bright, tissue-specific GFP labeling of native proteins
Authors: He Siwei , Cuentas-Condori Andrea , Miller David M.
Published: September 2018

GFP labeling by genome editing can reveal the authentic location of a native protein but is frequently hampered by weak GFP signals and broad expression across a range cell types in multicellular animals. To overcome these problems, we engineered aNativeAndTissue-specific Fluorescence (NATF) strategy which combines CRISPR/Cas-9 and split-GFP to yield bright, cell-specific protein labeling. We use CRISPR/Cas9 to insert a tandem array of seven copies of the GFP11 β-strand (gfp11x7) at the genomic locus of each target protein. The resultantgfp11x7knock-in strain is then crossed with separate reporter lines that express the complementing split-GFP fragment (gfp1-10) in specific cell types thus affording tissue-specific labeling of the target protein at its native level. We show that NATF reveals the otherwise undetectable intracellular location of the immunoglobulin protein, OIG-1, and demarcates a receptor auxiliary protein LEV-10 at cell-specific synaptic domains in theC. elegansnervous system.
A data-driven approach to selecting invited speakers at conferences: a step toward gender parity
Authors: Vallence Ann-Maree , Hinder Mark R , Fujiyama Hakuei
Published: September 2018

We present a data-driven approach that uses established metrics of scientific quality to select invited speakers; this approach enables gender parity in conference programs while ensuring high scientific standards.

Gender disparity continues to be an issue in STEM, with progress requiring consistent and focused efforts. Here, we present a data-driven approach to promote high quality, gender balanced invited speaker selection for neuroscience conferences. We have targeted invited speaker opportunities because underrepresentation of female speakers at international neuroscience conferences remains a major problem, and such opportunities are critical for career development. First, we audited the top ten neuroscience journals (indexed by SCImago Journal and Country Rank; SJR), identifying (1) highly cited papers, (2) gender of first and last authors, and (3) field-weighted citation impact and total publications of first and last authors. Second, we used these data to establish a database of high quality scientists that could be used to select speakers for conferences. We found that research quality (as indexed by field-weighted citation impact and total publications) of authors of highly cited publications in the top 10 neuroscience journals did not differ significantly for females and males. The comparison between the gender base rate in neuroscience and authors publishing highly cited papers in high-quality neuroscience journals shows that female representation, particularly at last author level, is less than the estimated base rate for neuroscience. In summary, we present a data-driven approach to invited speaker selection that would facilitate gender balanced conference programs while maintaining the highest of scientific standards. This approach minimizes the influence of implicit gender bias in speaker selection decisions by using scientific quality metrics that STEM researchers are familiar with, and indeed use to evaluate their own performance. Having an immediate effect on reducing gender disparity in conference programs, our approach would generate a positive spiral for more long-term reduction of gender disparity in STEM.
PlotsOfData – a web app for visualizing data together with its summaries
Authors: Postma Marten , Goedhart Joachim
Published: September 2018

Reporting of the actual data in graphs and plots increases transparency and enables independent evaluation. On the other hand, data summaries are often used in graphs since they aid interpretation. State-of-the art data visualizations can be made with the ggplot2 package, which uses the ideas of a ‘grammar of graphics’ to generate a graphic from multiple layers of data. However, ggplot2 requires coding skills and an understanding of the tidy data structure. To democratize state-of-the-art data visualization of raw data with a selection of statistical summaries, a web app was written using R/shiny that uses the ggplot2 package for generating plots. A multilayered approach together with adjustable transparency offers a unique flexibility, enabling users can to choose how to display the data and which of the data summaries to add. Four data summaries are provided, mean, median, boxplot, violinplot, to accommodate several types of data distributions. In addition, 95% confidence intervals can be added for visual inferences. By adjusting the transparency of the layers, the visualization of the raw data together with the summary can be tuned for optimal presentation and interpretation. The app is dubbed PlotsOfData and is available at: https://huygens.science.uva.nl/PlotsOfData/
Combination of dynamic turbidimetry and tube agglutination to identify procoagulant genes by transposon mutagenesis in Staphylococcus aureus
Authors: Luo Dong , Chen Qiang , Jiang Bei , Lin Shirong , Peng Linfeng , Zeng Lingbing , Hu Xiaomei , Chen Kaisen
Published: September 2018

Agglutinating function is responsible for an important pathogenic pattern in S.aureus. Although the mechanism of aggregation has been widely studied since S.aureus has been found, the agglutinating detailed process remains largely unknown. Here, we screened a transposon mutant library of Newman strain using tube agglutination and dynamic turbidmetry test and identified 8 genes whose insertion mutations lead to a decrease in plasma agglomerate ability. These partial candidate genes were further confirmed by gene knockout and gene complement as well as RT-PCR techniques. these insertion mutants, including NWMN_0166, NWMN_0674, NWMN_0756, NWMN_0952, NWMN_1282, NWMN_1228, NWMN_1345 and NWMN_1319, which mapped into coagulase, clumping factor A, oxidative phosphorylation, energy metabolism, protein synthesis and regulatory system, suggesting that these genes may play an important role in aggregating ability. The newly constructed knockout strains of coa, cydA and their complemented strains were also tested aggregating ability. The result of plasma agglutination was consistent between coa knockout strain and coa mutant strain, meanwhile, cydA complement strain didn’t restored its function. Further studies need to confirm these results. These findings provide novel insights into the mechanisms of aggregating ability and offer new targets for development of drugs in S.aureus.
Effects of a complex mixture of persistent organic pollutants (POPs) on steroidogenesis in H295R cells under 10 μM forskolin stimulation - results from a pilot study
Authors: Mohammed Ahmed Kareem Eldin , Frøysa Håvard G , André Karlsen Odd , Elisabeth Zimmer Karin , Friis Berntsen Hanne , Verhaegen Steven , Ropstad Erik , Kellmann Ralf , Goksøyr Anders
Published: September 2018

This study describes the utilization of an LC-MS/MS based H295R assay to assess an environmentally relevant mixture of persistent organic pollutants (POPs). H295R cells were exposed to the POP mixture in two conditions stimulated with 10 μM forskolin and unstimulated. Most importantly, the unstimulated cells responded to the low concentration of the mixture with a significant down-regulation of dehydroepiandrosterone (DHEA). This response was not observed in forskolin-stimulated cells. In stimulated H295R cells, exposure to the highest concentration showed a trend towards induced production of mineralocorticoids and glucocorticoids, although this was not significant. On the other hand, in the same exposure concentration and condition, estrogen and androgen production tended to be down-regulated. In addition to these patterns of responses being different in the stimulated vs unstimulated condition, four steroids were not detectable in the unstimulated condition.
A rotifer-derived paralytic compound prevents transmission of schistosomiasis to a mammalian host
Authors: Gao Jiarong , Yang Ning , Lewis Fred A. , Yau Peter , Collins James J. , Sweedler Jonathan V. , Newmark Phillip A.
Published: September 2018

Schistosomes are parasitic flatworms that infect over 200 million people, causing the neglected tropical disease, schistosomiasis. A single drug, praziquantel, is used to treat schistosome infection. Limitations in mass drug administration programs and the emergence of schistosomiasis in non-tropical areas indicate the need for new strategies to prevent infection. It has been known for several decades that rotifers colonizing the schistosome’s snail intermediate host produce a water-soluble factor that paralyzes cercariae, the life-cycle stage infecting humans. In spite of its potential for preventing infection, the nature of this factor has remained obscure. Here, we report the purification and chemical characterization of Schistosome Paralysis Factor (SPF), a novel tetracyclic alkaloid produced by the rotifer Rotaria rotatoria. We show that this compound paralyzes schistosome cercariae and prevents infection, and does so more effectively than analogous compounds. This molecule provides new directions for understanding cercariae motility and new strategies for preventing schistosome infection.
Novel Comparison of Evaluation Metrics for Gene Ontology Classifiers Reveals Drastic Performance Differences
Authors: Plyusnin Ilya , Holm Liisa , Törönen Petri
Published: September 2018

Automated protein annotation using the Gene Ontology (GO) plays an important role in the biosciences. Evaluation has always been considered central to developing novel annotation methods, but little attention has been paid to the evaluation metrics themselves. Evaluation metrics define how well an annotation method performs and allows for them to be ranked against one another. Unfortunately, most of these metrics were adopted from the machine learning literature without establishing whether they were appropriate for GO annotations.

We propose a novel approach for comparing GO evaluation metrics calledArtificial Dilution Series(ADS). Our approach uses existing annotation data to generate a series of annotation sets with different levels of correctness (referred to as their signal level). We calculate the evaluation metric being tested for each annotation set in the series, allowing us to identify whether it can separate different signal levels. Finally, we contrast these results with severalfalse positive annotation sets, which are designed to expose systematic weaknesses in GO assessment.

We compared 37 evaluation metrics for GO annotation using ADS and identified drastic differences between metrics. We show that some metrics struggle to differentiate between different signal levels, while others give erroneously high scores to the false positive data sets. Based on our findings, we provide guidelines on which evaluation metrics perform well with the Gene Ontology and propose improvements to several well-known evaluation metrics. In general, we argue that evaluation metrics should be tested for their performance and we provide software for this purpose (https://bitbucket.org/plyusnin/ads/). ADS is applicable to other areas of science where the evaluation of prediction results is non-trivial.

Author Summary

In the biosciences, predictive methods are becoming increasingly necessary as novel sequences are generated at an ever-increasing rate. The volume of sequence data necessitates Automated Function Prediction (AFP) as manual curation is often impossible. Unfortunately, selecting the best AFP method is complicated by researchers using different evaluation metrics. Furthermore, many commonly-used metrics can give misleading results. We argue that the use of poor metrics in AFP evaluation is a result of the lack of methods to benchmark the metrics themselves. We propose an approach called Artificial Dilution Series (ADS). ADS uses existing data sets to generate multiple artificial AFP results, where each result has a controlled error rate. We use ADS to understand whether different metrics can distinguish between results with known quantities of error. Our results highlight dramatic differences in performance between evaluation metrics.
The cell cycle regulator GpsB functions as cytosolic adaptor for multiple cell wall enzymes
Authors: Cleverley Robert M. , Rutter Zoe J. , Rismondo Jeanine , Corona Federico , Tsui Ho-Ching Tiffany , Alatawi Fuad A. , Daniel Richard A. , Halbedel Sven , Massidda Orietta , Winkler Malcolm E. , Lewis Richard J.
Published: September 2018

Bacterial growth and cell division requires precise spatiotemporal regulation of the synthesis and remodelling of the peptidoglycan layer that surrounds the cytoplasmic membrane. GpsB is a cytosolic protein that affects cell wall synthesis by binding to the cytoplasmic mini-domains of peptidoglycan synthases to ensure their correct subcellular localisation. Here we have discovered critical structural features for the interaction of GpsB with peptidoglycan synthases from three different bacteria and demonstrated their importance for cell wall growth and viability. We have used these structural motifs to predict and confirm novel partners of GpsB in Bacillus subtilis, illuminating the role of this key regulator of peptidoglycan synthesis. GpsB thus functions as an adaptor, to mediate the interaction between membrane proteins, scaffolding proteins, signalling proteins and enzymes to generate larger protein complexes at specific sites in a bacterial cell cycle-dependent manner. Given the importance of GpsB in pathogenic bacteria, this study has not only revealed mechanistic details of how cell wall synthesis is co-ordinated with the bacterial cell cycle but could also represent a starting point for the design of much needed new antibiotics.
Subcutaneous Neurotrophin-3 infusion induces corticospinal neuroplasticity and improvements in dexterity and walking in elderly rats after large cortical stroke
Authors: Duricki Denise , Kakanos Sotiris , Haenzi Barbara , Wayman Christina , Bödecker Nora , Vogelgesang Antje , Cash Diana , Moon Lawrence
Published: September 2018

There is an urgent need for a therapy which reverses disability after stroke when initiated in a time frame suitable for the majority of new victims. Neurotrophin-3 (NT3) is a growth factor made by muscle spindles and skin which is required for the survival, development and function of locomotor circuits involving afferents from muscle and skin that mediate proprioception and tactile sensation. Its level declines in muscle and other tissues postnatally. We show that levels of NT-3 in the bloodstream were low in humans with ischemia stroke relative to young healthy controls. Accordingly, we set out to determine whether subcutaneous delivery of NT3 improves sensorimotor recovery after stroke in elderly rats. We show that one-month-long subcutaneous infusion of NT3 protein induces sensorimotor recovery after cortical stroke in elderly rats. Specifically, in a randomised, blinded pre-clinical trial, we show improved dexterity, walking and sensory function in rats following cortical ischemic stroke when treatment with NT3 is initiated 24 hours after stroke. Importantly, NT-3 was given in a clinically feasible time frame via this straightforward route. MRI and histology showed that recovery was not due to neuroprotection, as expected given the delayed treatment. Rather, anterograde tracing showed that corticospinal axons from the less-affected hemisphere sprouted in the spinal cord from cervical levels 2 to 8. Importantly, Phase I and II clinical trials by others show that repeated, subcutaneously administered high doses of recombinant NT-3 are safe and well tolerated in humans with other conditions. This paves the way for NT-3 as a therapy for stroke.
The mutational and phenotypic spectrum of TUBA1A-associated tubulinopathy
Authors: Hebebrand Moritz , Hüffmeier Ulrike , Uebe Steffen , Ekici Arif B. , Kraus Cornelia , Krumbiegel Mandy , Reis André , Thiel Christian T. , Popp Bernt
Published: September 2018

Background

The TUBA1A-associated tubulinopathy is clinically heterogeneous with brain malformations, microcephaly, developmental delay and epilepsy being the main clinical features. It is an autosomal dominant disorder mostly caused by de novo variants in TUBA1A.

Results

In three individuals with developmental delay we identified heterozygous de novo missense variants in TUBA1A using exome sequencing. While the c.1307G>A, p.(Gly436Asp) variant was novel, the two variants c.518C>T, p.(Pro173Leu) and c.641G>A, p.(Arg214His) were previously described. We compared the variable phenotype observed in these individuals with a carefully conducted review of the current literature and identified 166 individuals, 146 born and 20 fetuses with a TUBA1A variant. In 107 cases with available clinical information we standardized the reported phenotypes according to the Human Phenotype Ontology. The most commonly reported features were developmental delay (98%), anomalies of the corpus callosum (96%), microcephaly (76%) and lissencephaly (70%), although reporting was incomplete in the different studies. We identified a total of 121 distinct variants, including 15 recurrent ones. Missense variants cluster in the C-terminal region around the most commonly affected amino acid position Arg402 (13.3%). In a three-dimensional protein modelling, 38.6% of all disease causing variants including those in the C-terminal region are predicted to affect binding of microtubule-associated proteins or motor proteins. Genotype-phenotype analysis for recurrent variants showed an overrepresentation of certain clinical features. However, individuals with these variants are often reported in the same publication.

Conclusions

With 166 individuals, we present the most comprehensive phenotypic and genotypic standardized synopsis for clinical interpretation of TUBA1A variants. Despite this considerable number, a detailed genotype-phenotype characterization is limited by large inter-study variability in reporting.
A FASII inhibitor prevents staphylococcal evasion of daptomycin by inhibiting phospholipid decoy production
Authors: Pee Carmen J. E. , Pader Vera , Ledger Elizabeth V. K. , Edwards Andrew M.
Published: September 2018

Daptomycin is a treatment of last resort for serious infections caused by drug-resistant Gram-positive pathogens such as methicillin-resistantStaphylococcus aureus. We have shown recently thatS. aureuscan evade daptomycin by releasing phospholipid decoys that sequester and inactivate the antibiotic, leading to treatment failure. Since phospholipid release occurs via an active process we hypothesised that it could be inhibited, thereby increasing daptomycin efficacy. To identify opportunities for therapeutic interventions that block phospholipid release, we first determined how the host environment influenced the release of phospholipids and inactivation of daptomycin byS. aureus. The addition of certain host-associated fatty acids to the growth medium enhanced phospholipid release. However, in serum, the sequestration of fatty acids by albumin restricted their availability toS. aureussufficiently to prevent their use in the generation of released phospholipids. This finding implied that in host tissuesS. aureusis likely to be completely dependent upon endogenous phospholipid biosynthesis to generate lipids for release, providing a target for therapeutic intervention. To test this, we exposedS. aureusto AFN-1252, an inhibitor of the staphylococcal FASII fatty acid biosynthetic pathway, together with daptomycin. AFN-1252 efficiently blocked daptomycin-induced phospholipid decoy production, even in the case of isolates resistant to AFN-1252, which prevented the inactivation of daptomycin and resulted in sustained bacterial killing. In turn, daptomycin prevented the fatty acid-dependent emergence of AFN-1252-resistant isolates. In summary, AFN-1252 significantly enhances daptomycin activity againstS. aureusby blocking the production of phospholipid decoys, whilst daptomycin blocks the emergence of resistance to AFN-1252.
CRISPR-interference based modulation of mobile genetic elements in bacteria
Authors: Nyerges Ákos , Bálint Balázs , Cseklye Judit , Nagy István , Pál Csaba , Fehér Tamás
Published: September 2018

Spontaneous mutagenesis of synthetic genetic constructs by mobile genetic elements frequently results in the rapid loss of advantageous functions. Previous efforts to minimize such mutations required the exceedingly time-consuming manipulation of bacterial chromosomes and the complete removal of insertional sequences (ISes). To this aim, we developed a single plasmid-based system (pCRIS) that applies CRISPR-interference to inhibit the transposition of bacterial ISes. pCRIS expresses multiple guide RNAs to direct inactivated Cas9 (dCas9) to simultaneously silence IS1, IS3, IS5, and IS150at up to 38 chromosomal loci inEscherichia coli,in vivo. As a result, the transposition rate of all four targeted ISes dropped to negligible levels at both chromosomal and episomal targets, increasing the half-life of exogenous protein expression. Most notably, pCRIS, while requiring only a single plasmid delivery performed within a single day, provided a reduction of IS-mobility comparable to that seen in genome-scale chromosome engineering projects. Global transcriptomics analysis revealed nevertheless only minute alterations in the expression of untargeted genes. Finally, the transposition-silencing effect of pCRIS was easily transferable across multipleE. colistrains. The plasticity and robustness of our IS-silencing system make it a promising tool to stabilize bacterial genomes for synthetic biology and industrial biotechnology applications.
Study on physicochemical properties and microbial diversity of flammulina velutipes residue during rapid fermentation
Authors: Shi Guangying , Wang Yuxin , Wang Pingzhi , Gu Yizhu
Published: September 2018

In order to investigate the effects of different mass ratios of corn straw, super absorbent resin (SAR) and cellulose decomposing strains on fermentation of flammulina velutipes residue, the cellulose degradation rate, germination index, bacterial diversity, urease activity, cellulase activity and other indicators were evaluated comprehensively so as to determine the optimal fermentation parameters. The research results indicated that the three factors of corn straw, high water-absorbent resin (SAR), and cellulose-decomposing strains have the tendency to enhance fermentation in the process. In the orthogonal test, the treatment with the highest cellulose degradation rate was T6. By 24 days, all the treated seeds germination Indices (GIs) were higher than 80%, which indicated that they were basically harmless to crops. The cellulase activity and urease activity of each treatment showed the characteristics of first rising and then decreasing as the fermentation time prolonged. In general, the T6 (the added amount of corn straw was 10%, the amount of super absorbent resin was 0.15%, and the amount of cellulose-decomposing strains was 2%) was the suitable mass ratio of additives in the fermentation which provided a certain theoretical support for resource utilization of flammulina velutipes residue.
Food collection behavior ofApis melliferaandTetragonisca angustulabees inBrassica napusL. in response to different environmental covariates
Authors: Camargo Simone Cristina , Garcia Regina Conceição , de Oliveira Newton Tavares Escocard , de Vasconcelos Edmar Soares , Galhardo Douglas , Ströher Sandra Mara , Hartleben Alceu Maurício , Pires Bruno Garcia , Piñeros Gustavo Andrés Patiño , Díaz David Fernando Gómez , Ribeiro Renato de Jesus , Radtke Thiago Henrique , Santos Pedro da Rosa , de Toledo Vagner de Alencar Arnaut
Published: September 2018

The objective was to evaluate the behavior ofApis melliferaandTetragonisca angustulabees in pollination tests inBrassica napusat different times of the day, temperature and relative humidity. The experimental design was completely with eight treatments and two pollination tests, repeated in five randomized blocks during seven days of observations for two years, totaling 560 records. During the visits, the following parameters were recorded: collected resources, nectar collection site, time spent on flower, number of flowers visited in one minute, pollen load in the pollen basket and bee contact with anthers and stigma. Data were analyzed using generalized linear models. The number of Africanized andT. angustulabees collecting nectar increased with the passage of time throughout the day and with the decrease of relative humidity. The same was observed for nectar collection in both nectaries. The proportion of bees collecting pollen was higher in the morning hours, as well as when there was an increase in temperature for the two species of bees. Foraging behavior ofA. melliferainB. napuscrop favored its pollination, indifferent of which collected floral resource as they came into contact with anthers and stigma.T. angustulabees performed pollination only during pollen collection. Pollination ofB. napuswas more effective in the warmer hours of the morning, when more of both species of bees carried out pollen collection. Due to its foraging behavior,A. melliferahad greater efficiency for pollination ofB. napus; however, the association with T. angustulamay potentiate the benefits generated for the crop by cross-pollination.
Studies on effect of gold nanoparticles onMeloidogyne incognitaand tomato plants growth and development
Authors: Thakur Rajni Kant , Dhirta Babita , Shirkot Poonam
Published: September 2018

The plant parasitic nematodes are one of world major agricultural pest, causing in excess of 157 billion dollars in worldwide damage annually. This study has provided evidence that gold nanoparticles have great utility for management of root-knot nematodes in tomato crop. The effect of gold nanoparticles onMeloidogyne incognitaJ2 was remarkable under the direct exposure in water, after three hours of incubation of Meloidogyne incognita with GNPs showed the 100% mortality. The lesser survival rate ofMeloidogyne incognitain soil treatment showed the strong nematicidal effect of gold nanoparticles. Subsequently, the pot experiment had shown the beneficial effects of gold nanoparticles for intensively managing the root-knot nematode. The Pot experiment not only showed us that GNPs were lethal to root-knot nematodes were also induces growth of tomato plants and didn’t have any kind of negative impact on plant growth. In our study, GNPs were found to be safe and lethal to Meloidogyne incognita.
Microplastic-mediated transport of PCBs? A depuration study with Daphnia magna
Authors: Gerdes Zandra , Ogonowski Martin , Nybom Inna , Ek Caroline , Adolfsson-Erici Margaretha , Barth Andreas , Gorokhova Elena
Published: September 2018

The role of microplastic (MP) as a carrier of persistent organic pollutants (POPs) to aquatic organisms has been a topic of debate. However, theoretically, the reverse POP transport can occur at higher relative contaminant concentrations in the organism than in the microplastic. The effect of microplastic on the PCB removal in planktonic animals was evaluated using the cladoceran Daphnia magna with a high body burden of polychlorinated biphenyls (PCB 18, 40, 128 and 209) exposed to a mixture of microplastic and algae (with 77% MP by mass); daphnids exposed to only algae served as the control. As the endpoints, we used PCB body burden, growth, fecundity and elemental composition (%C and %N) of the daphnids. We found that PCB 209 was removed more efficiently in the daphnids fed with microplastic, while there was no difference for the ΣPCBs between the microplastic-exposed and control animals. Effects of the microplastic exposure on fecundity were of low biological significance, even though both the starting PCB body burden and the microplastic exposure concentrations were high and greatly exceeding environmentally relevant concentrations.
The functional organisation of the hippocampus along its long axis is gradual and predicts recollection
Authors: Przezdzik Izabela , Faber Myrthe , Fernández Guillén , Beckmann Christian F. , Haak Koen V.
Published: September 2018

Understanding the functional organisation of the hippocampus is crucial for understanding its role in cognition and disorders in which it is implicated. Different views have been proposed of how function is distributed along its long axis: one view suggests segregation, whereas the alternative view postulates a more gradual organisation. Here, we applied a novel ‘connectopic mapping’ data-analysis approach to the resting-state fMRI data of participants of the Human Connectome Project, and demonstrate that the functional organisation of the hippocampal longitudinal axis is gradual rather than segregated into parcels. In addition, we show that inter-individual variations in this gradual organisation predicts variations in recollection memory better than a characterisation based on parcellation. These results present an important step forward in understanding the functional organisation of the human hippocampus and have important implications for translating between rodent and human research.
Mitotic CDK promotes replisome disassembly, fork breakage, and complex DNA rearrangements
Authors: Deng Lin , Wu R. Alex. , Kochenova Olga V. , Pellman David , Walter Johannes C.
Published: September 2018

DNA replication errors generate complex chromosomal rearrangements and thereby contribute to tumorigenesis and other human diseases. Although the events that trigger these errors are not well understood, one candidate is mitotic entry before the completion of DNA replication. To address the impact of mitosis on DNA replication, we employed Xenopus egg extracts. When mitotic CDK (Cyclin B1-CDK1) is used to drive these extracts into mitosis, the E3 ubiquitin ligase TRAIP promotes ubiquitylation of the replicative CMG (CDC45/MCM2–7/GINS) helicase at stalled forks and at forks that have completed DNA synthesis. In both cases, ubiquitylation is followed by CMG extraction from chromatin by the CDC48/p97 ATPase. At stalled forks, CMG removal results in fork breakage and complex end joining events involving deletions and template-switching. Our results identify TRAIP-dependent replisome disassembly as a novel trigger of replication fork collapse and propose it underlies complex DNA rearrangements in mitosis.

HIGHLIGHTS

TRAIP-dependent MCM7 ubiquitylation removes all CMGs from chromatin in mitosis

CMG unloading from stalled forks causes replication fork breakage

Replication fork breakage in mitosis causes complex rearrangements

New model of replication fork collapse
Tightly-linked antagonistic-effect loci underlie polygenic demographic variation inC. elegans
Authors: Bernstein Max R. , Zdraljevic Stefan , Andersen Erik C. , Rockman Matthew V.
Published: September 2018

Recent work has provided strong empirical support for the classic polygenic model for trait variation. Population-based findings suggest that most regions of genome harbor variation affecting most traits. This view is hard to reconcile with the experience of researchers who define gene functions using mutagenesis, comparing mutants one at a time to the wild type. Here, we use the approach of experimental genetics to show that indeed, most genomic regions carry variants with detectable effects on complex traits. We used high-throughput phenotyping to characterize demography as a multivariate trait in growing populations ofCaenorhabditis eleganssensitized by nickel stress. We show that demography under these conditions is genetically complex in a panel of recombinant inbred lines. We then focused on a 1.4-Mb region of the X chromosome. When we compared two near isogenic lines (NILs) that differ only at this region, they were phenotypically indistinguishable. When we used additional NILs to subdivide the region into fifteen intervals, each encompassing ~0.001 of the genome, we found that eleven of intervals have significant effects. These effects are often similar in magnitude to those of genome-wide significant QTLs mapped in the recombinant inbred lines but are antagonized by the effects of variants in adjacent intervals. Contrary to the expectation of small additive effects, our findings point to large-effect variants whose effects are masked by epistasis or linkage disequilibrium between alleles of opposing effect.
High-order theta harmonics account for the detection of slow gamma
Authors: Zhou Y. , Sheremet A. , Qin Y. , Kennedy J.P. , DiCola N.M. , Maurer A. P.
Published: September 2018

ABSTRACT

Local field potential (LFP) oscillations are the superposition of excitatory/inhibitory postsynaptic potentials. In the hippocampus, the 20-55 Hz range (‘slow gamma’) is proposed to support cognition independent of other frequencies. However, this band overlaps with theta harmonics. We aimed to dissociate the generators of slow gamma versus theta harmonics with current source density and different LFP decompositions. Hippocampal theta harmonic and slow gamma generators were not dissociable. Moreover, comparison of wavelet, ensemble empirical-mode (EEMD), and Fourier decompositions produced distinct outcomes with wavelet and EEMD failing to resolve high-order theta harmonics well defined by Fourier analysis. The varying sizes of the time-frequency atoms used by wavelet distributed the higher-order harmonics over a broader range giving the impression of a low frequency burst (“slow gamma”). The absence of detectable slow gamma refutes a multiplexed model of cognition in favor of the energy cascade hypothesis in which dependency across oscillatory frequencies exists.
Interleukin-6 Receptor Signalling and Abdominal Aortic Aneurysm Growth Rates
Authors: Paige Ellie , Clément Marc , Lareyre Fabien , Sweeting Michael , Raffort Juliette , Grenier Céline , Finigan Alison , Harrison James , Peters James E. , Sun Benjamin B. , Butterworth Adam S. , Harrison Seamus C. , Bown Matthew J. , Lindholt Jes S. , Badger Stephen A. , Kullo Iftikhar J. , Powell Janet , Norman Paul E. , Scott D Julian A. , Bailey Marc A. , Rose-John Stefan , Danesh John , Freitag Daniel F. , Paul Dirk S. , Mallat Ziad
Published: September 2018

Background

The Asp358Ala variant (rs2228145; A>C) in the interleukin-6 receptor (IL6R) gene has been implicated in the development of abdominal aortic aneurysms (AAAs), but its effect on AAA growth over time is not known. We aimed to investigate the clinical association between the IL6R-Asp358Ala variant and AAA growth, and to assess the effect of blocking the IL-6 signalling pathway in mouse models of aneurysm rupture.

Method

Using data from 2,863 participants with AAA from nine prospective cohorts, age- and sex-adjusted mixed-effects linear regression models were used to estimate the association between the IL6R-Asp358Ala variant and annual change in AAA diameter (mm/year). In a series of complementary randomised trials in mice, the effect of blocking the IL-6 signalling pathways was assessed on plasma biomarkers, systolic blood pressure, aneurysm diameter and time to aortic rupture and death.

Results

After adjusting for age and sex, baseline aneurysm size was 0.55mm (95% confidence interval [CI]: 0.13, 0.98mm) smaller per copy of the minor allele [C] of the Asp358Ala variant. There was no evidence of a reduction in AAA growth rate (change in growth=-0.06mm per year [−0.18, 0.06] per copy of the minor allele). In two mouse models of AAA, selective blockage of the IL-6 trans-signalling pathway, but not combined blockage of both, the classical and trans-signalling pathways, was associated with improved survival (p<0.05).

Conclusions

Our proof-of-principle data are compatible with the concept that IL-6 trans-signalling is relevant to AAA growth, encouraging larger-scale evaluation of this hypothesis.
Collective intercellular communication through ultra-fast hydrodynamic trigger waves
Authors: Mathijssen Arnold J. T. M. , Culver Joshua , Bhamla M. Saad , Prakash Manu
Published: September 2018

The biophysical relationships between sensors and actuators [1–5] have been fundamental to the development of complex life forms; Abundant flows are generated and persist in aquatic environments by swimming organisms [6–13], while responding promptly to external stimuli is key to survival [14–19]. Here, akin to a chain reaction [20–22], we present the discovery of hydrodynamic trigger waves in cellular communities of the protistSpirostomum ambiguum, propagating hundreds of times faster than the swimming speed. Coiling its cytoskeleton,Spirostomumcan contract its long body by 50% within milliseconds [23], with accelerations reaching 14g-forces. Surprisingly, a single cellular contraction (transmitter) is shown to generate long-ranged vortex flows at intermediate Reynolds numbers, which can trigger neighbouring cells, in turn. To measure the sensitivity to hydrodynamic signals (receiver), we further present a high-throughput suction-flow device to probe mechanosensitive ion channel gating [24] by back-calculating the microscopic forces on the cell membrane. These ultra-fast hydrodynamic trigger waves are analysed and modelled quantitatively in a universal framework of antenna and percolation theory [25, 26]. A phase transition is revealed, requiring a critical colony density to sustain collective communication. Our results suggest that this signalling could help organise cohabiting communities over large distances, influencing long-term behaviour through gene expression, comparable to quorum sensing [16]. More immediately, as contractions release toxins [27], synchronised discharges could also facilitate the repulsion of large predators, or conversely immobilise large prey. We postulate that beyond protists numerous other freshwater and marine organisms could coordinate with variations of hydrodynamic trigger waves.
From space to time: Spatial inhomogeneities lead to the emergence of spatio-temporal activity sequences in spiking neuronal networks
Authors: Spreizer Sebastian , Aertsen Ad , Kumar Arvind
Published: September 2018

Spatio-temporal sequences of neuronal activity are observed in many brain regions in a variety of tasks and are thought to form the basis of any meaningful behavior. Mechanisms by which a neuronal network can generate spatio-temporal activity sequences have remained obscure. Existing models are biologically untenable because they require manual embedding of a feedforward network within a random network or supervised learning to train the connectivity of a network to generate sequences. Here, we propose a biologically plausible, generative rule to create spatio-temporal activity sequences in a network model of spiking neurons with distance dependent connectivity. We show that the emergence of spatio-temporal activity sequences requires: (1) individual neurons preferentially project a small fraction of their axons in a specific direction, and (2) the preferential projection direction of neighboring neurons is similar. Thus, an anisotropic but correlated connectivity of neuron groups suffices to generate spatio-temporal activity sequences in an otherwise random neuronal network model.
A florigen paralog is required for short-day vernalization in a pooid grass
Authors: Woods Daniel P. , Dong Yinxin , Bouché Frédéric , Bednarek Ryland , Rowe Mark , Ream Thomas S. , Amasino Richard M.
Published: September 2018

Perception of seasonal cues is critical for reproductive success in many plants. Exposure to winter cold is a cue that can confer competence to flower in the spring via a process known as vernalization. In certain grasses, exposure to short days is another winter cue that can lead to a vernalized state. In Brachypodium distachyon, we find that natural variation for the ability of short days to confer competence to flower is due to allelic variation of the florigen paralog FT-like9 (FTL9). An active FTL9 allele is required for the acquisition of floral competence, demonstrating a novel role for a member of the florigen family of genes. Loss of the short-day vernalization response appears to have arisen once in B. distachyon and spread through diverse lineages indicating that this loss has adaptive value, perhaps by delaying spring flowering until the danger of cold damage to flowers has subsided.
Subcellular Time Series Modeling of Heterogeneous Cell Protrusion
Authors: Kim Yeesock , Choi Hee June , Lee Kwonmoo
Published: September 2018

In this paper, a new biological modeling approach is proposed for predicting complex heterogeneous subcellular behaviors. Cell protrusion which initiates cell migration has a significant amount of subcellular heterogeneity in micrometer length and minute time scales. It is driven by actin polymerization, e.g., pushing the plasma membrane forward, and then regulated by a multitude of actin regulators. While mathematical modeling is central to system-level understandings of cell protrusion, most of the modeling is based on the ensemble average of actin regulator dynamics at the cellular or population levels, preventing from capturing the heterogeneous cellular activities. With these in mind, a systematic modeling framework is proposed in this paper for predicting velocities of heterogeneous protrusion of migrating cells driven by multiple molecular mechanisms. The modeling framework is developed through the integration of the multiple AutoRegressive eXogenous (ARX) models employing probability density input variables. Unlike conventional ARX models, it provides an effective framework for modeling heterogeneous subcellular behaviors with complex nonlinearities and uncertainties of dynamic systems. To train and validate the proposed model, numerous subcellular time series are extracted from time-lapse movies of migrating PtK1 cells using spinning disk confocal microscope: The current edge velocities and fluorescent intensities of mDia1, actin at the leading edge are used as the input while the future cell edge velocities are selected as an output. It is demonstrated that the proposed approach is highly effective in predicting the future trends of heterogeneous cell protrusion. In particular, by capturing the various multiple activities from the dataset, it is expected that it would improve the understanding of the molecular mechanism underlying cellular and subcellular heterogeneity.
Reduced serotonin receptors and transporters in normal aging adults: a meta-analysis of PET and SPECT imaging studies
Authors: Karrer Teresa M. , McLaughlin Casey L. , Guaglianone Carmela P. , Samanez-Larkin Gregory R.
Published: September 2018

Alterations in serotonin (5-HT) function have been hypothesized to underlie a range of physiological, emotional, and cognitive changes in older age. Here, we conducted a quantitative synthesis and comparison of the effects of age on 5-HT receptors and transporters from cross-sectional PET and SPECT imaging studies. Random-effects meta-analyses of 31 studies including 1087 healthy adults yielded large negative effects of age in 5-HT-2A receptors (largest in global cortex), moderate negative effects of age in 5-HT transporters (largest in thalamus), and small negative effects of age in 5-HT-1A receptors (largest in parietal cortex). Presynaptic 5-HT-1A autoreceptors in raphe/midbrain, however, were preserved across adulthood. Adult age differences were significantly larger in 5-HT-2A receptors compared to 5-HT-1A receptors. A meta-regression showed that 5-HT target, radionuclide, and publication year significantly moderated the age effects. The findings overall identify reduced serotonergic signal transmission in healthy aging. The evidence for the relative preservation of 5-HT-1A compared to 5-HT-2A receptors may partially explain psychological age differences, such as why older adults use more emotion-focused rather than problem-focused coping strategies.
A unified framework for unconstrained and constrained ordination of microbiome read count data
Authors: Hawinkel Stijn , Kerckhof Frederiek-Maarten , Bijnens Luc , Thas Olivier
Published: September 2018

Explorative visualization techniques provide a first summary of microbiome read count datasets through dimension reduction. A plethora of dimension reduction methods exists, but many of them focus primarily on sample ordination, failing to elucidate the role of the bacterial species. Moreover, implicit but often unrealistic assumptions underlying these methods fail to account for overdispersion and differences in sequencing depth, which are two typical characteristics of sequencing data. We combine log-linear models with a dispersion estimation algorithm and flexible response function modelling into a framework for unconstrained and constrained ordination. The method allows easy filtering of technical confounders. As opposed to most existing ordination methods, the assumptions underlying the method are stated explicitly and can be verified using simple diagnostics. The combination of unconstrained and constrained ordination in the same framework is unique in the field and greatly facilitates microbiome data exploration. We illustrate the advantages of our method on simulated and real datasets, while pointing out flaws in existing methods. The algorithms for fitting and plotting are available in the R-packageRCM.
Natural enemies of armored scales (Hemiptera: Diaspididae) and soft scales (Hemiptera: Coccoidae) in Chile: molecular and morphological identification
Authors: Amouroux P. , Crochard D. , Correa M.C.G. , Groussier G. , Kreiter P. , Roman C. , Guerrieri E. , Garonna A.P. , Malausa T. , Zaviezo T.
Published: September 2018

Scale insects (Hemiptera: Coccoidea) are key pests of agricultural crops and ornamental plants worldwide. Their populations are difficult to control, even with insecticides, due to their cryptic habits. Moreover, there is growing concern over the use of synthetic pesticides for their control, due to deleterious environmental effects and the emergence of resistant populations of target pests. In this context, biological control may be an effective and sustainable approach. Hymenoptera Chalcidoidea includes natural enemies of scale insects that have been successfully used in many biological control programs. However, the correct identification of pest scale species and their natural enemies is particularly challenging because these insects are very small and highly specialized. Integrative taxonomy, coupling DNA barcoding and morphological analysis, has been successfully used to characterize pests and natural enemy species. In this study, we performed a survey of parasitoids and predators of armored and soft scales in Chile, based on 28S and COI barcodes. Fifty-three populations of Diaspididae and 79 populations of Coccidae were sampled over the entire length of the country, from Arica (18°S) to Frutillar (41°S), between January 2015 and February 2016. The phylogenetic relationships obtained by Bayesian inference from multilocus haplotypes revealed 40 putative species of Chalcidoidea, five Coccinellidae and three Neuroptera. In Chalcidoidea, 22 species were identified morphologically, resulting in new COI barcodes for 12 species and new 28S barcodes for 14 species. Two predator species (Rhyzobius lophantae and Coccidophilus transandinus) were identified morphologically, and two parasitoid species, Chartocerus niger and Signiphora bifasciata, were recorded for the first time in Chile.