bluuebunny/crossref_metadata_2025_split huggingface dataset:
A β-catenin-driven switch in TCF/LEF transcription factor binding to DNA target sites promotes commitment of mammalian nephron progenitor cells
Authors: Guo Qiuyu , Kim Albert , Li Bin , Ransick Andrew , Bugacov Helena , Chen Xi , Lindstrom Nils , Brown Aaron , Oxburgh Leif , Ren Bing , McMahon Andrew P. 
Published: October 2020

AbstractThe canonical Wnt pathway transcriptional co-activator β-catenin regulates self-renewal and differentiation of mammalian nephron progenitor cells (NPCs). We modulated β-catenin levels in NPC cultures using the GSK3 inhibitor CHIR9902 (CHIR) to examine opposing developmental actions of β-catenin. Low CHIR-mediated maintenance and expansion of NPCs is independent of direct engagement of TCF/LEF/ β-catenin transcriptional complexes at low-CHIR dependent cell-cycle targets. In contrast, in high CHIR, TCF7/LEF1/β-catenin complexes replaced TCF7L1/TCF7L2 binding on enhancers of differentiation-promoting target genes. Chromosome confirmation studies showed pre-established promoter-enhancer connections to these target genes in NPCs. High CHIR-associatedde novolooping was observed in positive transcriptional feedback regulation to the canonical Wnt pathway. Thus, β-catenin’s direct transcriptional role is restricted to the induction of NPCs where rising β-catenin levels switch inhibitory TCF7L1/TCF7L2 complexes to activating LEF1/TCF7 complexes at primed gene targets poised for rapid initiation of a nephrogenic program.
Specificities of exosome versus small ectosome secretion revealed by live intracellular tracking and synchronized extracellular vesicle release of CD9 and CD63
Authors: Mathieu Mathilde , Névo Nathalie , Jouve Mabel , Valenzuela José Ignacio , Maurin Mathieu , Verweij Frederik , Palmulli Roberta , Lankar Danielle , Dingli Florent , Loew Damarys , Rubinstein Eric , Boncompain Gaёlle , Perez Franck , Théry Clotilde 
Published: October 2020

ABSTRACTDespite their important and multiple roles in intercellular communications, the different populations of extracellular vesicles (EVs) and their secretion mechanisms are not fully characterized yet. In particular, how and to what extent EVs form either as intraluminal vesicles of endocytic compartments (exosomes), or at the plasma membrane (ectosomes) remains unclear. We followed in HeLa cells the intracellular trafficking of the EV markers CD9 and CD63 from the endoplasmic reticulum to their residency compartment and identified transient co-localization both at the plasma membrane (PM) and in endosomes, before they finally segregate. CD9 was more abundantly released in EVs than CD63. However, when forcing expression of CD63 at the PM, by mutating its lysosome-addressing motive, its secretion in EVs was increased. Thus, in HeLa cells, small ectosomes are more prominently released than exosomes. By comparative proteomic analysis, we identified a few surface proteins likely specific of either exosomes (e.g. LAMP1) or ectosomes (e.g. BSG, SLC3A2), based on their known intracellular location in lysosomes or the PM, and on the different effects on their release of Bafilomycin A1, a drug that neutralizes endosomal pH. Our work sets the path for molecular and functional discrimination of exosomes and small ectosomes in any cell type.
Deep ultraviolet light based wide-field fluorescence microscope for brain imaging
Authors: Kasaragod Deepa , Zhu Meina , Terai Haruhi , Kawakami Koichi , Aizawa Hidenori 
Published: October 2020

ABSTRACTThree-dimensional (3D) cellular scale imaging techniques that improve our understanding of the brain architecture is crucial for structural and functional integration and analysis of normal and pathological conditions in the brain. We have developed a wide-field fluorescent microscope using deep ultra violet (DUV) light emitting diode as the illumination source. This microscope employs oblique illumination of deep UV light and the optical sectioning is obtained on the tissue surface over a few micron thickness; largely attributed to the large absorption and hence low tissue penetration of the DUV light. Fluorescence emissions in the visible range that are spectrally separates allows for multiple channel of fluorophore detection using single or a combination of dyes. The fluorescence signal is captured using water immersion objectives and a color camera. Arduino Mega 2560 controlled 3-axis motorised microscope stage is developed for obtaining the wide-field imaging. To enable 3D imaging, the microscope setup is integrated with vibrating microtome that can slice thin sections for serial block-face imaging. In this paper, we show the versatility of the DUV microscope as a microscopy tool for use in neuroscience labs for a range of 2D brain imaging applications. We also present its applicability for 3D imaging of rodent brain in combination with whole brain staining protocol.
A curated dataset of modern and ancient high-coverage shotgun human genomes
Authors: Delser Pierpaolo Maisano , Jones Eppie R. , Hovhannisyan Anahit , Cassidy Lara , Pinhasi Ron , Manica Andrea 
Published: October 2020

AbstractOver the last few years, genome-wide data for a large number of ancient human samples have been collected. Whilst datasets of capture SNPs have been collated, high coverage shotgun genomes (which are relatively few but allow certain type of analyses not possible with ascertained captured SNPs) have to be reprocessed by individual groups from raw reads. This task is computationally intensive. Here, we release a dataset including 34 whole-genome sequenced samples, previously published and distributed worldwide, together with the genetic pipeline used to process them. The dataset contains 73,435,604 sites called across 18 ancient and 16 modern individuals and includes sequence data from four previously published ancient samples which we sequenced to higher coverage (10-18x). Such a resource will allow researchers to analyse their new samples with the same genetic pipeline and directly compare them to the reference dataset without re-processing published samples. Moreover, this dataset can be easily expanded to increase the sample distribution both across time and space.
Deep-learning based denoising and reconstruction of super-resolution structured illumination microscopy images
Authors: Shah Zafran Hussain , Müller Marcel , Wang Tung-Cheng , Scheidig Philip Maurice , Schneider Axel , Schüttpelz Mark , Huser Thomas , Schenck Wolfram 
Published: October 2020

AbstractSuper-resolution structured illumination microscopy (SR-SIM) provides an up to two-fold enhanced spatial resolution of fluorescently labeled samples. The reconstruction of high quality SR-SIM images critically depends on patterned illumination with high modulation contrast. Noisy raw image data, e.g. as a result of low excitation power or low exposure times, result in reconstruction artifacts. Here, we demonstrate deep-learning based SR-SIM image denoising that results in high quality reconstructed images. A residual encoding-decoding convolution neural network (RED-Net) was used to successfully denoise computationally reconstructed noisy SR-SIM images. We also demonstrate the entirely deep-learning based denoising and reconstruction of raw SIM images into high-resolution SR-SIM images. Both image reconstruction methods prove to be very robust against image reconstruction artifacts and generalize very well over various noise levels. The combination of computational reconstruction and subsequent denoising via RED-Net shows very robust performance during inference after training even if the microscope settings change.
Refining physico-chemical rules for herbicides using an antimalarial library
Authors: Sukhoverkov Kirill V. , Corral Maxime G. , Leroux Julie , Haywood Joel , Johnen Philipp , Newton Trevor , Stubbs Keith A. , Mylne Joshua S. 
Published: October 2020

ABSTRACTSuccessful herbicides, like drugs, have physico-chemical properties that usually fall within certain limits. A recent analysis of 334 herbicides showed similar properties to the ‘rule of five’ for human orally-delivered drugs, but herbicides diverged from this for proton donors, partition coefficients and molecular weight. To refine rules for herbicides, we exploited the close evolutionary relationship betweenP. falciparumand plants by screening the Malaria Box, a 400-compound library composed of novel chemical scaffolds with activity against blood stage malaria parasitePlasmodium falciparum. A high proportion (52 of 400) were herbicidal toArabidopsis thalianaon agar plates. Thirty-nine of these 52 herbicidal compounds were tested on soil and 16 compounds were herbicidal. These data were used to predict whether a herbicidal hit found on agar will work on soil-grown plants. The physico-chemical parameters were weighted to logP and formal charge and used to generate weighted scores to a large chemical library of liver-stage effective antimalarial leads. Of the six top-scoring compounds, one had a potency comparable to commercial herbicides. This novel compound MMV1206386 had no close structural matches among commercial herbicides. Physiological profiling suggested that MMV1206386 has a new mode of action and overall demonstrates how weighted rules can help during herbicide discovery programs.
A new twist of rubredoxin function inM. tuberculosis
Authors: Sushko Tatsiana , Kavaleuski Anton , Grabovec Irina , Kavaleuskaya Anna , Vakhrameev Daniil , Bukhdruker Sergei , Marin Egor , Kuzikov Alexey , Masamrekh Rami , Sigolaeva Larisa V. , Shumyantseva Victoria , Tsumoto Kouhei , Borshchevskiy Valentin , Gilep Andrei , Strushkevich Natallia 
Published: October 2020

AbstractElectron transfer mediated by metalloproteins drives many biological processes. Rubredoxins are ubiquitous iron-containing electron carriers that play important roles in bacterial adaptation to changing environmental conditions. InMycobacterium tuberculosis, oxidative and acidic stresses as well as iron starvation induce rubredoxin expression. However, their functions duringM. tuberculosisinfection is unknown. In the present work, we show that rubredoxin B (RubB) supports catalytic activity of mycobacterial cytochrome P450s, CYP124, CYP125, and CYP142, which are important for bacterial viability and pathogenicity. We solved the crystal structure of RubB and characterized the interaction between RubB and CYPs using site-directed mutagenesis. Mutations that neutralized single charge on the surface of RubB did not dramatically decrease activity of studied CYPs, and isothermal calorimetry (ITC) experiments indicated that interactions are transient and not highly specific. Our findings suggest that a switch from ferredoxins to rubredoxins support CYP activity inM. tuberculosis-infected macrophages. Our electrochemical experiments suggest potential applications of RubB in biotechnology.
A skyline birth-death process for inferring the population size from a reconstructed tree with occurrences
Authors: Andréoletti Jérémy , Zwaans Antoine , Warnock Rachel C. M. , Aguirre-Fernández Gabriel , Barido-Sottani Joëlle , Gupta Ankit , Stadler Tanja , Manceau Marc 
Published: October 2020

AbstractPhylodynamic models generally aim at jointly inferring phylogenetic relationships, model parameters, and more recently, population size through time for clades of interest, based on molecular sequence data. In the fields of epidemiology and macroevolution these models can be used to estimate, respectively, the past number of infected individuals (prevalence) or the past number of species (paleodiversity) through time. Recent years have seen the development of “total-evidence” analyses, which combine molecular and morphological data from extant and past sampled individuals in a unified Bayesian inference framework. Even sampled individuals characterized only by their sampling time, i.e. lacking morphological and molecular data, which we calloccurrences, provide invaluable information to reconstruct past population sizes.Here, we present new methodological developments around the Fossilized Birth-Death Process enabling us to (i) efficiently incorporate occurrence data while remaining computationally tractable and scalable; (ii) consider piecewise-constant birth, death and sampling rates; and (iii) reconstruct past population sizes, with or without knowledge of the underlying tree. We implement our method in the RevBayes software environment, enabling its use along with a large set of models of molecular and morphological evolution, and validate the inference workflow using simulations under a wide range of conditions.We finally illustrate our new implementation using two empirical datasets stemming from the fields of epidemiology and macroevolution. In epidemiology, we apply our model to the Covid-19 outbreak on the Diamond Princess ship. We infer the total prevalence throughout the outbreak, by taking into account jointly the case count record (occurrences) along with viral sequences for a fraction of infected individuals. In macroevolution, we present an empirical case study of cetaceans. We infer the diversity trajectory using molecular and morphological data from extant taxa, morphological data from fossils, as well as numerous fossil occurrences. Our case studies highlight that the advances we present allow us to further bridge the gap between between epidemiology and pathogen genomics, as well as paleontology and molecular phylogenetics.
RL-118 and 11β-HSD1 target engagement through TAPS assay: behaviour and molecular analysis
Authors: Puigoriol-Illamola D. , Companys-Alemany J. , Homer N. , Leiva R. , Vázquez S. , Mole D. , Griñán-Ferré C. , Pallàs M. 
Published: October 2020

1.AbstractTaking into consideration the convergence of ageing, stress and neurodegenerative diseases, such as AD, there is impaired GC signalling. Therefore, the study of GC-mediated stress response to chronic moderate stressful situations, as account in daily life, becomes of huge interest to design pharmacological strategies to prevent neurodegeneration.To address this issue, SAMP8 were exposed for 4 weeks to the CMS paradigm and treated with RL-118, an 11β-HSD1 inhibitor. In fact, several pieces of evidence link the inhibition of this enzyme with reduction of GC levels and cognitive improvement, while CMS exposure has been associated with reduced cognitive performance. The aim of this project was to assess whether RL-118 treatment could restore the deleterious effects of CMS on cognition and behavioural abilities, but also on molecular mechanisms that compromise healthy ageing in SAMP8 mice.On the one hand, we determined the target engagement between RL-118 and 11β-HSD1. Therefore all the beneficial effects previously described in SAMP8 treated with the drug can undoubtedly be attributed to the inhibition of this enzyme. Besides, herein we observed decreased DNA methylation, hydroxymethylation and histone phosphorylation induced by CMS but, on the contrary, increased after RL-118 treatment. In addition, CMS exposure produced ROS damage accumulation, and increments of pro-oxidant enzymes as well as pro-inflammatory mediators through NF-κB pathway and astrogliosis markers, likeGfap. Ofnote, those modifications were recovered by 11β-HSD1 inhibition. Remarkably, although CMS altered mTORC1 signalling, autophagy was increased in SAMP8 treated with RL-118 mice. Also, we found amyloidogenic APP processing pathway favoured and decreased synaptic plasticity and neuronal remodelling markers in mice under CMS, but changed after RL-118 treatment. In consequence, detrimental effects on behaviour and cognitive performance were detected in CMS exposed mice, but restored after concomitant 11β-HSD1 inhibition by RL-118.Overall, CMS is a feasible intervention to understand the influence of stress on epigenetic mechanisms underlying cognition and accelerating senescence. However and most important, 11β-HSD1 inhibition through RL-118 turned up to restore the majority of these detrimental effects caused by CMS, indicating that GC excess attenuation may become a potential therapeutic strategy for age-related cognitive decline and AD.
Blood gene expression-based prediction of lethality after respiratory infection by influenza A virus in mice
Authors: Milanez-Almeida Pedro , Martins Andrew J. , Torabi-Parizi Parizad , Franco Luis M. , Tsang John S. , Germain Ronald N. 
Published: October 2020

AbstractLethality after respiratory infection with influenza A virus (IAV) is associated with potent immune activation and lung tissue damage. In a well-controlled animal model of infection, we sought to determine if one could predict lethality using transcriptional information obtained from whole blood early after influenza virus exposure. We started with publicly available transcriptomic data from the lung, which is the primary site of the infection and pathology, to derive a multigene transcriptional signature of death reflective of innate inflammation associated with tissue damage. We refined this affected tissue signature with data from infected mouse and human blood to develop and validate a machine learning model that can robustly predict survival in mice after IAV challenge using data obtained from as little as 10 μl of blood from early time points post infection. Furthermore, in genetically identical, cohoused mice infected with the same viral bolus, the same model can predict the lethality of individual animals but, intriguingly, only within a specific time window that overlapped with the early effector phase of adaptive immunity. These findings raise the possibility of predicting disease outcome in respiratory virus infections with blood transcriptional data and pave the way for translating such approaches to humans.
The labor-managed firm, Jaroslav Vanek and me
Authors: Dow Gregory K. 
Published: October 2020

PurposeThe purpose of this article is to summarize the relationship between the research of Jaroslav Vanek on labor-managed firms (LMFs) and the research of Gregory K. Dow on the same topic.Design/methodology/approachThe article reviews the research of Jaroslav Vanek in the 1970s and explains how this influenced the publications of Gregory K. Dow extending from the 1980s to the present. A particular focus involves Dow's book “The Labor-Managed Firm: Theoretical Foundations” published by Cambridge University Press in 2018. The methodology is to present an intellectual history in narrative form. The scope of the paper is the economic theory of the LMF.FindingsThe article finds that Dow's interest in LMFs was stimulated by Vanek's publications from the early 1970s. However, Dow's publications in the 1980s were motivated to a large degree by efforts to overcome the limitations of Vanek's theory of the LMF, a goal that shaped much of Dow's later research in the field.Originality/valueThe paper illuminates the strong intellectual influence Jaroslav Vanek exerted on the economic theory of the LMF. Readers who want information about the influences on Dow's work may also find it useful.
Buckling behavior of laminated composite cylinders under external hydrostatic pressure
Authors: Li Zhun , Pan Guang , Shen KeChun 
Published: October 2020

PurposeThe objective of this paper is to investigate numerically the buckling behavior of submersible composite cylinders.Design/methodology/approachBy means of FEM and golden section method, the search of hoop winding layers, longitudinal winding layers and helical winding layers are studied to optimize the buckling pressure. Considering the mid-strengthening cylinder, the size and distribution of stiffeners are studied systematically.FindingsThe results show that laying the hoop winding layers in the two outer sidewalls and the longitudinal winding layers in the middle of the shell is helpful to increase the buckling pressure, and the optimal helical winding angle changes with slenderness ratio.Originality/valueFor mid-strengthening cylinder, the effect of helical winding angle of stiffener on buckling pressure becomes weak gradually with the increase of stiffener thickness. With the increasing of the spacing between stiffeners, the buckling pressure increases first and decreases later. What is more, the mid-strengthening cylinder is less sensitive to the initial geometric imperfections than unstiffened shells.
Awake Prone Positioning in COVID‐19 Hypoxemic Respiratory Failure: Exploratory Findings in a Single‐center Retrospective Cohort Study
Authors: Padrão Eduardo M. H. , Valente Fernando S. , Besen Bruno A. M. P. , Rahhal Hassan , Mesquita Paula S. , de Alencar Julio C. G. , da Costa Millena G. P. , Wanderley Annelise P. B. , Emerenciano Debora L. , Bortoleto Felipe M. , Fortes Julio C. L. , Marques Bruno , de Souza Stefany F. B. , Marchini Júlio F. M. , Neto Rodrigo A. B. , de Souza Heraldo P. ,   for the COVIDTEAM
Published: October 2020

AbstractBackgroundAwake prone positioning has been widely used in patients with COVID‐19 respiratory failure to avoid intubation despite limited evidence. Our objective was to evaluate if prone positioning is associated with a reduced intubation rate when compared to usual care.MethodsThis was a retrospective cohort study in the emergency department of a large quaternary hospital in Sao Paulo. We retrieved data from all admitted patients in need of oxygen supplementation (>3 L/min) and tachypnea (>24 ipm) from March 1 to April 30, 2020, excluding those who had any contraindication to the prone position or who had an immediate need for intubation. The primary endpoint was endotracheal intubation up to 15 days. Secondary outcomes included a 6‐point clinical outcome ordinal scale, mechanical ventilation–free days, admission to the intensive care unit, and need of hemodialysis and of vasoactive drugs, all assessed at or up to 15 days. We analyzed unadjusted and adjusted effect estimates with Cox proportional hazards models, logistic regression, quantile regression, and sensitivity analyses using propensity score models.ResultsOf 925 suspected COVID‐19 patients admitted off mechanical ventilation, 166 patients fulfilled inclusion and exclusion criteria: 57 were exposed to prone positioning and 109 to usual care. In the intervention group, 33 (58%) were intubated versus 53 (49%) in the control group. We observed no difference in intubation rates in the univariate analysis (hazard ratio = 1.21, 95% confidence interval [CI] = 0.78 to 1.88, p = 0.39) nor in the adjusted analysis (hazard ratio = 0.90, 95% CI = 0.55 to 1.49, p = 0.69). Results were robust to the sensitivity analyses. Secondary outcomes did not differ between groups.ConclusionsAwake prone positioning was not associated with lower intubation rates. Caution is necessary before widespread adoption of this technique, pending results of clinical trials.
Caring for “Hassle‐Free Highs” in Amsterdam
Authors: Hardon Anita , Hymans Takeo David , van Schipstal Inge , Mishra Swasti , Berning Moritz , Murray Hayley , Kamps Daan , Mandler Tait 
Published: October 2020

SummaryIn this article we present some of our ethnographic findings from the city of Amsterdam, where health authorities and practitioners have implemented harm reduction strategies that build on and reinforce young drug users’ practices of self‐regulation and care. Amsterdam’s harm reduction policies build on the premises that harm is not a direct, always present consequence of recreational drug use and that harm reduction strategies will be more effective when they engage with the collective, material, and affective practices constantly evolving within drug‐using communities. This approach to caring for drug‐using youth is “unsettled” in two ways. In light of both, the city carefully tailors drug information campaigns to speak to the lived experiences of drug users. First, it concerns finding the right balance between warning drug users about negative effects and acknowledging that they are seeking and experiencing positive effects. Second, it concerns the ever‐changing market for recreational drugs. Ethnographic fieldwork in the ChemicalYouth project sought to better understand the lived experiences of young drug users and what they do to minimize risks. We identified five distinct and interlocking self‐regulation techniques that youth themselves employ and share with their peers in their quest for “hassle‐free highs.”