bluuebunny/crossref_metadata_2025_split huggingface dataset:
Online tests for sexually transmitted infections – Friend or Foe? An analysis of providers in the United Kingdom
Authors: Clarke Eleanor , Horner Paddy , Muir Peter , Turner Katy M. E. , Harding-Esch Emma M. 
Published: July 2021

ABSTRACTObjectivesOnline testing for sexually transmitted infections (STIs) may contribute to overcoming barriers to traditional testing such as stigma and inconvenience. However, regulation of these tests is lacking, and the quality of services is variable, with potential short- and long-term personal, clinical and public health implications. This study aimed to evaluate online tests available in the UK against national standards.MethodsProviders of online STI tests (self-sampling and self-testing) in the UK were identified by an internet search of Google and Amazon (June 2020). Website information on tests and care was collected, and further information requested from providers via an online survey, sent twice (July 2020, April 2021). The information obtained was compared to British Association for Sexual Health and HIV (BASHH) guidelines for diagnostics and standards of STI management.Results31 providers were identified: 13 self-test, 18-self-sample, and two laboratories that serviced multiple providers. Seven responded to the online survey. Many conflicts with national guidelines were identified, including: lack of health promotion information, lack of sexual history taking, use of tests licensed for professional use only marketed for self-testing, inappropriate infections tested for, incorrect specimen type used, and lack of advice for post-diagnosis management.ConclusionsVery few online providers met the BASHH national STI management guidelines standards that were assessed, and there is concern that this will also be the case in areas that were not covered by this study. For-profit providers were the least compliant, with concerning implications for patient care and public health. Regulatory change is urgently needed to ensure that online providers are compliant with national guidelines to ensure high-quality patient care, and providers are held to account if non-compliant.Key message boxOnline providers help overcome many barriers to STI testing and are increasingly popular, but quality of services is not assuredMany online testing services, particularly for-profit providers, did not comply with national guidelinesSubstandard services can lead to serious personal, clinical and public healthimplications, such as inappropriate testing, inappropriate antimicrobial prescribing, unnecessary emotional distress and missed diagnosesRegulatory change is required to ensure online providers comply with national guidelines and are held to account when they do not
Effective Connectivity in Subcortical Visual Structures in De Novo Patients with Parkinson’s Disease
Authors: Bellot Emmanuelle , Kauffmann Louise , Coizet Véronique , Meoni Sara , Moro Elena , Dojat Michel 
Published: July 2021

AbstractBackgroundPD is associated with non-motor symptoms appearing before the motor symptoms onset. Recent studies report dysfunctions of visual structures at early stages of PD.ObjectiveThis study addresses effective connectivity in the visual network of PD patients.MethodsUsing brain functional MRI and Dynamic Causal Modeling analysis, we investigated the connectivity between the superior colliculus, the lateral geniculate nucleus and the primary visual area V1 in 22 de novo untreated PD patients and six months after starting dopaminergic treatment compared to age-matched healthy controls.ResultsOur findings indicate that the superior colliculus drives cerebral activity for luminance contrast processing both in healthy controls and untreated PD patients. The same effective connectivity was observed with neuromodulatory differences in terms of neuronal dynamic interactions. The modulation induced by luminance contrast changes of the superior colliculus connectivity (self-connectivity and connectivity to the lateral geniculate nucleus) was inhibited in PD patients (effect of contrast: p = 0.79 and p = 0.77 respectively). The introduction of dopaminergic medication failed to restore the effective connectivity modulation observed in the healthy controls.InterpretationThe deficits in luminance contrast processing in PD seem due to a deficiency in connectivity adjustment from the superior colliculus to the lateral geniculate nucleus and to V1. Administration of a dopaminergic treatment over six months was not able to normalize the observed alterations in inter-regional coupling. These findings highlight the presence of early dysfunctions in primary visual areas, which might be used as early markers of the disease.
Hot and sour: parasite adaptations to honey bee body temperature and pH
Authors: Palmer-Young Evan C , Raffel Thomas R , Evans Jay D 
Published: July 2021

ABSTRACTHost temperature and gut chemistry can shape resistance to parasite infection. Heat and acidity can limit trypanosomatid infection in warm-blooded hosts, and could shape infection resistance in insects as well. The colony-level endothermy and acidic guts of social bees provide unique opportunities to study how temperature and acidity shape insect-parasite associations. We compared temperature and pH tolerance between three trypanosomatid parasites from social bees and a related trypanosomatid from poikilothermic mosquitoes, which have alkaline guts.Relative to the mosquito parasites, all three bee parasites had higher heat tolerance that reflected levels of endothermy in hosts. Heat tolerance of the honey bee parasiteCrithidia mellificaewas exceptional for its genus, implicating honey bee endothermy as a filter of parasite establishment. The lesser heat tolerance of the emergingLotmaria passimsuggests possible spillover from a less endothermic host. Whereas both honey bee parasites tolerated the acidic pH’s found in bee intestines, mosquito parasites tolerated the alkaline conditions found in mosquito midguts, suggesting that both gut pH and temperature could structure host-parasite specificity. Elucidating how host temperature and gut pH affect infection—and corresponding parasite adaptations to these factors—could help explain trypanosomatids’ distribution among insects and invasion of mammals.
eQTL mapping using allele-specific gene expression
Authors: Zhabotynsky Vasyl , Huang Licai , Little Paul , Hu Yi-Juan , de Villena Fernando Pardo-Manuel , Zou Fei , Sun Wei 
Published: July 2021

AbstractUsing information from allele-specific gene expression (ASE) can sub-stantially improve the power to map gene expression quantitative trait loci (eQTLs). However, such practice has been limited, partly due to high computational cost and the requirement to access raw data that can take a large amount of storage space. To address these computational challenges, we have developed a computational framework that uses a statistical method named TReCASE as its computational engine, and it is computationally feasible for large scale analysis. We applied it to map eQTLs in 28 human tissues using the data from the Genotype-Tissue Expression (GTEx) project. Compared with a popular linear regression method that does not use ASE data, TReCASE can double the number of eGenes (i.e., genes with at least one significant eQTL) when sample size is relatively small, e.g., n = 200. We also demonstrated how to use the ASE data that we have collected to study dynamic eQTLs whose effect sizes vary with respect to another variable, such as age. We find the majority of such dynamic eQTLs are due to some underlying latent factors, such as cell type proportions. We further compare TReCASE versus another method RASQUAL. TReCASE is ten times or more faster than RASQUAL and it provides more robust type I error control.
Multivalent, asymmetric IL-2-Fc fusions provide optimally enhanced regulatory T cell selectivity
Authors: Orcutt-Jahns Brian , Emmel Peter C. , Snyder Eli M. , Taylor Scott D. , Meyer Aaron S. 
Published: July 2021

AbstractThe common γ-chain receptor cytokines coordinate the proliferation and function of immune cell populations. One of these cytokines, interleukin (IL)-2, has potential as a therapy in autoimmune disease but is limited in effectiveness by its modest specificity toward regulatory T cells (Tregs). Engineering Treg-selective IL-2 has primarily focused on retaining binding to the high-affinity receptor, expressed more highly on Tregs, while reducing binding to the lower affinity receptor with broader expression. However, other parameters, such as the orientation and valency of Fc fusion, have signaling effects that have never been systematically explored. Here, we systematically profiled the signaling responses to a panel of wild type and mutein IL-2-Fc fusions across time, cell types, and concentrations. Exploring these responses, we found that dimeric muteins have unique specificity for Tregs through binding avidity. A mechanistic model of receptor interactions could capture these effects and directed the design of tetravalent IL-2-Fc fusions with greater Tregspecificity than possible with current design strategies. Exploration of other surface targets on Tregs revealed that there are no other binding moieties that could be fused to IL-2 for greater selectivity. Instead, IL2Rα itself is a maximally unique surface target for Tregs, and so avidity is likely the only route to more selective Treginteraction. However, the binding model revealed that asymmetrical, multivalent IL-2 fusions can bias avidity effects toward IL2Rα for even further enhanced Tregselectivity. These findings present a comprehensive analysis of how ligand properties and their effects on surface receptor-ligand interactions translate to selective activation of immune cell populations, and consequently reveals two new routes toward therapeutic cytokines with superior Tregselectivity that can be exploited for designing selective therapies in many other contexts.Significance StatementSignaling in off-target immune cells has hindered the effectiveness of IL-2 as an immunotherapy. We show that IL-2-Fc fusions with higher valency can exhibit enhanced regulatory T cell selectivity. This altered selectivity is explained by the kinetics of surface receptor-ligand binding and can be quantitatively predicted using a multivalent binding model. Using these insights, we successfully develop two new strategies for IL-2 therapies with unprecedented selectivity.HighlightsCurrent IL-2 therapies are limited by a selectivity/target potency tradeoff.Multivalency enhances selectivity for Tregs through IL2Rα avidity.Tregselectivity cannot be enhanced by targeting other surface protein markers.Multivalency can decouple selectivity from signaling using asymmetric cytokine fusions.
Novel measures of Morris water maze performance that use vector field maps to assess accuracy, uncertainty, and intention of navigational searches
Authors: Meenakshi P. , Mehrotra D. , Nruthyathi N. , Almeida-Filho D. , Lee Y.-S. , Silva A.J. , Balaji J. 
Published: July 2021

AbstractMost commonly used behavioural measures for testing learning and memory in the Morris water maze (MWM) involve comparisons of an animal’s residence time in different quadrants of the pool. Such measures are limited in their ability to test different aspects of the animal’s performance. Here, we describe novel measures of performance in the MWM that use vector fields to capture the motion of mice as well as their search pattern in the maze. Using these vector fields, we develop quantitative measures of performance that are intuitive and more sensitive than classical measures. First, we describe search patterns in terms of vector field properties and use these properties to define three metrics of spatial memory namely Spatial Accuracy, Uncertainty and, Intensity of Search. We demonstrate the usefulness of these measures using four different data sets including comparisons between different strains of mice, an analysis of two mouse models of Noonan syndrome (Ptpn11 D61G and Ptpn11 N308D/+), and a study of goal reversal training. Importantly, besides highlighting novel aspects of performance in this widely used spatial task, our measures were able to uncover previously undetected differences, including in an animal model of Noonan syndrome, which we rescued with the mitogen activated protein kinase kinase (MEK) inhibitor SL327. Thus, our results show that our approach breaks down performance in the Morris water maze into sensitive measurable independent components that highlight differences in spatial learning and memory in the MWM that were undetected by conventional measures.
Automated verification, assembly, and extension of GBM stem cell network model with knowledge from literature and data
Authors: Holtzapple Emilee , Cochran Brent , Miskov-Zivanov Natasa 
Published: July 2021

AbstractSignaling network models are usually assembled from information in literature and expert knowledge or inferred from data. The goal of modeling is to gain mechanistic understanding of key signaling pathways and provide predictions on how perturbations affect large-scale processes such as disease progression. For glioblastoma multiforme (GBM), this task is critical, given the lack of effective treatments and pace of disease progression. Both manual and automated assembly of signaling networks from data or literature have drawbacks. Existing GBM networks, as well as networks assembled using state-of-the-art machine reading, fall short when judged by the quality and quantity of information, as well as certain attributes of the overall network structure. The contributions of this work are two-fold. First, we propose an automated methodology for verification of signaling networks. Next, we discuss automation of network assembly and extension that relies on methods and resources used for network verification, thus, implicitly including verification in these processes. In addition to these methods, we also present, and verify a comprehensive GBM network assembled with a hybrid of manual and automated methods. Finally, we demonstrate that, while an automated network assembly is fast, such networks still lack precision and realistic network topology.
Trycycler: consensus long-read assemblies for bacterial genomes
Authors: Wick Ryan R. , Judd Louise M. , Cerdeira Louise T. , Hawkey Jane , Méric Guillaume , Vezina Ben , Wyres Kelly L. , Holt Kathryn E. 
Published: July 2021

AbstractAssembly of bacterial genomes from long-read data (generated by Oxford Nanopore or Pacific Biosciences platforms) can often be complete: a single contig for each chromosome or plasmid in the genome. However, even complete bacterial genome assemblies constructed solely from long reads still contain a variety of errors, and different assemblies of the same genome often contain different errors. Here, we present Trycycler, a tool which produces a consensus assembly from multiple input assemblies of the same genome. Benchmarking using both simulated and real sequencing reads showed that Trycycler consensus assemblies contained fewer errors than any of those constructed with a single long-read assembler. Post-assembly polishing with Medaka and Pilon further reduced errors and yielded the most accurate genome assemblies in our study. As Trycycler can require human judgement and manual intervention, its output is not deterministic, and different users can produce different Trycycler assemblies from the same input data. However, we demonstrated that multiple users with minimal training converge on similar assemblies that are consistently more accurate than those produced by automated assembly tools. We therefore recommend Trycycler+Medaka+Pilon as an ideal approach for generating high-quality bacterial reference genomes.Data availabilitySupplementary figures, tables and code can be found at: github.com/rrwick/Trycycler-paperReads, assemblies and reference sequences can be found at: bridges.monash.edu/articles/dataset/Trycycler_paper_dataset/14890734
Pro-inflammatory Cytokine GM-CSF Improves Learning/Memory and Brain Pathology in Dp16 Down Syndrome Mice and Improves Learning/Memory in Wild-Type Mice
Authors: Ahmed Md. Mahiuddin , Wang Athena Ching-Jung , Elos Mihret , Chial Heidi J. , Sillau Stefan , Solano D. Adriana , Coughlan Christina , Aghili Leila , Anton Paige , Markham Neil , Adame Vanesa , Gardiner Katheleen J. , Boyd Timothy D. , Potter Huntington 
Published: July 2021

AbstractDown syndrome (DS) is characterized by chronic neuroinflammation, peripheral inflammation, astrogliosis, imbalanced excitatory/inhibitory neuronal function, and cognitive deficits in both humans and mouse models. Suppression of inflammation has been proposed as a therapeutic approach to treating DS co-morbidities, including intellectual disability (DS/ID). Conversely, we discovered previously that treatment with the pro-inflammatory cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) improved cognition and reduced biomarkers of brain pathology in humans with Alzheimer’s disease (AD), another inflammatory disorder, and in a mouse model of AD. To investigate the effects of GM-CSF treatment on DS/ID, we assessed behavior and brain pathology in 12-14 month-old DS mice (Dp[16]1Yey) and their wild-type (WT) littermates, neither of which develop amyloid, and found that GM-CSF treatment improved performance in the radial arm water maze in both Dp16 and WT mice compared to placebo. Dp16 mice also showed abnormal astrocyte morphology and aggregation and fewer calretinin-positive interneurons, both of which were improved by GM-CSF treatment. These findings suggest that stimulating and/or modulating inflammation and the innate immune system with GM-CSF treatment may enhance cognition in both people with DS/ID and in the typical aging population.
Soft drinks can be misused to give false “false positive” SARS-CoV-2 lateral flow device results
Authors: Oni L , Hawcutt DB , Buchan IE , Semple MG 
Published: July 2021

BackgroundThe COVID-19 pandemic created the need for very large scale, rapid testing to prevent and contain transmission of the SARS-CoV-2 virus. Lateral flow device (LFD) immunoassays meet this need by indicating the presence of SARS-CoV-2 antigen from nose/throat swab washings in 30 minutes without laboratory processing, and can be manufactured quickly at low cost. Since March 2021, UK schools have asked pupils without symptoms to test twice weekly. Pupils have posted on social media about using soft drinks to create positive results. The aim of this study was to systematically test a variety soft drinks to determine whether they can cause false “false positive” LFD results.MethodsThis study used 14 soft drinks and 4 artificial sweeteners to determine the outcome of misusing them as analyte for the Innova SARS-CoV-2 antigen rapid qualitative LFD. The pH value, sugar content and ingredients of each sample are described. The LFD results were double read and a subset was repeated using the same devices and fake analytes but differently sourced.FindingsOne sample (1/14; 7%), spring water, produced a negative result. Ten drinks (10/14; 71%) produced a positive or weakly positive result. Three samples (3/14; 21%) produced void results, mostly the fruit concentrate drinks. There was no apparent correlation between the pH value (pH 5.0 in 13/14, 93%; pH 6.5 in 1/14; 7%) or the sugar content (range 0-10.7 grams per 100mls) of the drinks and their LFD result. The 4 artificial sweeteners all produced negative results. A subset of the results was fully replicated with differently sourced materials.InterpretationSeveral soft drinks can be misused to give false positive SARS-CoV-2 LFD results. Daily LFD testing should be performed first thing in the morning, prior to the consumption of any food or drinks, and supervised where feasible.FundingThis work was self-funded by author LO and the LFD were gifted for use in this study.Research in contextEvidence before this studyLateral flow devices (LFD) for SARS-CoV-2 antigen testing have been used extensively in the UK and internationally in COVID-19 pandemic responses, providing rapid testing at low costRecent reports from young people on social media suggested soft drinks might be misused as LFD analyte and produce a seemingly positive resultAdded value of this studyVarious common soft drinks used as fake analyte can produce false positive SARS-CoV-2 LFD resultsArtificial sweeteners alone in fake analyte solution did not produce false positive resultsImplications of all the available evidenceSoft drinks misused as analyte can produce false “false positive” SARS-CoV-2 LFD resultsDaily testing is best done first thing in the morning, prior to any food or drink, and under supervision where possible
The BLMP-1 transcription factor promotes oscillatory gene expression to achieve timely molting
Authors: Hauser Yannick P. , Meeuse Milou W.M. , Gaidatzis Dimos , Großhans Helge 
Published: July 2021

AbstractGene expression oscillators can coordinate developmental events in space and time. In C. elegans, a gene expression oscillator directs rhythmic accumulation of ∼25% of the transcriptome, and thus thousands of transcripts, presumably to control molting, a process of rhythmic skin regeneration. Recently, a reverse genetic screen identified several transcription factors important for molting. Here, we characterize one of these, BLMP-1, orthologous to the mammalian transcription repressor PRDM1. We find it to be important for timely molting, and oscillatory gene expression. We propose a dual function for BLMP-1 in shaping oscillatory gene expression and coupling it to a set of direct targets, which ensures cuticular integrity. With mammalian PRDM1/BLIMP1 promoting regular cycles of postnatal hair follicle regeneration, our findings point to the possible existence of a fundamentally conserved clock mechanism in control of rhythmic skin regeneration.
CXCL17 is an endogenous inhibitor of CXCR4 via a novel mechanism of action
Authors: White Carl W. , Kilpatrick Laura E. , Dale Natasha , Abhayawardana Rekhati S. , Dekkers Sebastian , Stocks Michael J , Pfleger Kevin D. G. , Hill Stephen J. 
Published: July 2021

AbstractCXCL17 is the most recently described chemokine. It is principally expressed by mucosal tissues, where it facilitates chemotaxis of monocytes, dendritic cells, and macrophages and has antimicrobial properties. CXCL17 is also implicated in the pathology of inflammatory disorders and progression of several cancers, as well as being highly upregulated during viral infections of the lung. However, the exact role of CXCL17 in health and disease is largely unknown, mainly due to a lack of known molecular targets mediating CXCL17 functional responses. Using a range of bioluminescence resonance energy transfer (BRET) based assays, here we demonstrate that CXCL17 inhibits CXCR4-mediated signalling and ligand binding. Moreover, CXCL17 interacts with neuropillin-1, a VEGFR2 co-receptor. Additionally, we find CXCL17 only inhibits CXCR4 ligand binding in intact cells and demonstrate that this effect is mimicked by known glycosaminoglycan binders, surfen and protamine sulfate. This indicates that CXCL17 inhibits CXCR4 by a unique mechanism of action that potentially requires the presence of a glycosaminoglycan containing accessory protein. Altogether, our results reveal that CXCL17 is an endogenous inhibitor of CXCR4 and represents an important discovery in our understanding of the (patho) physiological functions of CXCL17 and regulation of CXCR4 signalling.