bluuebunny/crossref_metadata_2025_split huggingface dataset:
Turnover of MCMV-expanded CD8+ T-cells is similar to that of memory phenotype T-cells and independent of the magnitude of the response
Authors: Baliu-Piqué Mariona , Drylewicz Julia , Zheng Xiaoyan , Borkner Lisa , Swain Arpit C. , Otto Sigrid , de Boer Rob J. , Tesselaar Kiki , Cicin-Sain Luka , Borghans José A.M. 
Published: November 2021

AbstractThe potential of memory T-cells to provide protection against re-infection is beyond question. Yet, it remains debated whether long-term T-cell memory is due to long-lived memory cells. There is ample evidence that blood-derived memory phenotype CD8+ T-cells maintain themselves through cell division, rather than through longevity of individual cells. It has recently been proposed, however, that there may be heterogeneity in the lifespans of memory T-cells, depending on factors such as exposure to cognate antigen. Cytomegalovirus (CMV) infection induces not only conventional, contracting T-cell responses, but also inflationary CD8+ T-cell responses, which are maintained at unusually high numbers, and are even thought to continue to expand over time. It has been proposed that such inflating T-cell responses result from the accumulation of relatively long-lived CMV-specific memory CD8+ T-cells. Using in vivo deuterium labelling and mathematical modelling, we found that the average production rates and expected lifespans of mouse CMV-specific CD8+ T-cells are very similar to those of bulk memory-phenotype CD8+ T-cells. Even CMV-specific inflationary CD8+ T-cell responses that differ three-fold in size, were found to turn over at similar rates.
Stenoparib, an inhibitor of cellular poly (ADP-ribose) polymerases (PARPs), blocks in vitro replication of SARS-CoV-2 variants
Authors: Zarn Katherine E , Jaramillo Sierra A , Zapata Anthony R , Stone Nathan E , Jones Ashley N , Nunnally Haley E , Settles Erik W , Ng Ken , Keim Paul S , Knudsen Steen , Nuijten Patricia M , Tijsma Aloys SL , French Christopher T 
Published: November 2021

AbstractWe recently published a preliminary assessment of the activity of a poly (ADP-ribose) polymerase (PARP) inhibitor, stenoparib, also known as 2X-121, which inhibits viral replication by affecting pathways of the host. Here we show that stenoparib effectively inhibits a SARS-CoV-2 wt (BavPat1/2020) strain and four additional variant strains; alpha (B.1.1.7), beta (B.1.351), delta (B.1.617.2) and gamma (P.1) in vitro, with 50% effective concentration (EC50) estimates of 4.1 μM, 8.5 μM, 24.1 μM, 8.2 μM and 13.6 μM, respectively. A separate experiment focusing on a combination of 10 μM stenoparib and 0.5 μM remdesivir, an antiviral drug, resulted in over 80% inhibition of the alpha (B.1.1.7) variant, which is substantially greater than the effect achieved with either drug alone, suggesting at least additive effects from combining the different mechanisms of activity of stenoparib and remdesivir.
Immediate and mid-term effect of a natural topical product in patients with musculoskeletal pain: randomized, double-blinded, and placebo-controlled clinical trial
Authors: Ramon Silvia , de Unzurrunzaga Rocio , Nishishinya Betina , Lucenteforte Giacomo , García Miguel , Barastegui David , Unzueta Itziar , Arcalis Antonio , Cugat Ramon 
Published: November 2021

AbstractIntroductionMusculoskeletal pain is a common affection due to ageing, sedentarism and injuries. The objective of this trial is to prove efficacy of a natural topical composition containing Arnica montana, Hypericum perforatum, Calendula officinalis, Melaleuca sp. and menthol in pain management in adults with acute or chronic pain.MethodsThis randomized, double-blinded and placebo-controlled trial included 200 patients with musculoskeletal pain, 100 in the intervention group receiving the topical formula and 100 in the placebo group, receiving a similar formula without active ingredients. The products were applied topically twice daily for 14 days in affected areas. Immediate pain alleviation and stiffness perception were monitored for two hours at days 0, 7 at 14. Pain reduction and recovery perception upon sustained application were assessed after 7 and 14 days.ResultsIntervention immediately reduced pain and stiffness at rest and in motion 30 minutes after application and kept being superior to placebo in all short-term timepoints (p < 0.05). Immediate pain reduction was maintained even at late stages of recovery. A two-week sustained intervention resulted in significant pain reduction and improvement in recovery perception. Even if both groups reached statistical significance with respect to baseline due to spontaneous lesion recovery, a significantly improved recovery was reported in the intervention group with respect to placebo.ConclusionsIntervention was found to reduce pain and stiffness upon minutes of its application and to improve pain and mobility over the 14 days of treatment, showing benefits both for immediate alleviation and for longer term recovery.Level of EvidenceTherapeutic Level I
Creation and evaluation of full-text literature-derived, feature-weighted disease models of genetically determined developmental disorders
Authors: Yates T.M , Lain A. , Campbell J. , Simpson T.I. , FitzPatrick D.R. 
Published: November 2021

AbstractThere are >2500 different genetically-determined developmental disorders (DD), which, as a group, show very high levels of both locus and allelic heterogeneity. This has led to the wide-spread use of evidence-based filtering of genome-wide sequence data as a diagnostic tool in DD. Determining whether the association of a filtered variant at a specific locus is a plausible explanation of the phenotype in the proband is crucial and commonly requires extensive manual literature review by both clinical scientists and clinicians. Access to a database of weighted clinical features extracted from rigorously curated literature would increase the efficiency of this process and facilitate the development of robust phenotypic similarity metrics. However, given the large and rapidly increasing volume of published information, conventional biocuration approaches are becoming impractical.Here, we present a scalable, automated method for extraction of categorical phenotypic descriptors from full-text literature. Papers identified through literature review were downloaded and parsed using the Cadmus custom retrieval package. Human Phenotype Ontology terms were extracted using MetaMap, with 76-83% precision and 72-81% recall. Mean terms per paper increased from 9 in title + abstract, to 69 using full text. We demonstrate that these literature-derived disease models plausibly reflect true disease expressivity more accurately than gold standard manually-curated models, through comparison with prospectively gathered data from the Deciphering Developmental Disorders study. AUC for ROC curves increased by 5-10% through use of literature-derived models. This work shows that scalable automated literature curation increases performance and adds weight to the need for this strategy to be integrated into informatic variant analysis pipelines.
Of masks and methylene blue - the use of methylene blue photochemical treatment to decontaminate surgical masks contaminated with a tenacious small non-enveloped norovirus
Authors: Wielick Constance , Fries Allyson , Dams Lorène , Razafimahefa Ravo M. , Heyne Belinda , Harcourt Brian H. , Lendvay Thomas S. , Willaert Jean François , de Jaeger Simon , Haubruge Eric , Thiry Etienne , Ludwig-Begall Louisa F. 
Published: November 2021

ABSTRACTBackgroundIn the context of the SARS-CoV-2 pandemic, reuse of personal protective equipment, specifically that of medical face coverings, has been recommended. The reuse of these typically single-use only items necessitates procedures to inactivate contaminating human respiratory and gastrointestinal pathogens. We previously demonstrated decontamination of surgical masks and respirators contaminated with infectious SARS-CoV-2 and various animal coronaviruses via low concentration- and short exposure methylene blue photochemical treatment (10 µM methylene blue, 30 minutes of 12,500-lux red light or 50,000 lux white light exposure).MethodsHere, we describe the adaptation of this protocol to the decontamination of a more resistant, non-enveloped gastrointestinal virus and demonstrate efficient photodynamic inactivation of murine norovirus, a human norovirus surrogate.ResultsMethylene blue photochemical treatment (100 µM methylene blue, 30 minutes of 12,500-lux red light exposure) of murine norovirus-contaminated masks reduced infectious viral titres by over four orders of magnitude on surgical mask surfaces.Discussion and ConclusionsInactivation of a norovirus, the most difficult to inactivate of the respiratory and gastrointestinal human viruses, can predict the inactivation of any less resistant viral mask contaminant. The protocol developed here thus solidifies the position of methylene blue photochemical decontamination as an important tool in the package of practical pandemic preparedness.
Exposure contrasts of pregnant women during the Household Air Pollution Intervention Network randomized controlled trial
Authors: Johnson Michael , Pillarisetti Ajay , Piedrahita Ricardo , Balakrishnan Kalpana , Peel Jennifer L. , Steenland Kyle , Underhill Lindsay J. , Rosa Ghislaine , Kirby Miles A. , Díaz-Artiga Anaité , McCracken John , Clark Maggie L. , Waller Lance , Chang Howard , Wang Jiantong , Dusabimana Ephrem , Ndagijimana Florien , Sambandam Sankar , Mukhopadhyay Krishnendu , Kearns Katherine , Campbell Devan , Kremer Jacob , Rosenthal Joshua , Checkley William , Clasen Thomas , Naeher Luke 
Published: November 2021

AbstractBackgroundExposure to PM2.5 arising from solid fuel combustion is estimated to result in approximately 2.3 million premature deaths and 90 million lost disability-adjusted life years annually. ‘Clean’ cooking interventions attempting to mitigate this burden have had limited success in reducing exposures to levels that may yield improved health outcomes.ObjectivesThis paper reports exposure reductions achieved by a liquified petroleum gas (LPG) stove and fuel intervention for pregnant mothers in the Household Air Pollution Intervention Network (HAPIN) randomized controlled trial.MethodsThe HAPIN trial included 3,195 households primarily using biomass for cooking in Guatemala, India, Peru, and Rwanda. 24-hour exposures to PM2.5, carbon monoxide (CO), and black carbon (BC) were measured for pregnant women once before randomization into control (n=1605) and LPG arms (n=1590) and twice thereafter (aligned with trimester). Changes in exposure were estimated by directly comparing exposures between intervention and control arms and by using linear mixed-effect models to estimate the impact of the intervention on exposure levels.ResultsMedian exposures of PM2.5, BC, and CO post-randomization in the intervention arm were lower by 66% (70.7 versus 24.0 μg/m3), 71% (9.6 versus 2.8 μg/m3), and 83% (1.2 versus ppm), respectively, compared to the control arm. Exposure reductions were similar across research locations. Post-intervention PM2.5 exposures in the intervention arm were at the lower end of what has been reported for LPG and other clean fuel interventions, with 69% of PM2.5 samples falling below the WHO Annual Interim Target 1 of 35 μg/m3.DiscussionThis study indicates that an LPG intervention with high displacement of traditional cooking can reduce exposures to levels thought to be associated with health benefits. Success in reducing exposures was likely due to strong performance of, and high adherence to the intervention.
Engineering of extracellular vesicles for small molecule-regulated cargo loading and cytoplasmic delivery of bioactive proteins
Authors: Somiya Masaharu , Kuroda Shun’ichi 
Published: November 2021

AbstractCytoplasmic delivery of functional proteins into target cells remains challenging for many biological agents to exert their therapeutic effects. Extracellular vesicles (EVs) are expected to be a promising platform for protein delivery; however, efficient loading of proteins of interest (POIs) into EVs remains elusive. In this study, we utilized small compound-induced heterodimerization between FK506 binding protein (FKBP) and FKBP12-rapamycin-binding (FRB) domain, to sort bioactive proteins into EVs using the FRB-FKBP system. When CD81, a typical EV marker protein, and POI were fused with FKBP and FRB, respectively, rapamycin induced the binding of these proteins through FKBP-FRB interaction and recruited the POIs into EVs. The released EVs, displaying virus-derived membrane fusion protein, delivered the POI cargo into recipient cells and their functionality in the recipient cells was confirmed. Furthermore, we demonstrated that CD81 could be replaced with other EV-enriched proteins, such as CD63 or HIV Gag. Thus, the FRB-FKBP system enables the delivery of functional proteins and paves the way for EV-based protein delivery platforms.
3D reconstruction of cell nuclei in a full Drosophila brain
Authors: Mu Shang , Yu Szi-chieh , Turner Nicholas L. , McKellar Claire E. , Dorkenwald Sven , Collman Forrest , Koolman Selden , Moore Merlin , Morejohn Sarah , Silverman Ben , Willie Kyle , Willie Ryan , Bland Doug , Burke Austin , Ashwood Zoe , Luther Kyle , Castro Manuel , Ogedengbe Oluwaseun , Silversmith William , Wu Jingpeng , Halageri Akhilesh , Macrina Thomas , Kemnitz Nico , Murthy Mala , Seung H. Sebastian 
Published: November 2021

AbstractWe reconstructed all cell nuclei in a 3D image of a Drosophila brain acquired by serial section electron microscopy (EM). The total number of nuclei is approximately 133,000, at least 87% of which belong to neurons. Neuronal nuclei vary from several hundred down to roughly 5 cubic micrometers. Glial nuclei can be even smaller. The optic lobes contain more than two times the number of cells than the central brain. Our nuclear reconstruction serves as a spatial map and index to the cells in a Drosophila brain.
Mouse oocytes develop in cysts with the help of nurse cells
Authors: Niu Wanbao , Spradling Allan C. 
Published: November 2021

SummaryMammalian oocytes develop initially in cysts containing many more germ cells than the primordial oocytes they generate. We identified abundant nurse cells with reduced unique molecular identifiers (UMI)/cell from ovaries aged E14.5 to P1. Low UMI nurse cells are found in cysts and express the same major meiotic genes as pro-oocytes of the same stage, suggesting they are oocyte sisters that are signaled to transfer cytoplasm at different times and only subsequently diverge. Oocyte vs nurse cell selection occurs in cysts with a robust microtubule cytoskeleton, that closely interact with somatic cells and that develop a dense actin cytoskeleton around nurse cell nuclei that are held back from cytoplasmic transfer. Mouse and Drosophila nurse cells undergo programmed cell death by acidification from adjacent somatic pre-granulosa cells that express V-ATPases and cathepsin proteins. Disrupting acidification in cultured mouse ovaries blocked nurse cell turnover. About 200 genes are induced in mouse dictyate oocytes as previously reported, including Tuba1c and Tubb2b, genes that we find contribute to Balbiani body formation. Thus, mouse oocytes are specified within germline cysts and develop with the assistance of nurse cells using highly conserved mechanisms.
A New Bioink for Improved 3D Bioprinting of Bone-Like Constructs
Authors: Marsh Adam C. , Apu Ehsanul Hoque , Bunn Marcus , Contag Christopher H. , Ashammakhi Nureddin , Chatzistavrou Xanthippi 
Published: November 2021

ABSTRACTBone tissue loss can occur due to disease, trauma or following surgery, in each case treatment involving the use of bone grafts or biomaterials is usually required. Recent development of three-dimensional (3D) bioprinting (3DBP) has enabled the printing of customized bone substitutes. Bioinks used for bone 3DBP employ various particulate phases such as ceramic and bioactive glass particles embedded in the bioink creating a composite. When composite bioinks are used for 3DBP based on extrusion, particles are heterogeneously distributed causing damage to cells due to stresses created during flow in the matrix of the composite. Therefore, the objective of this study was to develop cell-friendly osteopromotive bioink mitigating the risk of cell damage due to the flow of particles. Towards this end, we have linked organic and inorganic components, gelatin methacryloyl (GelMA) and Ag-doped bioactive glass (Ag-BaG), to produce a hybrid material, GelMA-Ag-BaG (GAB). The distribution of the elements present in the Ag-BaG in the resulting hybrid GAB structure was examined. Rheological properties of the resulting hydrogel and its printability, as well as the degree of swelling and degradation over time, were also evaluated. GAB was compared to GelMA alone and GelMA-Ag-BaG nanocomposites. Results showed the superiority of the hybrid GAB bioink in terms of homogenous distribution of the elements in the structure, rheological properties, printability, and degradation profiles. Accordingly, this new bioink represents a major advance for bone 3DBP.
AlphaFold Models Illuminate Half of Dark Human Proteins
Authors: Binder Jessica L. , Berendzen Joel , Stevens Amy O. , He Yi , Wang Jian , Dokholyan Nikolay V. , Oprea Tudor I. 
Published: November 2021

ABSTRACTWe investigate the use of confidence scores to predict the accuracy of a given AlphaFold model for drug discovery. Predicted accuracy is improved by eliminating confidence scores below 80, due to effects of disorder. 95% of models corresponding to a set of recent crystal structures are accurate at the fold level. Conformational discordance in the training set has a more significant effect on accuracy than sequence divergence. We propose criteria for models and residues that are possibly useful for virtual screening, by which AlphaFold provides models for half of understudied (dark) human proteins and two-thirds of residues in those models.
WITHDRAWN: Whi5 and Stb1 define redundant pathways through which the G1 cyclin Cln3 promotes cell division
Authors: Honey Sangeet , Futcher Bruce 
Published: November 2021

Withdrawal StatementThe authors have withdrawn their manuscript owing to a defect in the WHI5* STB1* strain used in Fig. 3, Fig. 4, and Table 2. In this strain, for reasons still unknown to us, the GAL-CLN3 gene is expressed moderately well even in the absence of galactose, and is only slightly induced upon the addition of galactose. Since CLN3 is not being substantially induced in the experiments of Fig. 3 and Fig. 4 in this WHI5* STB1* strain, no conclusion can be drawn as to whether there is or is not signaling from CLN3 to Start in a WHI5* STB1* mutant. Results in the manuscript not involving this strain appear to be correct. If you have any questions, please contact the corresponding author.
Phylogeny of theFormicoxenusgenus-group (Hymenoptera: Formicidae) reveals isolated lineages ofLeptothorax acervorumin the Iberian Peninsula predating the Last Glacial Maximum
Authors: Ojeda Dario I. , John Max , Hammond Robert L. , Savolainen Riitta , Vepsäläinen Kari , Kvamme Torstein 
Published: November 2021

AbstractTheFormicoxenusgenus-group comprises six genera within the tribe Crematogastrini. The group is well known for repeated evolution of social parasitism among closely related taxa and cold-adapted species with large distribution ranges in the Nearctic and Palearctic regions. Previous analyses based on nuclear markers (ultraconserved elements, UCEs) and mitochondrial genes suggest close relationship betweenFormicoxenusMayr, 1855,LeptothoraxMayr, 1855 andHarpagoxenusForel, 1893. However, scant sampling has limited phylogenetic assessment of these genera. Also, previous phylogeographic analyses ofL. acervorum(Fabricius, 1793) have been limited to its West-Palearctic range of distribution, which has provided a narrow view on recolonization, population structure and existing refugia of the species. Here, we inferred the phylogenenetic history of genera within theFormicoxenusgenus-group and reconstructed the phylogeography ofL. acervorumwith more extensive sampling. We employed four datasets consisting of whole genomes and sequences of the COI. The topologies of previous nuclear and our inferences based on mitochondrial genomes were overall congruent. Further,Formicoxenusmay not be monophyletic. We found several monophyletic lineages that do not correspond to the current species described withinLeptothorax, especially in the Nearctic region. We identified a monophyleticL. acervorumlineage that comprises both Nearctic and Palearctic locations. The most recent expansion withinL. acervorumprobably occurred within the last 0.5 Ma with isolated populations predating the Last Glacial Maximum (LGM), which are localized in at least two refugial areas (Pyrenean and Northern plateau) in the Iberian Peninsula. The patterns recovered suggest a shared glacial refugium in the Iberian Peninsula with cold-adapted trees that currently share high-altitude environments in this region.
Syotti: Scalable Bait Design for DNA Enrichment
Authors: Alanko Jarno , Slizovskiy Ilya , Lokshtanov Daniel , Gagie Travis , Noyes Noelle , Boucher Christina 
Published: November 2021

AbstractBait-enriched sequencing is a relatively new sequencing protocol that is becoming increasingly ubiquitous as it has been shown to successfully amplify regions of interest in metagenomic samples. In this method, a set of synthetic probes (“baits”) are designed, manufactured, and applied to fragmented metagenomic DNA. The probes bind to the fragmented DNA and any unbound DNA is rinsed away, leaving the bound fragments to be amplified for sequencing. This effectively enriches the DNA for which the probes were designed. Most recently, Metsky et al. (Nature Biotech 2019) demonstrated that bait-enrichment is capable of detecting a large number of human viral pathogens within metagenomic samples. In this work, we formalize the problem of designing baits by defining the Minimum Bait Cover problem, which aims to find the smallest possible set of bait sequences that cover every position of a set of reference sequences under an approximate matching model. We show that the problem is NP-hard, and that it remains NP-hard under very restrictive assumptions. This indicates that no polynomial-time exact algorithm exists for the problem, and that the problem is intractable even for small and deceptively simple inputs. In light of this, we design an efficient heuristic that takes advantage of succinct data structures. We refer to our method as syotti. The running time of syotti shows linear scaling in practice, running at least an order of magnitude faster than state-of-the-art methods, including the recent method of Metsky et al. At the same time, our method produces bait sets that are smaller than the ones produced by the competing methods, while also leaving fewer positions uncovered. Lastly, we show that syotti requires only 25 minutes to design baits for a dataset comprised of 3 billion nucleotides from 1000 related bacterial substrains, whereas the method of Metsky et al. shows clearly super-linear running time and fails to process even a subset of 8% of the data in 24 hours. Our implementation is publicly available at https://github.com/jnalanko/syotti.