bluuebunny/crossref_metadata_2025_split huggingface dataset:
Longitudinal alterations in fronto-striatal glutamate are associated with functioning during inhibitory control in autism spectrum disorder and obsessive compulsive disorder
Authors: Hollestein Viola , Buitelaar Jan K. , Brandeis Daniel , Banaschewski Tobias , Kaiser Anna , Hohmann Sarah , Oranje Bob , Gooskens Bram , Durston Sarah , Lythgoe David J. , Naaijen Jilly 
Published: April 2020

AbstractBackgroundAutism spectrum disorder (ASD) and obsessive compulsive disorder (OCD) are neurodevelopmental disorders with overlapping symptomatology. Both show deficits in inhibitory control, which are associated with altered functioning and glutamate concentrations in the fronto-striatal circuitry. These parameters have never been examined together. Here we, for the first time, used a multi-center, longitudinal approach to investigate fronto-striatal functioning during an inhibitory control task and its association with fronto-striatal glutamate concentrations across these two disorders.Methods74 adolescents with ASD (24) or OCD (15) and controls (35) aged 8-17 were recruited across three sites of the European TACTICS consortium. They underwent two magnetic resonance imaging (MRI) sessions with a one-year interval. This included proton magnetic resonance spectroscopy (1H-MRS; n=74) and functional MRI during an inhibitory control task (n=57). We used linear mixed effects models to investigate, over time, the relationship between fronto-striatal functioning and glutamate concentrations across these groups and continuous measures of overlapping compulsivity symptoms.ResultsDuring failed inhibitory control, in OCD increased striatal glutamate was associated with increased neural activation of ACC, an effect that decreased over time. During successful inhibitory control, higher ACC glutamate was positively associated with striatal activation in OCD and compulsivity across time. ACC glutamate levels decreased over time in the ASD group compared to controls, while striatal glutamate decreased over time, independent of diagnosis.ConclusionsSignificant differences in fronto-striatal glutamate were observed in ASD and OCD, affecting functional activity during failed- and successful inhibitory control differently, especially in OCD, with effects changing over time.
Visual attention modulates the integration of goal-relevant evidence and not value
Authors: Sepulveda Pradyumna , Usher Marius , Davies Ned , Benson Amy , Ortoleva Pietro , De Martino Benedetto 
Published: April 2020

AbstractWhen choosing between options, such as food items presented in plain view, people tend to choose the option they spend longer looking at. The prevailing interpretation is that visual attention increases value. However, in previous studies, ‘value’ was coupled to a behavioural goal, since subjects had to choose the item they preferred. This makes it impossible to discern if visual attention has an effect on value, or, instead, if attention modulates the information most relevant for the goal of the decision-maker. Here we present the results of two independent studies—a perceptual and a value-based task—that allow us to decouple value from goal-relevant information using specific task-framing. Combining psychophysics with computational modelling, we show that, contrary to the current interpretation, attention doesnotboost value, but instead it modulates goal-relevant information. This work provides a novel and more general mechanism by which attention interacts with choice.
Inhibition of Wnt signalling by Notch via two distinct mechanisms
Authors: Acar Ahmet , Hidalgo-Sastre Ana , Leverentz Michael K. , Mills Christopher G. , Woodcock Simon , Baron Martin , Collu Giovanna M. , Brennan Keith 
Published: April 2020

SummaryNotch and Wnt are two essential signalling pathways that help to shape animals during development and to sustain adult tissue homeostasis. Although, they are often active at the same time within a tissue, they typically have opposing effects on cell fate decisions. In fact, crosstalk between the two pathways is important in generating the great diversity of cell types that we find in metazoans. However, several different mechanisms have been proposed that allow Notch to limit Wnt signalling, driving a Notch-ON/Wnt-OFF state. Here we explore these different mechanisms in vertebrate cells and demonstrate two distinct mechanisms by which Notch itself, can limit the transcriptional activity of β-catenin. At the membrane, independently of DSL ligands, Notch1 can antagonise β-catenin activity through an endocytosis mediated mechanism that is dependent upon its interaction with Deltex and sequesters β-catenin into the membrane fraction. Within the nucleus, the intracellular domain of Notch1 can also limit β-catenin induced transcription through the formation of a complex that requires its interaction with RBPjκ. We believe these mechanisms contribute to the robustness of cell-fate decisions by sharpening the distinction between opposing Notch/Wnt responses.
A modular microscale granuloma model for immune-microenvironment signaling studiesin vitro
Authors: Berry Samuel B. , Gower Maia S. , Su Xiaojing , Seshadri Chetan , Theberge Ashleigh B. 
Published: April 2020

AbstractTuberculosis (TB) is one of the most potent infectious diseases in the world, causing more deaths than any other single infectious agent. TB infection is caused by inhalation ofMycobacterium tuberculosis(Mtb) and subsequent phagocytosis and migration into the lung tissue by innate immune cells (e.g., alveolar macrophages, neutrophils, dendritic cells), resulting in the formation of a fused mass of immune cells known as the granuloma. Considered the pathological hallmark of TB, the granuloma is a complex microenvironment that is crucial for pathogen containment as well as pathogen survival. Disruption of the delicate granuloma microenvironmentvianumerous stimuli, such as variations in cytokine secretions, nutrient availability, and the makeup of immune cell population, can lead to an active infection. Herein, we present a novelin vitromodel to examine the soluble factor signaling between a mycobacterial infection and its surrounding environment. Adapting a newly developed suspended microfluidic platform, known as Stacks, we established a modular microscale infection model containing human immune cells and a model mycobacterial strain that can easily integrate with different microenvironmental cues through simple spatial and temporal “stacking” of each module of the platform. We validate the establishment of suspended microscale (4 μL) infection cultures that secrete increased levels of proinflammatory factors IL-6, VEGF, and TNFα upon infection and form 3D aggregates (granuloma model) encapsulating the mycobacteria. As a proof of concept to demonstrate the capability of our platform to examine soluble factor signaling, we cocultured anin vitroangiogenesis model with the granuloma model and quantified morphology changes in endothelial structures as a result of culture conditions (P < 0.05 when comparing infected vs. uninfected coculture systems). We envision our modularin vitrogranuloma model can be further expanded and adapted for studies focusing on the complex interplay between granulomatous structures and their surrounding microenvironment, as well as a complementary tool to augmentin vivosignaling and mechanistic studies.
Polyphosphate FunctionsIn Vivoas Iron Chelator and Fenton Inhibitor
Authors: Beaufay Francois , Quarles Ellen , Franz Allison , Katamanin Olivia , Wholey Wei-Yun , Jakob Ursula 
Published: April 2020

AbstractMaintaining cellular iron homeostasis is critical for organismal survival. Whereas iron depletion negatively affects the many metabolic pathways that depend on the activity of iron-containing enzymes, any excess of iron can cause the rapid formation of highly toxic reactive oxygen species (ROS) through Fenton chemistry. Although several cellular iron chelators have been identified, little is known about if and how organisms can prevent the Fenton reaction. By studying the effects of cisplatin, a commonly used anticancer drug and effective antimicrobial, we discovered that cisplatin elicits severe iron stress and oxidative DNA damage in bacteria. We found that both of these effects are successfully prevented by polyphosphate (polyP), an abundant polymer consisting solely of covalently linked inorganic phosphates. Subsequentin vitroandin vivostudies revealed that polyP provides a crucial iron reservoir under non-stress conditions, and effectively complexes free iron and blocks ROS formation during iron stress. These results demonstrate that polyP, a universally conserved biomolecule, plays a hitherto unrecognized role as an iron chelator and an inhibitor of the Fenton reaction.
Screening for inborn errors of metabolism using untargeted metabolomics and out-of-batch controls
Authors: Bongaerts Michiel , Bonte Ramon , Demirdas Serwet , Jacobs Ed H. , Oussoren E. , van der Ploeg Ans T. , Wagenmakers Margreet A.E.M. , Hofstra Robert M.W. , Blom Henk J. , Reinders Marcel J.T. , Ruijter George J. G. 
Published: April 2020

MotivationUntargeted metabolomics is an emerging technology in the laboratory diagnosis of inborn errors of metabolism (IEM). In order to judge if metabolite levels are abnormal, analysis of a large number of reference samples is crucial to correct for variations in metabolite concentrations resulting from factors such as diet, age and gender. However, a large number of controls requires the use of out-of-batch controls, which is hampered by the semi-quantitative nature of untargeted metabolomics data, i.e. technical variations between batches. Methods to merge and accurately normalize data from multiple batches are urgently needed.Methods & resultsBased on six metrics, we compared existing normalization methods on their ability to reduce batch effects from eight independently processed batches. Many of those showed marginal performances, which motivated us to developMetchalizer, a normalization method which uses 17 stable isotope-labeled internal standards and a mixed effect model. In addition, we propose a regression model with age- and sex as covariates fitted on control samples obtained from all eight batches.Metchalizerapplied on log-transformed data showed the most promising performance on batch effect removal as well as in the detection of 178 known biomarkers across 45 IEM patient samples and performed at least similar to an approach using 15 within-batch controls. Furthermore, our regression model indicates that 10-24% of the considered features showed significant age-dependent variations.ConclusionsOur comprehensive comparison of normalization methods showed that ourLog-Metchalizerapproach enables the use out-of-batch controls to establish clinically-relevant reference values for metabolite concentrations. These findings opens possibilities to use large scale out-of-batch control samples in a clinical setting, increasing throughput and detection accuracy.AvailabilityMetchalizeris available athttps://github.com/mbongaerts/Metchalizer/
Double-targeted knockdown of miR-21 and CXCR4 inhibits malignant glioma progression by suppression of the PI3K/AKT and Raf/MEK/ERK pathways
Authors: Liu Feijiao , Yang Bo 
Published: April 2020

AbstractBackgroundCurrently, miR-21 and CXCR4 are being extensively investigated as two unrelated key regulators in glioma malignancy. In this study, we investigated the combined effect of these two factors on glioma progression.MethodsWe confirmed the expression of miR-21 and CXCR4 in malignant glioma tissue and glioma cells with qRT-PCR and western blotting. Single-targeted knockdown of miR-21 and CXCR4, as well as double-targeted knockdown of miR-21 and CXCR4 lentiviral vectors were constructed and they were transfected to U87 and U251 cells. Cell proliferation, apoptosis, invasion, and migration from different treatment groups were assessed by MTT assay, Flow Cytometry analysis, Transwell analysis, and Scratch assay, respectively. U87 xenograft mice were constructed to detect roles and potential mechanisms of miR-21 and CXCR4 in malignant glioma tumor growth.ResultsThe expression of miR-21 and CXCR4 was increased in tumor tissues and cell lines. Inhibition of miR-21, CXCR4, and miR-21 and CXCR4 together all reduced the migration, invasiveness, proliferation and enhanced apoptosis in glioma cells, as well as reduced tumor volume and mass in xenograft model. The inhibition effect was strongest in double-targeted knockdown of miR-21 and CXCR4 group, whose downstream pathways involved in AKT axis and ERK axis activation.ConclusionsOur findings reported that double-targeted knockdown of miR-21 and CXCR4 could more effectively inhibit the proliferation, migration, invasion and growth of transplanted tumor and promote cell apoptosis, which were involved in the PI3K/AKT and Raf/MEK/ERK signaling pathways.
A pan-cancer landscape of somatic substitutions in non-unique regions of the human genome
Authors: Tarabichi Maxime , Demeulemeester Jonas , Verfaillie Annelien , Flanagan Adrienne M. , Loo Peter Van , Konopka Tomasz 
Published: April 2020

AbstractAround 13% of the human genome displays high sequence similarity with at least one other chromosomal position and thereby poses challenges for computational analyses such as detection of somatic events in cancer. We here extract features of sequencing data from across non-unique regions and employ a machine learning pipeline to describe a landscape of somatic substitutions in 2,658 cancers from the PCAWG cohort. We show mutations in non-unique regions are consistent with mutations in unique regions in terms of mutation load and substitution profiles, and can be validated with linked-read sequencing. This uncovers hidden mutations in ~1,700 coding sequences and thousands of regulatory elements, including known cancer genes, immunoglobulins, and highly mutated gene families.
In vivoidentification of apoptotic and extracellular vesicle-bound live cells using image-based deep learning
Authors: Kranich Jan , Chlis Nikolaos-Kosmas , Rausch Lisa , Latha Ashretha , Schifferer Martina , Kurz Tilman , Kia Agnieszka Foltyn-Arfa , Simons Mikael , Theis Fabian J. , Brocker Thomas 
Published: April 2020

SUMMARYThein vivodetection of dead cells remains a major challenge due to technical hurdles. Here we present a novel method, where injection of fluorescent Milk fat globule-EGF factor 8 protein (MFG-E8)in vivocombined with imaging flow cytometry and deep learning allows the identification of dead cells based on their surface exposure of phosphatidylserine (PS) and other image parameters. A convolutional autoencoder (CAE) was trained on defined pictures and successfully used to identify apoptotic cellsin vivo. However, unexpectedly, these analyses also revealed that the great majority of PS+cells were not apoptotic, but rather live cells associated with PS+extracellular vesicles (EVs). During acute viral infection apoptotic cells increased slightly, while up to 30% of lymphocytes were decorated with PS+EVs of Dendritic cell exosomal origin. The combination of recombinant fluorescent MFG-E8 and the CAE-method will greatly facilitate analyses of cell death and EVsin vivo.
A widely distributed hydrogenase oxidises atmospheric H2during bacterial growth
Authors: Islam Zahra F. , Welsh Caitlin , Bayly Katherine , Grinter Rhys , Southam Gordon , Gagen Emma J. , Greening Chris 
Published: April 2020

AbstractDiverse aerobic bacteria persist by consuming atmospheric hydrogen (H2) using group 1h [NiFe]-hydrogenases. However, other hydrogenase classes are also distributed in aerobes, including the group 2a [NiFe]-hydrogenase. Based on studies focused on Cyanobacteria, the reported physiological role of the group 2a [NiFe]-hydrogenase is to recycle H2produced by nitrogenase. However, given this hydrogenase is also present in various heterotrophs and lithoautotrophs lacking nitrogenases, it may play a wider role in bacterial metabolism. Here we investigated the role of this enzyme in three species from different phylogenetic lineages and ecological niches:Acidithiobacillus ferrooxidans(phylum Proteobacteria),Chloroflexus aggregans(phylum Chloroflexota), andGemmatimonas aurantiaca(phylum Gemmatimonadota). qRT-PCR analysis revealed that the group 2a [NiFe]-hydrogenase of all three species is significantly upregulated during exponential growth compared to stationary phase, in contrast to the profile of the persistence-linked group 1h [NiFe]-hydrogenase. Whole-cell biochemical assays confirmed that all three strains aerobically respire H2to sub-atmospheric levels, and oxidation rates were much higher during growth. Moreover, the oxidation of H2supported mixotrophic growth of the carbon-fixing strainsC. aggregansandA. ferrooxidans.Finally, we used phylogenomic analyses to show that this hydrogenase is widely distributed and is encoded by 13 bacterial phyla. These findings challenge the current persistence-centric model of the physiological role of atmospheric H2oxidation and extends this process to two more phyla, Proteobacteria and Gemmatimonadota. In turn, these findings have broader relevance for understanding how bacteria conserve energy in different environments and control the biogeochemical cycling of atmospheric trace gases.
Optimization of cryopreservation andin vitrofertilization techniques for the African turquoise killifishNothobranchius furzeri
Authors: Dolfi Luca , Suen Tsz Kin , Ripa Roberto , Antebi Adam 
Published: April 2020

AbstractOver the last decade, the African turquoise killifish,Nothobranchius furzeri, has emerged as an important model system for the study of vertebrate biology and ageing. However, rearing this fish in captivity can pose challenges, due to the short window of fertility, inbreeding problems, and the continuous maintenance of different strains and transgenic lines. To date, the main means of long term strain maintenance is to arrest embryos in diapause, a poorly understood and unreliable method. To solve these problems, we developed a robust protocol to cryopreserve sperm and to revive them forin vitrofertilization (IVF), as a better option for long term storage ofN. furzerilines. We tested a variety of extender and activator buffers for spermin vitrofertilization, as well as cryoprotectants to achieve maximal long term storage and fertilization conditions tailored to this species. Our optimized protocol was able to preserve sperm in a cryogenic condition for months and to revive an average of 40% upon thawing. Thawed sperm were able to fertilize nearly the same number of eggs as natural fertilization, with an average of ~25% and peaks of ~55% fertilization. This technical advance will greatly facilitate the use ofN. furzerias a model organism.
Simulating flow induced migration in vascular remodelling
Authors: Tabibian Ashkan , Ghaffari Siavash , Vargas Diego A. , Van Oosterwyck Hans , Jones Elizabeth A.V. 
Published: April 2020

AbstractShear stress induces directed endothelial cell (EC) migration in blood vessels leading to vessel diameter increase and induction of vascular maturation. Other factors, such as EC elongation and interaction between ECs and non-vascular areas are also important. Computational models have previously been used to study collective cell migration. These models can be used to predict EC migration and its effect on vascular remodelling during embryogenesis. We combined live time-lapse imaging of the remodelling vasculature of the quail embryo yolk sac with flow quantification using a combination of micro-Particle Image Velocimetry and computational fluid dynamics. We then used the flow and remodelling data to inform a model of EC migration during remodelling. To obtain the relation between shear stress and velocityin vitrofor EC cells, we developed a flow chamber to assess how confluent sheets of ECs migrate in response to shear stress. Using these data as an input, we developed a multiphase, self-propelled particles (SPP) model where individual agents are driven to migrate based on the level of shear stress while maintaining appropriate spatial relationship to nearby agents. These agents elongate, interact with each other, and with avascular agents at each time-step of the model. We compared predicted vascular shape to real vascular shape after 4 hours from our time-lapse movies and performed sensitivity analysis on the various model parameters. Our model shows that shear stress has the largest effect on the remodelling process. Importantly, however, elongation played an especially important part in remodelling. This model provides a powerful tool to study the input of different biological processes on remodelling.Author summaryShear stress is known to play a leading role in endothelial cell (EC) migration and hence, vascular remodelling. Vascular remodelling is, however, more complicated than only EC migration. To achieve a better understanding of this process, we developed a computational model in which, shear stress mediated EC migration has the leading role and other factors, such as avascular regions and EC elongation, are also accounted for. We have tested this model for different vessel shapes during remodelling and could study the role that each of these factors play in remodelling. This model gives us the possibility of addition of other factors such as biochemical signals and angiogenesis which will help us in the study of vascular remodelling in both development and disease.
Does the Antisecretory Peptide AF-16 modulate fluid balance and inflammation in experimental peritonitis induced sepsis?
Authors: Barrueta Tenhunen Annelie , van der Heijden Jaap , Blokhin Ivan , Massaro Fabrizia , Arne Hansson Hans , Feinstein Ricardo , Larsson Anders , Tenhunen Jyrki 
Published: April 2020

AbstractSepsis is a life-threatening condition due to a dysregulated immunological response to infection. Apart from source control and broad-spectrum antibiotics, management is based on fluid resuscitation and vasoactive drugs. Fluid resuscitation implicates the risk of volume overload, which in turn is associated with longer stay in intensive care, prolonged use of mechanical ventilation and increased mortality.Antisecretory factor (AF), an endogenous protein, is detectable in most tissues and in plasma. The biologically active site of the protein is located in an 8-peptide sequence, contained in a synthetic 16-peptide fragment, named AF-16. The protein as well as the peptide AF-16 has multiple modulatory effects on abnormal fluid transport and edema formation/resolution as well as in a variety of inflammatory conditions. Apart from its’ anti-secretory and anti-inflammatory characteristics, AF is an inhibitor of capillary leakage in intestine. It is not known whether the protein AF or the peptide AF-16 can ameliorate symptoms in sepsis. We hypothesized that AF-16 decreases the degree of hemodynamic instability, the need of fluid resuscitation, vasopressor dose and tissue edema in fecal peritonitis.To test the hypothesis, we induced peritonitis and sepsis by injecting autologous fecal solution into abdominal cavity of anesthetized pigs, and randomized (in a blind manner) the animals to intervention (AF-16, n=8) or control (saline, n=8) group. After onset of hemodynamic instability (defined as mean arterial pressure < 60 mmHg maintained for > 5 minutes), resuscitation was initiated by an infusion of AF-16 or saline. We recorded respiratory and hemodynamic parameters hourly for twenty hours and collected post mortem tissue samples at the end of the experiment.No differences between the groups were observed regarding hemodynamics, fluid balance, lung mechanics, gas exchange or histology. This experimental study suggests that AF-16 does not modulate sepsis symptoms in peritonitis induced sepsis.