bluuebunny/crossref_metadata_2025 huggingface dataset:
Intraoperative Strain Elastosonography in Brain Tumor Surgery
Authors: Prada Francesco , Del Bene Massimiliano , Rampini Angela , Mattei Luca , Casali Cecilia , Vetrano Ignazio Gaspare , Gennari Antonio Giulio , Sdao Silvana , Saini Marco , Sconfienza Luca Maria , DiMeco Francesco
Published: November 2018

BACKGROUND

Sonoelastography is an ultrasound imaging technique able to assess mechanical properties of tissues. Strain elastography (SE) is a qualitative sonoelastographic modality with a wide range of clinical applications, but its use in brain tumor surgery has been so far very limited.

OBJECTIVE

To describe the first large-scale implementation of SE in oncological neurosurgery for lesions discrimination and characterization.

METHODS

We analyzed retrospective data from 64 patients aiming at (i) evaluating the stiffness of the lesion and of the surrounding brain, (ii) assessing the correspondence between B-mode and SE, and (iii) performing subgroup analysis for gliomas characterization

RESULTS

(i) In all cases, we visualized the lesion and the surrounding brain with SE, permitting a qualitative stiffness assessment. (ii) In 90% of cases, lesion representations in B-mode and SE were superimposable with identical morphology and margins. In 64% of cases, lesion margins were sharper in SE than in B-mode. (iii) In 76% of cases, glioma margins were sharper in SE than in B-mode. Lesions morphology/dimensions in SE and in B-mode were superimposable in 89%. Low-grade (LGG) and high-grade (HGG) gliomas were significantly different in terms of stiffness and stiffness contrast between tumors and brain, LGG appearing stiffer while HGG softer than brain (all P < ·001). A threshold of 2.5 SE score had 85.7% sensitivity and 94.7% specificity in differentiating LGG from HGG.

CONCLUSION

SE allows to understand mechanical properties of the brain and lesions in examination and permits a better discrimination between different tissues compared to B-mode. Additionally, SE can differentiate between LGG and HGG.
A Direct Aspiration First Pass Technique in Japanese Real-World Clinical Setting
Authors: Uno Junji , Kameda Katsuharu , Otsuji Ryosuke , Ren Nice , Nagaoka Shintaro , Maeda Kazushi , Ikai Yoshiaki , Gi Hidefuku
Published: November 2018

BACKGROUND

It is debatable whether mechanical thrombectomy has benefits in a real-world setting outside the more rigid and selective clinical trial environment.

OBJECTIVE

To evaluate clinical outcomes, efficacy, and safety of mechanical thrombectomy in single-center retrospective cohort case series.

METHODS

We reviewed prospectively collected data from our large-vessel occlusion stroke database to identify patients undergoing mechanical thrombectomy using Penumbra catheters (Penumbra, Almeida, California) as first-line devices. The primary outcomes were the modified Rankin Scale score at 90 d and recanalization rate. The secondary outcomes included the rates of hemorrhagic complications and mortality.

RESULTS

The entire study population included 298 patients. Thrombolysis in Cerebral Infarction Scale ≥2b was achieved in 86.6% of patients. Fifty-five patients (18.5%) were outside the 6 hr time window and 82 patients (27.5%) were over 80-yr old. The posterior circulation thrombectomy rate was 12.4%. At 90 d from onset, 49.3% of patients had favorable outcomes. The parenchymal hemorrhage type 2 (PH2) and subarachnoid hemorrhage rates were 2.3% and 11.7%, respectively. In multivariate analyses, cerebral blood flow/cerebral blood volume mismatch (odds ratio [OR] = 9.418; 95% confidence interval [CI], 3.680-27.726; P < .0001), onset to recanalization time (OR = 0.995; 95% CI, 0.991-0.998; P = .0003), and hemorrhagic complications including PH2 and subarachnoid hemorrhage (OR = 0.186; 95% CI, 0.070-0.455; P = .0002) were associated with favorable outcomes.

CONCLUSION

A direct aspiration first pass technique with an adjunctive device demonstrated high recanalization rates in old Japanese patients. Our patient cohort may reflect the application of endovascular techniques in acute ischemic stroke treatment in a real-world setting.
Transradial Approach for Complex Anterior and Posterior Circulation Interventions: Technical Nuances and Feasibility of Using Current Devices
Authors: Snelling Brian M , Sur Samir , Shah Sumedh S , Caplan Justin , Khandelwal Priyank , Yavagal Dileep R , Starke Robert M , Peterson Eric C
Published: November 2018

BACKGROUND

Despite several studies analyzing the safety of transradial access (TRA) for neurointervention compared to transfemoral approach (TFA), neurointerventionalists are apprehensive about implementing TRA. From our positive institutional experience, we now utilize TRA first line for a majority of our cases. Here, we present our single-institution experience.

OBJECTIVE

To determine safety and feasibility of TRA for neurointervention.

METHODS

Through retrospective review of patients receiving TRA for anterior and posterior circulation cerebrovascular interventions at our institution between December 2015 and January 2018, we present our experience regarding this transition, while focusing on technique, complications, feasibility, indications, and limitations.

RESULTS

One hundred five procedures were performed on 92 patients (anterior circulation: 77%; posterior circulation: 23%). Radial artery access was achieved in all patients. Twenty-nine cases constituted mechanical thrombectomy, 33 cases represented intracranial aneurysms treatments, and 33 cases included interventions like angioplasty, balloon test occlusion, chemotherapy delivery, and thrombolysis. TRA was used as second-line access to TFA in 5 instances due to aortic arch anomalies and atherosclerotic disease. Minor access-site complications were seen in 2.85% of patients. Ten procedures (9.0%) could not be completed with TRA, with crossover to TFA occurring in 7 cases.

CONCLUSION

TRA is safe and feasible for the majority of neurointerventional procedures and provides decreased risk of major access-site complications compared to TFA. Perceived limitations of TRA can likely be eliminated via operator experience and engineering ingenuity; thus, there is a role for TRA for neurointervention, especially in patients with increased risk of access-site complications from TFA.
Flight feather moult drives minimum daily heart rate in wild geese
Authors: Portugal Steven J. , White Craig. R. , Green Jonathan A. , Butler Patrick J.
Published: November 2018

Waterfowl undergo an annual simultaneous flight-feather moult that renders them flightless for the duration of the regrowth of the flight feathers. In the wild, this period of flightlessness could restrict the capacity of moulting birds to forage and escape predation. Selection might therefore favour a short moult, but feather growth is constrained and presumably energetically demanding. We therefore tested the hypothesis that for birds that undergo a simultaneous flight-feather moult, this would be the period in the annual cycle with the highest minimum daily heart rates, reflecting these increased energetic demands. Implantable heart rate data loggers were used to record year-round heart rate in six wild barnacle geese (Branta leucopsis), a species that undergoes a simultaneous flight-feather moult. The mean minimum daily heart rate was calculated for each individual bird over an 11-month period, and the annual cycle was divided into seasons based on the life-history of the birds. Mean minimum daily heart rate varied significantly between seasons and was significantly elevated during wing moult, to 200 ± 32 beats min−1, compared to all other seasons of the annual cycle, including both the spring and autumn migrations. The increase in minimum daily heart rate during moult is likely due to feather synthesis, thermoregulation and the reallocation of minerals and protein.
A stochastic model that explains axonal organelle pileups induced by a reduction of molecular motors
Authors: Lai Xiulan , Brown Anthony , Xue Chuan
Published: November 2018

Nerve cells are critically dependent on the transport of intracellular cargoes, which are moved by motor proteins along microtubule tracks. Impairments in this movement are thought to explain the focal accumulations of axonal cargoes and axonal swellings observed in many neurodegenerative diseases. In some cases, these diseases are caused by mutations that impair motor protein function, and genetic depletion of functional molecular motors has been shown to lead to cargo accumulations in axons. The evolution of these accumulations has been compared to the formation of traffic jams on a highway, but this idea remains largely untested. In this paper, we investigated the underlying mechanism of local axonal cargo accumulation induced by a global reduction of functional molecular motors in axons. We hypothesized that (i) a reduction in motor number leads to a reduction in the number of active motors on each cargo which in turn leads to less persistent movement, more frequent stops and thus shorter runs; (ii) as cargoes stop more frequently, they impede the passage of other cargoes, leading to local ‘traffic jams’; and (iii) collisions between moving and stopping cargoes can push stopping cargoes further away from their microtubule tracks, preventing them from reattaching and leading to the evolution of local cargo accumulations. We used a lattice-based stochastic model to test whether this mechanism can lead to the cargo accumulation patterns observed in experiments. Simulation results of the model support the hypothesis and identify key questions that must be tested experimentally.
Rapid and sensitive detection of uranyl ion with citrate-stabilized silver nanoparticles by the surface-enhanced Raman scattering technique
Authors: Jiang Jiaolai , Wang Shaofei , Deng Hui , Wu Haoxi , Chen Jun , Liao Junsheng
Published: November 2018

Uranium contamination poses a huge threat to human health due to its widespread use in the nuclear industry and weapons. We proposed a simple and convenient wet-state SERS method for uranyl detection based on the citrate-stabilized silver nanoparticles. The effect of citrate on the detection performance was also discussed. By using the citrate as an internal reference to normalize the peak of uranyl, a quantitative analysis was achieved and a good linear relationship of uranyl concentration from 0.2 to 5 µM with the limit of detection of 60 nM was obtained. With its simplicity, convenience and cost-effectiveness, this method has great potential for the detection of other molecules also.
Failure modes analysis of electrofluidic display under thermal ageing
Authors: Dong Baoqin , Tang Biao , Groenewold Jan , Li Hui , Zhou Rui , Henzen Alexander Victor , Zhou Guofu
Published: November 2018

Dielectric failure as well as optical switching failure in electrofluidic display (EFD) are still a bottleneck for sufficient device lifetime. In this study, a dielectric redundancy-designed multilayer insulator of ParyleneC/AF1600X was applied in an EFD device. The reliability performance was systematically studied by tracking the applied voltage-dependent leakage current and capacitance changes (I–V and C–V curves) with thermal ageing time. The multilayer insulator shows a more stable performance in leakage current compared to a single-layer insulator. The failure modes during operation underlying the single-layer and the multilayer dielectric appear to be different as exemplified by microscopic images. The single-layer AFX shows significant detachment. In addition, by quantitatively analysing the C–V curves with ageing time, we find that for the single AFX device, the dominant failure mode is ‘no-opening’ of the pixels. For the multilayer device, the dominant failure mode is ‘no-closing’ of the pixels. This study provides tools for distinguishing the basic failure modes of an EFD device and demonstrates a quantitative method for evaluating the reliability performance of the device under thermal ageing.
A protein phosphorylation module patterns theBacillus subtilisspore outer coat
Authors: Freitas Carolina , Plannic Jerneja , Isticato Rachele , Pelosi Assunta , Zilhão Rita , Serrano Mónica , Baccigalupi Loredana , Ricca Ezio , Elsholz Alexander K.W. , Losick Richard , Henriques Adriano O.
Published: November 2018

Assembly of theBacillus subtilisspore coat involves over 80 protein components, which self-organize into a basal layer, a lamellar inner coat, a striated electrondense outer coat and a more external crust. CotB is an abundant component of the outer coat. Its C-terminal moiety contains a region, termed SKRB, formed by a series of serine-rich repeats, which we show is phosphorylated by the coat-associated Ser/Thr kinase CotH at multiple Ser residues. Another coat protein, CotG, which contains a central repeat region, SKRG, interacts with the C-terminal moiety of CotB and promotes its phosphorylation by CotHin vivoand in a heterologous system. CotG itself is phosphorylated by CotH but phosphorylation is enhanced in the absence of CotB. Spores of acotHD288Astrain, producing an inactive form of the kinase, like those formed by acotGdeletion mutant, lack the characteristic pattern of electrondense outer coat striations, while retaining the crust. Specifically, in the absence of CotG or CotH activity, most of the outer coat proteins are assembled but form a layer of amorphous material that peels-off the spore if crust formation is genetically ablated. In contrast, deletion of the SKRBregion, has no major impact on the structure of the outer coat. Thus, phosphorylation of CotG by CotH is the principal factor establishing the structural pattern of the spore outer coat. The presence of thecotB/cotH/cotGcluster in several species closely related toB. subtilisand ofcotG-like proteins in nearly all spore-formers that also code for a CotH homologue hints at the importance of this protein phosphorylation module in the morphogenesis of the spore outer layers.
A revised biosynthetic pathway for the cofactor F420in bacteria
Authors: Bashiri Ghader , Antoney James , Jirgis Ehab N. M. , Shah Mihir V. , Ney Blair , Copp Janine , Stutely Stephanie M. , Sreebhavan Sreevalsan , Palmer Brian , Middleditch Martin , Tokuriki Nobuhiko , Greening Chris , Baker Edward N. , Scott Colin , Jackson Colin J.
Published: November 2018

Cofactor F420plays critical roles in primary and secondary metabolism in a range of bacteria and archaea as a low-potential hydride transfer agent. It mediates a variety of important redox transformations involved in bacterial persistence, antibiotic biosynthesis, pro-drug activation and methanogenesis. However, the biosynthetic pathway for F420has not been fully eluci-dated: neither the enzyme that generates the putative intermediate 2-phospho-L-lactate, nor the function of the FMN-binding C-terminal domain of the γ-glutamyl ligase (FbiB) in bacteria are known. Here we show that the guanylyltransferases FbiD and CofC accept phosphoenolpyruvate, rather than 2-phospho-L-lactate, as their substrate, leading to the formation of the previously uncharacterized intermediate, dehydro-F420-0. The C-terminal domain of FbiB then utilizes FMNH2 to reduce dehydro-F420-0, which produces mature F420species when combined with the γ-glutamyl ligase activity of the N-terminal domain. This new insight has allowed the heterologous expression F420from a recombinant F420biosynthetic pathway inEscherichia coli.
Dissecting the heterogeneous cortical anatomy of autism spectrum disorder using normative models
Authors: Zabihi Mariam , Oldehinkel Marianne , Wolfers Thomas , Frouin Vincent , Goyard David , Loth Eva , Charman Tony , Tillmann Julian , Banaschewski Tobias , Dumas Guillaume , Holt Rosemary , Baron-Cohen Simon , Durston Sarah , Bölte Sven , Murphy Declan , Ecker Christine , Buitelaar Jan K. , Beckmann Christian F. , Marquand Andre F.
Published: November 2018

Background

The neuroanatomical basis of autism spectrum disorder (ASD) has remained elusive, mostly due to high biological and clinical heterogeneity among diagnosed individuals. Despite considerable effort towards understanding ASD using neuroimaging biomarkers, heterogeneity remains a barrier, partly because studies mostly employ case-control approaches, which assume that the clinical group is homogeneous.

Methods

Here, we used an innovative normative modelling approach to parse biological heterogeneity in ASD. We aimed to dissect the neuroanatomy of ASD by mapping the deviations from a typical pattern of neuroanatomical development at the level of the individual and to show the necessity to look beyond the case-control paradigm to understand the neurobiology of ASD. We first estimated a vertex-wise normative model of cortical thickness development using Gaussian process regression, then mapped the deviation of each participant from the typical pattern. For this we employed a heterogeneous cross-sectional sample of 206 typically developing (TD) individuals (127 male), and 321 individuals (232 male) with ASD (aged 6-31).

Results

We found few case-control differences but the ASD cohort showed highly individualized patterns of deviations in cortical thickness that were widespread across the brain. These deviations correlated with severity of repetitive behaviors and social communicative symptoms, although only repetitive behaviors survived corrections for multiple testing.

Conclusions

Our results: (i) reinforce the notion that individuals with ASD show distinct, highly individualized trajectories of brain development and (ii) show that by focusing on common effects (i.e. the ‘average ASD participant’), the case-control approach disguises considerable inter-individual variation crucial for precision medicine.
Genomic variation in educational attainment modifies Alzheimer’s disease risk
Authors: Raghavan Neha S. , Vardarajan Badri , Mayeux Richard
Published: November 2018

Objective

To determine the putative protective relationship of educational attainment on Alzheimer’s disease (AD) risk using Mendelian randomization, and to test the hypothesis that by using genetic regions surrounding individually associated SNPs as the instrumental variable we can identify genes that contribute to the relationship.

Methods

We performed Mendelian randomization using genome-wide association study summary statistics from studies of educational attainment and AD in two stages. Our instrumental variable comprised of i) 1,271 SNPs significantly associated with educational attainment and ii) individual 2Mb regions surrounding the genome-wide significant SNPs.

Results

A causal inverse relationship between educational attainment and AD was identified by the 1,271 SNPs (odds ratio = 0.63; 95% CI, 0.54-0.74; p =4.08×10−8). Analysis of individual loci identified six regions that significantly replicated the causal relationship. Genes within these regions included LRRC2, SSBP2, and NEGR1; the latter a regulator of neuronal growth.

Conclusions

Educational attainment is an important protective factor for AD. Genomic regions that significantly paralleled the overall causal relationship contain genes expressed in neurons or involved in the regulation of neuronal development.
Apical progenitors remain multipotent throughout cortical neurogenesis
Authors: Oberst Polina , Fièvre Sabine , Baumann Natalia , Concetti Cristina , Jabaudon Denis
Published: November 2018

The diverse subtypes of excitatory neurons that populate the neocortex are born from progenitors located in the ventricular zone (apical progenitors, APs). During corticogenesis, APs progress through successive temporal states to sequentially generate deep- followed by superficial-layer neurons directly orviathe generation of intermediate progenitors (IPs). Yet little is known about the plasticity of AP temporal identity and whether individual progenitor subtypes remain multipotent throughout corticogenesis. To address this question, we used FlashTag (FT), a method to pulse-label and isolate APs in the mouse neocortex with high temporal resolution to fate-map neuronal progeny following heterochronic transplantation of APs into younger embryos. We find that unlike daughter IPs, which lose the ability to generate deep layer neurons when transplanted into a younger host, APs are temporally uncommitted and become molecularly respecified to generate normally earlier-born neuron types. These results indicate that APs are multipotent cells that are able to revert their temporal identity and re-enter past molecular and neurogenic states. AP fate progression thus occurs without detectable fate restriction during the neurogenic period of corticogenesis. These findings identify unforeseen cell-type specific differences in cortical progenitor fate plasticity, which could be exploited for neuroregenerative purposes.
Adaptive radiation of barbs of the genusLabeobarbus(Cyprinidae) in the East African river
Authors: Levin B.A. , Casal-López M. , Simonov E. , Dgebuadze Yu.Yu. , Mugue N.S. , Tiunov A.V. , Doadrio I. , Golubtsov A.S.
Published: November 2018

Large African barbs of the genusLabeobarbusare widely distributed in African freshwaters, and exhibit profound phenotypic plasticity that could be a prerequisite for adaptive radiation. Using morphological, molecular, and stable isotope analyses, we investigated whether an adaptive radiation has occurred in a riverine assemblage of theL. gananensiscomplex. This complex is composed of six phenotypically distinct sympatric forms inhabiting the Genale River (Ethiopian highlands, East Africa). Of the six forms, five were divergent in their mouth morphology, corresponding to ‘generalized’, ‘lipped’, ‘scraping’ (two forms) and ‘large-mouthed’ phenotypes. Stable isotope analysis revealed differences in 15N and 13C among these forms, representing different foraging strategies (omnivorous, scraping and piscivorous). Phylogenetic analysis of two mtDNA markers confirmed the monophyly ofL. gananensis, suggesting an intra-riverine radiation. However, the Genale assemblage appears to have originated through a combination of allopatric and sympatric events. Some of the specialized forms within this drainage originated independently from the local generalized forms in three different river regions within local ‘mini-flocks’ composed of two to three sympatric forms. Our study shows that adaptive radiation in rivers can be enhanced by a combination of sympatric speciation and temporal geographic isolation, leading to local sympatric speciation followed by migration.
Capturing sleep-wake cycles by using day-to-day smartphone touchscreen interactions
Authors: Borger Jay N. , Huber Reto , Ghosh Arko
Published: November 2018

Body movements drop with sleep and this behavioural signature is widely exploited to infer sleep duration. However, a reduction in body movements may also occur in periods of intense cognitive activity and the ubiquitous use of smartphones may capture these wakeful periods otherwise hidden in the standard measures of sleep. Here we continuously captured the gross body movements using standard wrist-worn accelerometers to quantify sleep (actigraphy) and logged the timing of the day-to-day touchscreen events (‘tappigraphy’). Using these measures, we addressed how the gross body movements overlap with the cognitively engaging digital behaviour (from n = 84 individuals, accumulating 1384 nights). We find that smartphone use was distributed across a broad spectrum of physical activity levels but consistently peaked at rest. We estimated the putative sleep onset and wake-up times from the actigraphy data to find that these times were well correlated to the estimates from tappigraphy (R2= 0.9 for sleep onset and wake-up time). However, actigraphy overestimated sleep as virtually all of the users used their phones during the putative sleep period. Interestingly, the probability of touches remained greater than zero for ~ 2 h after the putative sleep onset and ~ 2 h before the putative wake-up time. Our findings suggest that touchscreen interactions are widely integrated into modern sleeping habits – surrounding both sleep onset and waking-up periods – yielding a new approach to measuring sleep. Smartphone taps can be leveraged to update the behavioural signatures of sleep with these peculiarities of modern digital behaviour.
Towards the new normal: Transcriptomic and genomic changes in the two subgenomes of a 100,000 years old allopolyploid,Capsella bursa-pastoris
Authors: Kryvokhyzha Dmytro , Milesi Pascal , Duan Tianlin , Orsucci Marion , Wright Stephen I. , Glémin Sylvain , Lascoux Martin
Published: November 2018

Allopolyploidy has played a major role in plant evolution but its impact on genome diversity and expression patterns remains to be understood. Some studies found important genomic and transcriptomic changes in allopolyploids, whereas others detected a strong parental legacy and more subtle changes. The allotetraploidC. bursa-pastorisoriginated around 100,000 years ago and one could expect the genetic polymorphism of the two subgenomes to become more similar and their transcriptomes to start functioning together. To test this hypothesis, we sequenced the genomes and the transcriptomes (three tissues) of allote-traploidC. bursa-pastorisand its parental species, the outcrossingC. grandifloraand the self-fertilizingC. orientalis. Comparison of the divergence in expression between subgenomes, on the one hand, and divergence in expression between the parental species, on the other hand, indicated a strong parental legacy with a majority of genes exhibiting a conserved pattern andcis-regulation. However, a large proportion of the genes that were differentially expressed between the two subgenomes, were also undertrans-regulation reflecting the establishment of a new regulatory pattern. Parental dominance varied among tissues: expression in flowers was closer to that ofC. orientalisand expression in root and leaf to that ofC. grandiflora. Since deleterious mutations accumulated preferentially on theC. orientalissubgenome, the bias in expression towardsC. orientalisobserved in flowers suggests that expression changes could be adaptive and related to the selfing syndrome, while biases in the roots and leaves towards theC. grandiflorasubgenome may be reflective of the differential genetic load.
OPTIMIR, a novel algorithm for integrating available genome-wide genotype data into miRNA sequence alignment analysis
Authors: Thibord Florian , Perret Claire , Roux Maguelonne , Suchon Pierre , Germain Marine , Deleuze Jean-François , Morange Pierre-Emmanuel , Trégouët David-Alexandre ,   on behalf of the GENMED Consortium
Published: November 2018

Next-generation sequencing is an increasingly popular and efficient approach to characterize the full set of microRNAs (miRNAs) present in human biosamples. MiRNAs’ detection and quantification still remain a challenge as they can undergo different post transcriptional modifications and might harbor genetic variations (polymiRs) that may impact on the alignment step. We present a novel algorithm, OPTIMIR, that incorporates biological knowledge on miRNA editing and genome-wide genotype data available in the processed samples to improve alignment accuracy.

OPTIMIR was applied to 391 human plasma samples that had been typed with genome-wide genotyping arrays. OPTIMIR was able to detect genotyping errors, suggested the existence of novel miRNAs and highlighted the allelic imbalance expression of polymiRs in heterozygous carriers.

OPTIMIR is written in python, and freely available on the GENMED website (http://www.genmed.fr/index.php/fr/) and on Github (github.com/FlorianThibord/OptimiR).
Decision confidence: EEG correlates of confidence in different phases of a decision task
Authors: Krumpe Tanja , Gerjets Peter , Rosenstiel Wolfgang , Spüler Martin
Published: November 2018

Decision making is an essential part of daily life, in which balancing reasons and calculating risks to reach a certain confidence are important to make reasonable choices. To investigate the EEG correlates of confidence during decision making a study involving a forced choice recognition memory task was implemented. Subjects were asked to distinguish old from new pictures and rate their decision with either high or low confidence. Event-related potential (ERP) analysis was performed in four different phases covering all stages of decision making, including the information encoding, retrieval, decision formation, and feedback processing during the recognition task. Additionally, a single trial support-vector machine (SVM) classification was performed on the ERPs of each phase to get a measure of differentiability of the two levels of confidence on a single subject level. It could be shown that the level of decision confidence is significantly reflected in all stages of decision making but most prominently during feedback presentation. The main differences between high and low confidence can be found in the ERPs during feedback presentation after a correct answer, whereas almost no differences can be found in ERPs from feedback to wrong answers. In the feedback phase the two levels of confidence can be separated with a classification accuracy of up to 70 % on average over all subjects, therefore showing potential as a control state in a brain-computer Interface (BCI) application.
Swift Large-scale Examination of Directed Genome Editing (SLEDGE Hammer)
Authors: Hammouda Omar T. , Thumberger Thomas , Wittbrodt Joachim
Published: November 2018

In the era of CRISPR gene editing and genetic screening, there is an increasing demand for quick and reliable nucleic acid extraction pipelines for rapid genotyping of large and diverse sample sets. Despite continuous improvements of current workflows, the handling-time and material costs per sample remain the major limiting factors. Here we present a robust method for low-cost DIY-pipet tips addressing these needs; i.e. using a cellulose filter disc inserted into a regular pipet tip. These filter-in-tips allow for a rapid, stand-alone three-step genotyping workflow by simply binding the DNA contained in the primary lysate to the cellulose filter, washing it in water and eluting it directly into the buffer for the downstream application (e.g. PCR). This drastically cuts down processing time to maximum 30 seconds per sample, with the potential for parallelizing and automation. We show the ease and sensitivity of our procedure by genotyping genetically modified medaka and zebrafish embryos (targeted CRISPR/Cas9 knock-out and knock-in) in a 96-well plate format. The robust isolation and detection of multiple alleles of various abundancies in a mosaic genetic background allows phenotype-genotype correlation already in the injected generation, demonstrating the reliability and sensitivity of the filter-in-tips. Furthermore, our method is applicable across kingdoms with samples ranging from cells to tissues (e.g. plant seedlings, adult flies, mouse cell culture and tissue as well as adult fish fin-clips).
Two Nimrod receptors, NimC1 and Eater, synergistically contribute to bacterial phagocytosis inDrosophila melanogaster
Authors: Melcarne Claudia , Ramond Elodie , Dudzic Jan , Bretscher Andrew J , Kurucz Éva , Andó István , Lemaitre Bruno
Published: November 2018

Eater and NimC1 are transmembrane receptors of theDrosophilaNimrod family, specifically expressed in hemocytes, the insect blood cells. Previousex vivoandin vivoRNAi studies have pointed to their role in the phagocytosis of bacteria. Here, we have created a novel null mutant in NimC1 to re-evaluate the role of NimC1, alone or in combination with Eater, in the cellular immune response. We show that NimC1 functions as an adhesion moleculeex vivo, but in contrast to Eater is not required for hemocyte sessilityin vivo.Ex vivophagocytosis assays and electron microscopy experiments confirmed that Eater is the main phagocytic receptor for Gram-positive, but not Gram-negative bacteria, and contributes to microbe tethering to hemocytes. Surprisingly, theNimC1deletion did not impair phagocytosis of bacteria, nor their adhesion to the hemocytes. However, phagocytosis of both types of bacteria was almost abolished inNimC11;eater1hemocytes. This indicates that both receptors contribute synergistically to the phagocytosis of bacteria, but that Eater can bypass the requirement for NimC1. Finally, we uncovered that NimC1, but not Eater, is essential for uptake of latex beads and zymosan particles. We conclude that Eater and NimC1 are the two main receptors for phagocytosis of bacteria inDrosophila,and that each receptor likely plays distinct roles in microbial uptake.
Genome-wide by environment interaction studies (GWEIS) of depressive symptoms and psychosocial stress in UK Biobank and Generation Scotland
Authors: Arnau-Soler Aleix , Macdonald-Dunlop Erin , Adams Mark J. , Clarke Toni-Kim , MacIntyre Donald J. , Milburn Keith , Navrady Lauren , Scotland Generation ,   Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium, Hayward Caroline , McIntosh Andrew M. , Thomson Pippa A.
Published: November 2018

Stress is associated with poorer physical and mental health. To improve our understanding of this link, we performed genome-wide association studies (GWAS) of depressive symptoms and genome-wide by environment interaction studies (GWEIS) of depressive symptoms and stressful life events (SLE) in two UK population cohorts (Generation Scotland and UK Biobank). No SNP was individually significant in either GWAS, but gene-based tests identified six genes associated with depressive symptoms in UK Biobank (DCC, ACSS3, DRD2, STAG1, FOXP2 and KYNU; p < 2.77×10-6). Two SNPs with genome-wide significant GxE effects were identified by GWEIS in Generation Scotland: rs12789145 (53kb downstream PIWIL4; p = 4.95×10-9; total SLE) and rs17070072 (intronic to ZCCHC2; p = 1.46×10-8; dependent SLE). A third locus upstream CYLC2 (rs12000047 and rs12005200, p < 2.00×10-8; dependent SLE) when the joint effect of the SNP main and GxE effects was considered. GWEIS gene-based tests identified: MTNR1B with GxE effect with dependent SLE in Generation Scotland; and PHF2 with the joint effect in UK Biobank (p < 2.77×10-6). Polygenic risk scores (PRS) analyses incorporating GxE effects improved the prediction of depressive symptom scores, when using weights derived from either the UK Biobank GWAS of depressive symptoms (p = 0.01) or the PGC GWAS of major depressive disorder (p = 5.91×10-3). Using an independent sample, PRS derived using GWEIS GxE effects provided evidence of shared aetiologies between depressive symptoms and schizotypal personality, heart disease and COPD. Further such studies are required and may result in improved treatments for depression and other stress-related conditions.
The Participation and Motivations of Grant Peer Reviewers: A Comprehensive Survey
Authors: Gallo Stephen A , Thompson Lisa A , Schmaling Karen B , Glisson Scott R
Published: November 2018

Scientific peer reviewers play an integral role in the grant selection process, yet very little has been reported on the levels of participation or the motivations of scientists to take part in peer review. AIBS developed a comprehensive peer review survey that examined the motivations and levels of participation of grant reviewers. The survey was disseminated to 13,091 scientists in AIBS’s proprietary database. Of the 874 respondents, 76% indicated they had reviewed grant applications in the last 3 years; however, the number of reviews was unevenly distributed across this sample. Higher review loads were associated with respondents who had submitted more grant proposals over this time period, some of whom were likely to be study section members for large funding agencies. The most prevalent reason to participate in a review was to give back to the scientific community (especially among frequent grant submitters) and the most common reason to decline an invitation to review was lack of time. Interestingly, few suggested that expectation from the funding agency was a motivation to review. Most felt that review participation positively influenced their careers through improving grantsmanship and exposure to new scientific ideas. Of those who reviewed, respondents reported dedicating 2-5% of their total annual work time to grant review and, based on their self-reported maximum review loads, it is estimated they are participating at 56%-89% of their capacity, which may have important implications regarding the sustainability of the system. Overall, it is clear that participation in peer review is uneven and in some cases near capacity, and more needs to be done to create new motivations and incentives to increase the future pool of reviewers.
Nucleoid size scaling and intracellular organization of translation across bacteria
Authors: Gray William T. , Govers Sander K. , Xiang Yingjie , Parry Bradley R. , Campos Manuel , Kim Sangjin , Jacobs-Wagner Christine
Published: November 2018

The scaling of organelles with cell size is thought to be exclusive to eukaryotes. Here, we demonstrate that similar scaling relationships hold for the nucleoid in bacteria. Despite the absence of a nuclear membrane, nucleoid size strongly correlates with cell size, independent of changes in DNA amount and across various nutrient conditions. This correlation is observed in diverse bacteria, revealing a near-constant ratio between nucleoid and cell size for a given species. As in eukaryotes, the nucleocytoplasmic ratio in bacteria varies greatly among species. This spectrum of nucleocytoplasmic ratios is independent of genome size, and instead appears linked to the average cell size of the population. Bacteria with different nucleocytoplasmic ratios have different biophysical properties of the cytoplasm, impacting the mobility and localization of ribosomes. Together, our findings identify new organizational principles and biophysical features of bacterial cells, implicating the nucleocytoplasmic ratio and cell size as determinants of the intracellular organization of translation.
Limits to a classic paradigm: Most transcription factors regulate genes in multiple biological processes
Authors: Ledezma-Tejeida Daniela , Altamirano-Pacheco Luis , Fajardo Vicente , Collado-Vides Julio
Published: November 2018

Transcription factors (TFs) are important drivers of cellular decision-making. When bacteria encounter a change in the environment, transcription factors alter the expression of a defined set of genes in order to adequately respond. It is commonly assumed that genes regulated by the same TF should be involved in the same biological process. Examples of this are methods that rely on coregulation to infer function of not yet annotated genes. We have previously shown that only 21% of TFs regulate functionally homogeneous genes based on the proximity of their catalyzed reactions in the metabolic network. Here, we provide more evidence to support the claim that a one TF/one process relationship is not a general property. We show that the observed functional heterogeneity of regulons is not a result of the quality of the annotation of regulatory interactions, or the absence of protein-metabolite interactions, and is also present when function is defined by Gene Ontology terms. Furthermore, the observed functional heterogeneity is different from the one expected by chance, supporting the notion that it is a biological property. To further explore the relationship between transcriptional regulation and metabolism, we analyze 5 other types of regulatory groups and identify complex regulons (i.e. genes regulated by the same combination of TFs) as the most functionally homogeneous, which is supported by coexpression data. Whether higher levels of related functions exist beyond metabolism and current functional annotations, remains an open question.
Isolation and Identification of Enterovirus D111 in a Child with Acute Flaccid Paralysis in Nigeria
Authors: Faleye T.O.C. , Adewumi M.O. , Olayinka O.T. , Adeniji J.A
Published: November 2018

The WHO recommended cell-culture-based algorithm requires enterovirus (EV) isolates to produce reproducible cytopathic effect (R-CPE) in RD and/or L20b cell lines. Samples with non-reproducible CPE (NR-CPE) are considered negative for EVs. We investigated whether there could be EVs lurking in samples with NR-CPE.

Fifty-nine (59) cell culture supernatants (CCS) (collected between 2016 and 2017) recovered from RD and L20b cell culture tubes with NR-CPE, were analyzed in this study. The tubes had been previously inoculated with stool suspension from children (<15 years) in Nigeria with acute flaccid paralysis (AFP). All CCS were screened for Enteric Adenoviruses and group A Rotavirus using a rapid immunochromatographic test kit. Subsequently, they were passaged in HEp-2 cell line. All isolates were subjected to RNA extraction, cDNA synthesis, three (5l-UTR, VP1 and EV Species C [EV-C]) different PCR assays and sequencing of amplicons. EVs were further subjected to Illumina sequencing.

All CCS were negative for Adenoviruses and group A Rotaviruses. Four CCS produced R-CPE in HEp-2 cell line, three of which were positive for the 5l-UTR assay. Of the 3 isolates two and none were positive for the VP1 and EV-C assays, respectively. One of the two VP1 amplicons was successfully sequenced and identified as Echovirus 1(E1). Illumina sequencing of the three 5l- UTR positive isolates confirmed the E1 isolate and typed the remaining two as EV-Ds (94 and 111).

We describe the first EV-D94 and 111 isolates of Nigerian origin. We also show that NR-CPE could sometimes be caused by EVs that do not produce R-CPE in RD and L20b cell lines but do so in other cell lines like HEp-2.
Modelling conduction delays in the corpus callosum using MRI-measured g-ratio
Authors: Berman S. , Filo S. , Mezer A. A.
Published: November 2018

Conduction of action potentials along myelinated axons is affected by their structural features, such as the axonal g-ratio, the ratio between the inner and outer diameters of the myelin sheath surrounding the axon. The effect of g-ratio variance on conduction properties has been quantitatively evaluated using single-axon models. It has recently become possible to estimate a g-ratio weighted measurementin vivousing quantitative MRI. Nevertheless, it is still unclear whether the variance in the g-ratio in the healthy human brain leads to significant differences in conduction velocity. In this work we tested whether the g-ratio MRI measurement can be used to predict conduction delays in the corpus callosum.

We present a novel framework in which the structural properties of fibers (i.e. length and g-ratio, measured using MRI), are incorporated in a biophysical model of axon conduction, to predict conduction delays of long-range white matter fibers. We applied this framework to the corpus callosum, and found conduction delay estimates that are compatible with previously estimated values of conduction delays. We account for the variance in the velocity given the axon diameter distribution in the splenium, mid-body and genu, to further compare the fibers within the corpus callosum.

Conduction delays have been suggested to increase with age. Therefore, we investigated whether there are differences in the g-ratio and the fiber length between young and old adults, and whether this leads to a difference in conduction speed and delays. We found small but significant differences between the predicted delays of the two groups in the motor fibers of the corpus callosum. We also found that the motor fibers of the corpus callosum have the fastest conduction estimates. Using the axon diameter distributions, we found that the occipital fibers have the slowest estimations, while the frontal and motor fiber tracts have similar estimates.

Our study provides a framework for predicting conduction latenciesin vivo. The framework could have major implications for future studies of white matter diseases and large range network computations. Our results highlight the need for improving additionalin vivomeasurements of white matter microstructure.
DYT1 dystonia patient-derived fibroblasts have increased deformability and susceptibility to damage by mechanical forces
Authors: Gill Navjot Kaur , Ly Chau , Kim Paul H. , Saunders Cosmo A. , Fong Loren G. , Young Stephen G. , Luxton G.W. Gant , Rowat Amy C.
Published: November 2018

DYT1 dystonia is a neurological movement disorder that is caused by a loss-of-function mutation in the DYT1/TOR1A gene, which encodes torsinA, the luminal ATPase-associated (AAA+) protein. TorsinA is required for the assembly of functional linker of nucleoskeleton and cytoskeleton (LINC) complexes, and consequently the mechanical integration of the nucleus and the cytoskeleton. Despite the potential implications of altered mechanobiology in dystonia pathogenesis, the role of torsinA in regulating cellular mechanical phenotype, or mechanotype, in DYT1 dystonia remains unknown. Here, we define the mechanotype of mouse fibroblasts lacking functional torsinA as well as human fibroblasts isolated from DYT1 dystonia patients. We find that the deletion of torsinA or the expression of torsinA containing the DYT1 dystonia-causing ΔE302/303 (ΔE) mutation results in a more deformable cellular mechanotype. We observe a similar increased deformability of mouse fibroblasts that lack lamina-associated polypeptide 1 (LAP1), which interacts with and stimulates the ATPase activity of torsinA in vitro; as well as with depletion of the LINC complex proteins, Sad1/UNC-84 (SUN)1 and SUN2, lamin A/C, or lamin B1. Moreover, we report that DYT1 dystonia patient-derived fibroblasts are more compliant than fibroblasts isolated from unafflicted individuals. DYT1 fibroblasts also exhibit increased nuclear strain and decreased viability following mechanical stretch. Taken together, our results support a model where the physical connectivity between the cytoskeleton and nucleus contributes to cellular mechanotype. These findings establish the foundation for future mechanistic studies to understand how altered cellular mechanotype may contribute to DYT1 dystonia pathogenesis; this may be particularly relevant in the context of how neurons sense and respond to mechanical forces during traumatic brain injury, which is known to be a major cause of acquired dystonia.