bluuebunny/crossref_metadata_2025_split huggingface dataset:
An image based approach for predicting the effects of endocrine disrupting chemicals on human health using deep learning
Authors: Karatzas Pantelis , Kiouvrekis Yiannis , Stefaneas Petros , Sarimveis Haralambos 
Published: August 2020

AbstractIn recent years, deep neural networks, especially those exhibiting synergistic properties, have been at the cutting edge of image processing, producing very good results. So far, they have been able to successfully address issues of classification and recognition of objects depicted on images. In this paper, a novel idea is presented, where images of chemical structures are used as input information in deep learning neural network architectures aiming at the generation of Quantitative Structure Activity Relationship (QSAR) models, i.e. models that predict properties, activities or adverse effects of chemicals. The proposed method was applied to a case study of particular interest, which is the prediction of endocrine disrupting potential of chemicals. Two different deep learning architectures were applied. The produced ImageNet model proved successful, in terms of accuracy, performance and robustness on training and validation sets. The new approach is proposed to the community as an alternative or complementary method to current practices in QSAR modelling, which can automate and improve the creation of predictive models.
Paediatric Attendances and Acuity in the Emergency Department during the COVID-19 Pandemic
Authors: Rose Katy , Van-Zyl Kerry , Cotton Rachel , Wallace Susan , Cleugh Francesca 
Published: August 2020

ABSTRACTAimTo investigate the difference in both numbers and acuity of presentations to the Paediatric Emergency Department (PED) during the peak time period of the current global SARS-CoV-2 pandemic.DesignThis single centre retrospective observational study used routinely collected electronic health data to compare patient presentation characteristics between 21st March and 26th April 2020 compared to the equivalent time period in 2019.ResultsThere was a 90% decrease in attendances to PED, with a 10.23% reduction re-attendance rate. Children presenting were younger during the pandemic, with a median age difference of 2 years. They were more likely to present in an ambulance (9.63%), be admitted to hospital (5.75%) and be assigned the highest two Manchester triage categories (6.26%). There was a non-significant trend towards longer lengths of stay. The top 10 presenting complaints remained constant (although the order changed) between time periods. There was no difference in mortality or admission to PICU.ImplicationsOur data demonstrates that there has been a significant decrease in numbers of children seeking emergency department care. It suggests that presenting patients were proportionally sicker during the pandemic; however, we would argue that this is more in keeping with appropriate acuity for PED presentations, as there were no differences in PICU admission rate or mortality. We explore some of the possible reasons behind the decrease in presentations and the implications for service planning ahead of the winter months.
Rapid systematic review of the sensitivity of SARS-CoV-2 molecular testing on saliva compared to nasopharyngeal swabs
Authors: Peeters E. , Singh S. Kaur Dhillon Ajit , Vandesompele J. , Mestdagh P. , Hutse V. , Arbyn M. 
Published: August 2020

ABSTRACTBackgroundNasopharyngeal sampling has been the standard collection method for COVID-19 testing. Due to its invasive nature and risk of contamination for health care workers who collect the sample, non-invasive and safe sampling methods like saliva, can be used alternatively.MethodsA rapid systematic search was performed in PubMed and medRxiv, with the last retrieval on June 6th, 2020. Studies were included if they compared saliva with nasopharyngeal sampling for the detection of SARS-CoV-2 RNA using the same RT-qPCR applied on both types of samples. The primary outcome of interest was the relative sensitivity of SARS-CoV-2 testing on saliva versus nasopharyngeal samples (used as the comparator test). A secondary outcome was the proportion of nasopharyngeal-positive patients that tested also positive on a saliva sample.ResultsEight studies were included comprising 1070 saliva-nasopharyngeal sample pairs allowing assessment of the first outcome. The relative sensitivity of SARS-CoV-2 testing on saliva versus nasopharyngeal samples was 0.97 (95% CI=0.92-1.02). The second outcome incorporated patient data (n=257) from four other studies (n=97 patients) pooled with four studies from the first outcome (n=160 patients). This resulted in a pooled proportion of nasopharyngeal positive cases that was also positive on saliva of 86% (95% CI=77-93%).DiscussionSaliva could potentially be considered as an alternative sampling method when compared to nasopharyngeal swabs. However, studies included in this review often were small and involved inclusion of subjects with insufficient information on clinical covariates. Most studies included patients who were symptomatic (78%, 911/1167). Therefore, additional and larger studies should be performed to verify the relative performance of saliva in the context of screening of asymptomatic populations and contact-tracing.
Features and Functions of Systemic and Mucosal Humoral Immunity Among SARS-CoV-2 Convalescent Individuals
Authors: Butler Savannah E. , Crowley Andrew R. , Natarajan Harini , Xu Shiwei , Weiner Joshua A. , Lee Jiwon , Wieland-Alter Wendy , Connor Ruth I. , Wright Peter F. , Ackerman Margaret E. 
Published: August 2020

SummaryUnderstanding humoral immune responses to SARS-CoV-2 infection will play a critical role in the development of vaccines and antibody-based interventions. We report systemic and mucosal antibody responses in convalescent individuals who experienced varying disease severity. Robust antibody responses to diverse SARS-CoV-2 antigens and evidence of elevated responses to endemic CoV were observed among convalescent donors. SARS-CoV-2-specific IgA and IgG responses were often negatively correlated, particularly in mucosal samples, suggesting subject-intrinsic biases in isotype switching. Assessment of antibody-mediated effector functions revealed an inverse correlation between systemic and mucosal neutralization activity and site-dependent differences in the isotype of neutralizing antibodies. Serum neutralization correlated with systemic anti-SARS-CoV-2 IgG and IgM response magnitude, while mucosal neutralization was associated with nasal SARS-CoV-2-specific IgA. These findings begin to map how diverse Ab characteristics relate to Ab functions and outcomes of infection, informing public health assessment strategies and vaccine development efforts.
An examination of school reopening strategies during the SARS-CoV-2 pandemic
Authors: Landeros Alfonso , Ji Xiang , Lange Kenneth , Stutz Timothy C. , Xu Jason , Sehl Mary E. , Sinsheimer Janet S. 
Published: August 2020

AbstractThe SARS-CoV-2 pandemic led to closure of nearly all K-12 schools in the United States of America in March 2020. Although reopening K-12 schools for in-person schooling is desirable for many reasons, officials understand that risk reduction strategies and detection of cases are imperative in creating a safe return to school. Furthermore, consequences of reclosing recently opened schools are substantial and impact teachers, parents, and ultimately educational experiences in children. To address competing interests in meeting educational needs with public safety, we compare the impact of physical separation through school cohorts on SARS-CoV-2 infections against policies acting at the level of individual contacts within classrooms. Using an age-stratified Susceptible-Exposed-Infected-Removed model, we explore influences of reduced class density, transmission mitigation, and viral detection on cumulative prevalence. We consider several scenarios over a 6-month period including (1) multiple rotating cohorts in which students cycle through in-person instruction on a weekly basis, (2) parallel cohorts with in-person and remote learning tracks, (3) the impact of a hypothetical testing program with ideal and imperfect detection, and (4) varying levels of aggregate transmission reduction. Our mathematical model predicts that reducing the number of contacts through cohorts produces a larger effect than diminishing transmission rates per contact. Specifically, the latter approach requires dramatic reduction in transmission rates in order to achieve a comparable effect in minimizing infections over time. Further, our model indicates that surveillance programs using less sensitive tests may be adequate in monitoring infections within a school community by both keeping infections low and allowing for a longer period of instruction. Lastly, we underscore the importance of factoring infection prevalence in deciding when a local outbreak of infection is serious enough to require reverting to remote learning.
Precise genome engineering inDrosophilausing prime editing
Authors: Bosch Justin A. , Birchak Gabriel , Perrimon Norbert 
Published: August 2020

AbstractPrecise genome editing is a valuable tool to study gene function in model organisms. Prime editing, a precise editing system developed in mammalian cells, does not require double strand breaks or donor DNA and has low off-target effects. Here, we applied prime editing for the model organismDrosophila melanogasterand developed conditions for optimal editing. By expressing prime editing components in cultured cells or somatic cells of transgenic flies, we precisely installed premature stop codons in three classical visible marker genes,ebony,white, andforked. Furthermore, by restricting editing to germ cells, we demonstrate efficient germ line transmission of a precise edit inebonyto ~50% of progeny. Our results suggest that prime editing is a useful system inDrosophilato study gene function, such as engineering precise point mutations, deletions, or epitope tags.
A novel prokaryotic CRISPR-Cas12a based tool for programmable transcriptional activation and repression
Authors: Schilling Christoph , Koffas Mattheos A.G. , Sieber Volker , Schmid Jochen 
Published: August 2020

AbstractTranscriptional perturbation using inactivated CRISPR-nucleases (dCas) is a common method in eukaryotic organisms. While rare examples of dCas9 based tools for prokaryotes have been described, multiplexing approaches are limited due to the used effector nuclease. For the first time, a dCas12a derived tool for the targeted activation and repression of genes was developed. Therefore, a previously described SoxS activator domain was linked to dCas12a to enable programmable activation of gene expression. Proof of principle of transcriptional regulation was demonstrated based on fluorescence reporter assays using the alternative host organismPaenibacillus polymyxaas well asEscherichia coli. Single target and multiplex CRISPR interference targeting the exopolysaccharide biosynthesis ofP. polymyxawas shown to emulate polymer compositions of gene knock-outs. Simultaneous expression of 11 gRNAs targeting multiple lactate dehydrogenases and a butanediol dehydrogenase resulted in decreased lactate formation, as well as an increased butanediol production in microaerobic fermentation processes. Even though Cas12a is more restricted in terms of its genomic target sequences compared to Cas9, its ability to efficiently process its own guide RNAsin vivomakes it a promising tool to orchestrate sophisticated genetic reprogramming of bacterial cells or to screen for engineering targets in the genome. The developed tool will accelerate metabolic engineering efforts in the alternative host organismP. polymyxaand might be also applied for other bacterial cell factories.
Orphan CpG islands boost the regulatory activity of poised enhancers and dictate the responsiveness of their target genes
Authors: Pachano Tomás , Sánchez-Gaya Víctor , Mariner-Faulí María , Ealo Thais , Asenjo Helena G. , Respuela Patricia , Cruz-Molina Sara , van Ijcken Wilfred F. J. , Landeira David , Rada-Iglesias Álvaro 
Published: August 2020

ARTICLECpG islands (CGIs) represent a distinctive and widespread genetic feature of vertebrate genomes, being associated with ∼70% of all annotated gene promoters1. CGIs have been proposed to control transcription initiation by conferring nearby promoters with unique chromatin properties2–4. In addition, there are thousands of distal or orphan CGIs (oCGIs) whose functional relevance and mechanism of action are barely known5–7. Here we show that oCGIs are an essential component of poised enhancers (PEs)8, 9that boost their long-range regulatory activity and dictate the responsiveness of their target genes. Using a CRISPR/Cas9 knock-in strategy in mESC, we introduced PEs with or without oCGIs within topological associating domains (TADs) harbouring genes with different types of promoters. By evaluating the chromatin, topological and regulatory properties of the engineered PEs, we uncover that, rather than increasing their local activation, oCGIs boost the physical and functional communication between PEs and distally located developmental genes. Furthermore, we demonstrate that developmental genes with CpG rich promoters are particularly responsive to PEs and that such responsiveness depends on the presence of oCGIs. Therefore, our work unveils a novel role for CGIs as genetic determinants of the compatibility between genes and enhancers, thus providing major insights into how developmental gene expression programs are deployed under both physiological and pathological conditions10–12.
Automatic inference of demographic parameters using Generative Adversarial Networks
Authors: Wang Zhanpeng , Wang Jiaping , Kourakos Michael , Hoang Nhung , Lee Hyong Hark , Mathieson Iain , Mathieson Sara 
Published: August 2020

AbstractPopulation genetics relies heavily on simulated data for validation, inference, and intuition. In particular, since the evolutionary “ground truth” for real data is always limited, simulated data is crucial for training supervised machine learning methods. Simulation software can accurately model evolutionary processes, but requires many hand-selected input parameters. As a result, simulated data often fails to mirror the properties of real genetic data, which limits the scope of methods that rely on it. Here, we develop a novel approach to estimating parameters in population genetic models that automatically adapts to data from any population. Our method,pg-gan, is based on a generative adversarial network that gradually learns to generate realistic synthetic data. We demonstrate that our method is able to recover input parameters in a simulated isolation-with-migration model. We then apply our method to human data from the 1000 Genomes Project, and show that we can accurately recapitulate the features of real data.
CODEX, a neural network approach to explore signaling dynamics landscapes
Authors: Jacques Marc-Antoine , Dobrzyński Maciej , Gagliardi Paolo Armando , Sznitman Raphael , Pertz Olivier 
Published: August 2020

AbstractFluorescent biosensors routinely yield thousands of single-cell, heterogeneous, multi-dimensional signaling trajectories that are difficult to mine for relevant information. We present CODEX, an approach based on artificial neural networks to guide exploration of time-series datasets and to identify motifs in dynamic signaling states.
PD-1 blockade exacerbatesMycobacterium tuberculosisinfection in rhesus macaques
Authors: Kauffman Keith D , Sakai Shunsuke , Lora Nickiana E , Namasivayam Sivaranjani , Baker Paul J , Kamenyeva Olena , Foreman Taylor W , Nelson Christine E , Oliveira-de-Souza Deivide , Vinhaes Caian L. , Yaniv Ziv , Lindestam Arleham Cecilia S , Sette Alessandro , Freeman Gordon J , Moore Rashida ,   the NIAID/DIR Tuberculosis Imaging Program, Sher Alan , Mayer-Barber Katrin D , Andrade Bruno B , Kabat Juraj , Via Laura E , Barber Daniel L 
Published: August 2020

ABSTRACTBoosting immune cell function by targeting the co-inhibitory receptor PD-1 may have applications in the treatment of chronic infections. Here we examine the role of PD-1 duringMycobacterium tuberculosis(Mtb) infection of rhesus macaques. Animals treated with αPD-1 mAb developed worse disease and higher granuloma bacterial loads compared to isotype control treated monkeys. PD-1 blockade increased the number and functionality of granuloma Mtb-specific CD8 T cells. In contrast, Mtb-specific CD4 T cells in αPD-1 treated macaques were not increased in number or function in granulomas, upregulated high levels of CTLA-4 and exhibited reduced intralesional trafficking in live imaging studies. In granulomas of αPD-1 treated animals, multiple pro-inflammatory cytokines were elevated, and more cytokines correlated with bacterial loads, leading to the identification of a role for caspase 1 in the exacerbation of tuberculosis after PD-1 blockade. Lastly, increased Mtb bacterial loads after PD-1 blockade were found to associate with the composition of the intestinal microbiota prior to infection in individual macaques. Therefore, PD-1-mediated co-inhibition is required for control of Mtb infection in macaques, perhaps due to its role in dampening detrimental inflammation as well as allowing for normal CD4 T cell responses.
Age-independent influence of hematopoietic stem and progenitor cell populations during hematopoietic reconstitution
Authors: Gotzhein Frauke , Aranyossy Tim , Thielecke Lars , Sonntag Tanja , Thaden Vanessa , Fehse Boris , Müller Ingo , Glauche Ingmar , Cornils Kerstin 
Published: August 2020

ABSTRACTHematopoietic stem cell transplantation (HSCT) following myeloablative conditioning represents the only curative treatment option to overcome numerous hematologic malignancies. Despite the overall clinical success to achieve reconstitution of the blood system in many patients, the length of the aplastic phase until recovery response remains a critical parameter for patient survival. Fatal infections are the major risk factor for immunocompromised individuals and in many cases lead to transplant related morbidity and mortality. Therefore, we hypothesized that transplants from young donors might be beneficial for the spatiotemporal blood reconstitution in comparison to old grafts. Here we report on our multicolor-coded barcode system (BC32) to track hematopoietic stem and progenitor cell (HSPC) populations in a murine model of HSCT. By using different experimental settings of young and aged donor and recipient animals we compared the influence of age on graft composition, leukocyte recovery and more precisely, the contribution of individual HSPC subpopulations to the process. We show that blood reconstitution is substantially driven and maintained by HSCs and MPPs, while the latter accounted for higher output rates than HSCs, confirmed by FACS and NGS analyses. Reconstitution patterns were highly polyclonal and stable in all animals aside from variability between individual animals. This leads to the conclusion that HSPCs home, engraft and differentiate independently of donor and recipient age in our experimental conditions. Our findings add to ongoing efforts to expand the application of HSCT in older individuals while minimizing therapy related risks resulting from intensive myeloablative conditioning or incomplete blood reconstitution.
The application of drones for mosquito larval habitat identification in rural environments: a practical approach for malaria control?
Authors: Stanton Michelle C , Kalonde Patrick , Zembere Kennedy , Spaans Remy Hoek , Jones Christopher M 
Published: August 2020

AbstractSpatial and temporal trends in mosquito-borne diseases are driven by the locations and seasonality of larval habitat. One method of disease control is to decrease the mosquito population by removing habitat and/or reduce the likelihood of larvae developing into adults, known as larval source management (LSM). In malaria control, LSM is currently considered impractical in rural areas due to perceived difficulties in identifying target areas. High resolution drone mapping is being considered as a practical solution to address this barrier. In this paper, we use our experiences of drone-led larval habitat identification in Malawi to assess the accuracy and practicalities of this approach.Drone imagery and larval surveys were conducted in Kasungu district, Malawi between 2018-2020. Water bodies and aquatic vegetation were identified in the imagery using both manual methods and geographical object-based image analysis (GeoOBIA) and the performance of the classifications were compared. Larval sampling sites were characterised by biotic factors visible in drone imagery (e.g. vegetation coverage, type), and generalised linear mixed models were used to determine their association with larval presence.Imagery covering an area of 8.9km2across eight sites was captured. Characteristics associated with rural larval habitat were successfully identified using GeoOBIA (e.g. median accuracy = 0.98, median kappa = 0.96 using a standard RGB camera), with a median of 18.3% being classed as surface water, compared to 20.1% using manual identification. The GeoOBIA approach, however, required greater processing time and technical skills. Larval samples were captured from 326 sites, and a relationship was identified between larval presence and vegetation (log-OR=1.44, p=0.01). Vegetation type was also a significant factor when considering late stage anopheline larvae only.Our study demonstrates the potential for drone-acquired imagery as a tool to support the identification of mosquito larval habitat in rural areas where malaria is endemic. There are, however, technical challenges to overcome before it can be smoothly integrated into malaria control activities. Further consultations between experts and stakeholders in the fields of drones, image analysis and vector control are needed to develop more detailed guidance on how this technology can be most effectively exploited.
A MATLAB Toolbox for Modeling Genetic Circuits in Cell-Free Systems
Authors: Singhal Vipul , Tuza Zoltan A. , Sun Zachary Z. , Murray Richard M. 
Published: August 2020

AbstractWe introduce a MATLAB based simulation toolbox, called txtlsim, for anE. colibased Transcription-Translation (TX-TL) system. This toolbox accounts for several cell-free related phenomena, such as resource loading, consumption, and degradation, and in doing so, models the dynamics of TX-TL reactions for the entire duration of batch-mode experiments. We use a Bayesian parameter inference approach to characterize the reaction rate parameters associated with the core transcription, translation and mRNA degradation mechanics of the toolbox, allowing it to reproduce constitutive mRNA and protien expression trajectories. We demonstrate the use of this characterized toolbox in a circuit behavior prediction case study for an incoherent feed-forward loop.