bluuebunny/crossref_metadata_2025_split huggingface dataset:
Human Parainfluenza 2 & 4: clinical and genetic epidemiology in the UK, 2013-2017, reveals distinct disease features and co-circulating genomic subtypes
Authors: Chellapuri Akhil , Smitheman Matthew , Chappell Joseph G. , Clark Gemma , Howson-Wells Hannah C. , Berry Louise , Ball Jonathan K. , Irving William L. , Tarr Alexander W. , McClure C. Patrick 
Published: January 2022

AbstractHuman Parainfluenza viruses (HPIV) are constituted by four members of the genetically distinct genera of Respirovirus (type 1 and 3) and Orthorubulavirus (type 2 and 4), causing significant upper and lower respiratory tract infections in both children and adults worldwide. However, despite frequent molecular diagnosis, they are frequently considered collectively or with HPIV4 overlooked entirely. We therefore investigated clinical and viral epidemiological distinctions of the relatively less prevalent Orthorubulaviruses HPIV2 & 4 at a regional UK hospital across four winter epidemic seasons. HPIV2 & 4 infection was observed across all age groups, but predominantly in children under 9 and adults over 40, with almost twice as many HPIV4 as HPIV2 cases. Fever, abnormal haematology, elevated C-reactive protein and hospital admission were more frequently seen in HPIV2 than HPIV4 infection. Each of the four seasonal peaks of either HPIV2, HPIV4 or both, closely matched that of RSV, occurring in November and December and preceding that of Influenza A. A subset of viruses were partially sequenced, indicating co-circulation of multiple subtypes of both HPIV2 & 4, but with little variation between each epidemic season or from limited global reference sequences.
Analysis of clinical trial registry entry histories using the novel R package cthist
Authors: Carlisle Benjamin Gregory 
Published: January 2022

AbstractHistorical clinical trial registry data can only be retrieved by manually accessing individual clinical trials through registry websites. This limits the feasibility, accuracy and reproducibility of certain kinds of research on clinical trial activity and presents challenges to the transparency of the enterprise of human research. This paper presentscthist, a novel, free and open sourceRpackage that enables mass downloading of clinical trial registry entry histories and returns structured data for analysis.Documentation of the implementation of the packagecthistis provided, as well as 3 brief case studies with example code.
Immunogenicity of a third dose of BNT162b2 to ancestral SARS-CoV-2 & Omicron variant in adults who received two doses of inactivated vaccine
Authors: Leung Nancy H. L. , Cheng Samuel M. S. , Martín-Sánchez Mario , Au Niki Y. M. , Ng Yvonne Y. , Luk Leo L. H. , Chan Karl C. K. , Li John K. C. , Leung Yonna W. Y. , Tsang Leo C. H. , Chaothai Sara , Kwan Kelvin K. H. , Ip Dennis K. M. , Poon Leo L. M. , Leung Gabriel M. , Malik Peiris J. S. , Cowling Benjamin J. 
Published: January 2022

ABSTRACTBackgroundLimited data exist on antibody responses to mixed vaccination strategies involving inactivated COVID-19 vaccines, particularly in the context of emerging variants.MethodsWe conducted an open label trial of a third vaccine dose of an mRNA vaccine (BNT162b2, Fosun Pharma/BioNTech) in adults aged ≥30 years who had previously received two doses of inactivated COVID-19 vaccine. We collected blood samples before administering the third dose and 28 days later, and tested for antibodies to the ancestral virus using a binding assay (ELISA), a surrogate virus neutralization test (sVNT) and a live virus plaque reduction neutralization test (PRNT). We also tested for antibodies against the Omicron variant using live-virus PRNT.ResultsIn 315 participants, a third dose of BNT162b2 substantially increased antibody titers on each assay. Mean ELISA levels increased from an optical density (OD) of 0.3 to 2.2 (p<0. 001), and mean sVNT levels increased from an inhibition of 17% to 96% (p<0.001). In a random subset of 20 participants, the geometric mean PRNT50 titers rose very substantially by at least 24 fold from Day 0 to Day 28 against the ancestral virus (p<0.001) and rose by at least 11 fold against the Omicron variant (p<0.001). In daily monitoring, post-vaccination reactions subsided within 7 days for over 99% of participants.ConclusionsA third dose of COVID-19 vaccination with an mRNA vaccine substantially improved antibody levels against the ancestral virus and the Omicron variant with well-tolerated safety profile, in adults who had received two doses of inactivated vaccine 6 months earlier.SummaryIn this open label trial of Chinese adults aged ≥30 years who received two doses of inactivated COVID-19 vaccine 6 months earlier, third-dose mRNA vaccine substantially improved antibody levels against the ancestral virus and Omicron variant with well-tolerated safety profile.
Tonic GluD1 channel current is independent of G protein activity in the dorsal raphe nucleus
Authors: Copeland Daniel S. , Gantz Stephanie C. 
Published: January 2022

AbstractPreviously, using electrophysiological recordings from adult male and female mouse brain slices containing the dorsal raphe nucleus, we showed that GluD1R channels carry ionic current and are modulated via activation of Gαq-coupled α1-adrenergic receptors (α1-AR) in a GTP-dependent manner (Gantz et al., 2020). GluD1R channels also carry a tonic cation current, generally ~−20 pA at subthreshold membrane potentials (Gantz et al., 2020). The origin of tonic GluD1R channel current is unknown. Here, using the same preparation, we show there is no role of on-going G protein-coupled receptor activity in generating or sustaining tonic GluD1R channel current. Neither augmentation nor disruption of G protein activity had an effect on tonic GluD1R current. These results reveal that tonic GluD1R current arises from a mechanism separate from on-going activity of G protein-coupled receptors. Under current clamp, block of GluD1R channels hyperpolarized the membrane by ~10 mV at subthreshold potentials leading to reduced excitability. Thus, GluD1R channels carry a G protein-independent tonic current that contributes to subthreshold drive of action potential firing in the dorsal raphe nucleus.
Insights into the Human Gut Virome by Sampling a Population from the Indian Subcontinent
Authors: Bhardwaj Kanchan , Garg Anjali , Pandey Abhay Deep , Sharma Himani , Kumar Manish , Vrati Sudhanshu 
Published: January 2022

AbstractGut virome plays an important role in human physiology but remains poorly understood. This study reports an investigation of the human gut DNA-virome of a previously unexplored ethnic population through metagenomics of faecal samples collected from individuals residing in Northern India. Analysis shows that, similar to the populations investigated earlier, majority of the identified virome belongs to bacteriophages and a smaller fraction (< 20%) consists of viruses that infect animals, archaea, protists, multiple domains or plants. However, crAss-like phages, in this population, are dominated by the genera VII, VIII and VI. Interestingly, it also reveals the presence of a virus family, Sphaerolipoviridae, which has not been detected in the human gut earlier. Viral families, Siphoviridae, Myoviridae, Podoviridae, Microviridae, Herelleviridae and Phycodnaviridae are detected in all of the analyzed individuals, which supports the existence of a core virome. Lysogeny-associated genes were found in less than 10% of the assembled genomes and a negative correlation was observed in the richness of bacterial and free-viral species, suggesting that the dominant lifestyle of gut phage is not lysogenic. This is in contrast to some of the earlier studies. Further, several hundred high-quality viral genomes were recovered. Detailed characterization of these genomes would be useful for understanding the biology of these viruses and their significance in human physiology.ImportanceViruses are important constituents of the human gut microbiome but it remains poorly understood. The Indian subcontinent is a unique biogeographic region and the Indian population is known to harbour a distinct bacterial microbiome. However, the gut virome in this population has not been investigated earlier. Therefore, in this study, we investigated fecal samples of 12 healthy individuals to analyze their gut virome, through metagenomics.
Improving the Identification Coverage of Protein Interactome by Enhancing the Click Chemistry-based Cross-linking Enrichment Efficiency
Authors: Zhao Lili , Zhao Qun , An Yuxin , Gao Hang , Zhang Xiaodan , Liang Zhen , Zhang Lihua , Zhang Yukui 
Published: January 2022

ABSTRACTChemical cross-linking coupled with mass spectrometry has emerged as a powerful strategy which enables global profiling of protein interactome with direct interaction interfaces in complex biological systems. The alkyne-tagged enrichable cross-linkers are preferred to improve the coverage of low-abundance cross-linked peptides, combined with click chemistry for biotin conjugation to allow the cross-linked peptides enrichment. However, a systematic evaluation on the efficiency of click approaches (protein-based or peptide-based) and diverse cleavable click chemistry ligands (acid, reduction, photo) for cross-linked peptides enrichment and release is lacking. Herein, together with in vivo chemical cross-linking by alkyne-tagged cross-linker, we explored the click chemistry-based enrichment approaches on protein and peptide level with three cleavable click chemistry ligands, respectively. By comparison, the approach of protein-based click chemistry conjugation with acid-cleavable tag was demonstrated to permit the most cross-linked peptides identification. The advancement of this strategy enhanced the proteome-wide cross-linking analysis, permitting a detection of 5,017 protein-protein interactions among 1,909 proteins across all subcellular compartments with wide abundance distribution in cell. Therefore, all these results demonstrated a guideline value of our work for efficient cross-linked peptides enrichment, thus facilitated the in-depth profiling of protein interactome for functional analysis.GRAPHICAL ABSTRACT
Global analysis of biosynthetic gene clusters reveals conserved and unique natural products in entomopathogenic nematode-symbiotic bacteria
Authors: Shi Yi-Ming , Hirschmann Merle , Shi Yan-Ni , Ahmed Shabbir , Abebew Desalegne , Tobias Nicholas J. , Grün Peter , Crames Jan J. , Pöschel Laura , Kuttenlochner Wolfgang , Richter Christian , Herrmann Jennifer , Müller Rolf , Thanwisai Aunchalee , Pidot Sacha J. , Stinear Timothy P. , Groll Michael , Kim Yonggyun , Bode Helge B. 
Published: January 2022

ABSTRACTMicroorganisms contribute to the biology and physiology of eukaryotic hosts and affect other organisms through natural products. Xenorhabdus and Photorhabdus (XP) living in mutualistic symbiosis with entomopathogenic nematodes produce a myriad of natural products to mediate bacteria–nematode–insect interactions. However, a lack of systematic analysis of the biosynthetic gene clusters (BGCs) has limited the understanding of how natural products justify the bacterial niche specificity. Here we combine pangenome and sequence similarity networks to analyze BGCs from 45 XP species. The identified 1,000 BGCs belong to 176 families, over half of which are unknown. Eleven BGCs represent the most conserved families. We then homologously express the ubiquitous and unique BGCs and identify compounds featuring unusual architectures. The bioactivity evaluation demonstrates that the prevalent compounds are eukaryotic proteasome inhibitors, insect virulence factors, or insect immune suppressors. These findings account for the functional basis of bacterial natural products in this tripartite relationship.
Promoting Fc-Fc interactions between anti-capsular antibodies provides strong immune protection against Streptococcus pneumoniae
Authors: Aguinagalde Leire , den Boer Maurits A. , Castenmiller Suzanne M. , Zwarthoff Seline A. , Gosselaar-de Haas Carla J.C , Aerts Piet C. , Beurskens Frank J. , Schuurman Janine , Heck Albert J.R. , van Kessel Kok P.M. , Rooijakkers Suzan H.M. 
Published: January 2022

AbstractStreptococcus pneumoniae is the leading cause of community-acquired pneumonia and an important cause of childhood mortality. Despite the introduction of successful vaccines, the global spread of both non-vaccine serotypes and antibiotic-resistant strains reinforce the development of alternative therapies against this pathogen. One possible route is the development of monoclonal antibodies (mAbs) that induce killing of bacteria via the immune system. Here we investigate whether mAbs can be used to induce killing of pneumococcal serotypes for which the current vaccines show unsuccessful protection. Our study demonstrates that when human mAbs against pneumococcal capsule polysaccharides (CPS) have a poor capacity to induce complement activation, a critical process for immune protection against pneumococci, their activity can be strongly improved by hexamerization-enhancing mutations. Our data indicate that anti-capsular antibodies may have a low capacity to form higher-order oligomers (IgG hexamers) that are needed to recruit complement component C1. Indeed, specific point mutations in the IgG-Fc domain that strengthen hexamerization strongly enhance C1 recruitment and downstream complement activation on encapsulated pneumococci. Specifically, hexamerization-enhancing mutations E430G or E345K in CPS6-IgG strongly potentiate complement activation on S. pneumoniae strains that express capsular serotype 6 (CPS6), and the highly invasive serotype 19A strain. Furthermore, these mutations improve complement activation via mAbs recognizing CPS3 and CPS8 strains. Importantly, hexamer-enhancing mutations enable mAbs to induce strong phagocytosis and intracellular killing by human neutrophils. Finally, passive immunization with CPS6-IgG1-E345K protected mice from developing severe pneumonia. Altogether, this work provides an important proof-of-concept for future optimization of antibody therapies against encapsulated bacteria.
Anin vitroneurogenetics platform for precision disease modeling in the mouse
Authors: Cortes Daniel E. , Escudero Mélanie , Korgan Austin C. , Edwards Alyssa , Aydin Selcan C. , Munger Steven C. , Charland Kevin , Zhang Zhong-Wei , O’Connell Kristen M.S. , Reinholdt Laura G. , Pera Martin F. 
Published: January 2022

AbstractThe power and scope of disease modeling can be markedly enhanced through the incorporation of broad genetic diversity. In the the mouse, the introduction of pathogenic mutations into a single inbred strain sometimes fails to mimic human disease. We describe a cross-species precision disease modeling platform that exploits mouse genetic diversity to bridge cell-based modeling with whole organism analysis. We developed a universal protocol that permitted robust and reproducible neural differentiation of genetically diverse human and mouse pluripotent stem cell lines, then carried out a proof of concept study of the neurodevelopmental geneDYRK1A. The resultsin vitroreliably predicted the effects of genetic background onDYRK1Aloss of function phenotypes and identified optimal mouse strains forin vivodisease modeling. Transcriptomic comparison of responsive and unresponsive strains identified novel molecular pathways conferring sensitivity or resilience toDYRK1Aloss, and highlighted differential mRNA isoform usage as an important genetic determinant of response This cross-species strategy will be an powerful tool in the functional analysis of candidate disease variants identified through human genetic studies.Teaser: Genetically diverse mouse embryonic stem cells provide a rapid approach to precision modeling of human disease.
Immune response to COVID‐19 vaccination is attenuated by poor disease control and antimyeloma therapy with vaccine driven divergent T‐cell response
Authors: Ramasamy Karthik , Sadler Ross , Jeans Sally , Weeden Paul , Varghese Sherin , Turner Alison , Larham Jemma , Gray Nathanael , Carty Oluremi , Barrett Joe , Bowcock Stella , Oppermann Udo , Cook Gordon , Kyriakou Chara , Drayson Mark , Basu Supratik , Moore Sally , McDonald Sarah , Gooding Sarah , Javaid Muhammad K. 
Published: January 2022

SummaryMyeloma patients frequently respond poorly to bacterial and viral vaccination. A few studies have reported poor humoral immune responses in myeloma patients to COVID‐19 vaccination. Using a prospective study of myeloma patients in the UK Rudy study cohort, we assessed humoral and interferon gamma release assay (IGRA) cellular immune responses to COVID‐19 vaccination post second COVID‐19 vaccine administration. We report data from 214 adults with myeloma (n = 204) or smouldering myeloma (n = 10) who provided blood samples at least three weeks after second vaccine dose. Positive Anti‐spike antibody levels (> 50 iu/ml) were detected in 189/203 (92.7%), positive IGRA responses were seen in 97/158 (61.4%) myeloma patients. Only 10/158 (6.3%) patients were identified to have both a negative IGRA and negative anti‐spike protein antibody response. In all, 95/158 (60.1%) patients produced positive results for both anti‐spike protein serology and IGRA. After adjusting for disease severity and myeloma therapy, poor humoral immune response was predicted by male gender. Predictors of poor IGRA included anti‐CD38/anti‐BCMA (B‐cell maturation antigen) therapy and Pfizer‐BioNTech vaccination. Further work is required to understand the clinical significance of divergent cellular response to vaccination.
The dominant p.Thr274Pro mutation in the von Willebrand factor propeptide causes the von Willebrand disease type 1 phenotype in two unrelated patients
Authors: Pagliari Maria Teresa , Baronciani Luciano , Cordiglieri Chiara , Colpani Paola , Cozzi Giovanna , Siboni Simona M. , Peyvandi Flora 
Published: January 2022

AbstractBackgroundvon Willebrand factor propeptide (VWFpp) plays an important role in VWF multimerization and storage. VWFpp mutations have been previously associated with types 1, 3 and 2A/IIC von Willebrand disease (VWD).AimsTo characterize the novel p.Thr274Pro variant identified in two unrelated type 1 VWD patients.MethodsPhenotype tests were performed to evaluate patients’ plasma and platelets following the current ISTH‐SSC guidelines. Molecular analysis was performed using next‐generation sequencing. The pcDNA3.1‐VWF‐WT and mutant pcDNA3.1‐VWF‐Thr274Pro expression vectors were transiently transfected into HEK293 cells to evaluate recombinant (r)VWF constitutive and regulated secretion. For the latter, the transfected cells were stimulated with phorbol‐12‐myristate‐13‐acetate. Immunofluorescence staining was performed to assess the localization of WT‐rVWF and Thr274Pro‐rVWF in endoplasmic reticulum, lysosomes, cis‐/trans‐Golgi and pseudo‐Weibel Palade bodies.ResultsBiochemical characterization of patients’ plasma samples indicated a type 1 VWD diagnosis. Both patients were heterozygous for the p.Thr274Pro variant. Hybrid Thr274Pro/WT‐rVWF showed a secretion reduction of 36±4% according to patients’ plasma VWF:Ag levels, whereas Thr274Pro‐rVWF secretion was strongly impaired (21±2%). The amount of rVWF in cell lysates was nearly normal for both Thr274P (62±17%) and Thr274Pro/WT‐rVWF (72±23%). The regulated secretion was impaired for Thr274Pro/WT‐rVWF, whereas Thr274Pro‐rVWF was not released at all. Immunofluorescence staining revealed no particular differences between WT and Thr274Pro‐rVWF, although Thr274Pro‐rVWF showed less pseudo‐Weibel Palade bodies with a rounder shape than WT‐rVWF.ConclusionsThe novel p.Thr274Pro mutation has a dominant effect and it is responsible of patients’ type 1 VWD phenotype through a combined mechanism of reduced synthesis, impaired secretion and multimerization.
Role of speaker gender in toddler lexical processing
Authors: Bacon Desia , Saffran Jenny 
Published: January 2022

AbstractAdults and children utilize social category information during incremental language processing. Gender is a particularly salient social category that is often marked both in speakers' voices and the visual world. However, it is unknown whether toddlers exploit gender cues to draw connections between language and other aspects of their environment. The current study investigates whether toddlers use gender cues available in voices and objects during real‐time language processing. 22‐ to 24‐month‐old toddlers (N = 38) were tested in a looking‐while‐listening paradigm. On each trial, toddlers viewed two highly familiar objects designed to be prototypically masculine and feminine (via color and patterns) and heard either a male or female speaker label the target object. Lexical processing was facilitated when the vocal gender matched the gender of the target object. This work demonstrates that toddlers consider both object‐feature information and inferred speaker gender (based on speaker' voice) during online language processing.
The structure of tropical bat–plant interaction networks during an extreme El Niño‐Southern Oscillation event
Authors: Oliveira Hernani F. M. , Pinheiro Rafael Barros Pereira , Varassin Isabela Galarda , Rodríguez‐Herrera Bernal , Kuzmina Maria , Rossiter Stephen J. , Clare Elizabeth L. 
Published: January 2022

AbstractInteraction network structure reflects the ecological mechanisms acting within biological communities, which are affected by environmental conditions. In tropical forests, higher precipitation usually increases fruit production, which may lead frugivores to increase specialization, resulting in more modular and less nested animal–plant networks. In these ecosystems, El Niño is a major driver of precipitation, but we still lack knowledge of how species interactions change under this influence. To understand bat–plant network structure during an extreme El Niño‐Southern Oscillation event, we determined the links between plantivorous bat species and the plants they consume by DNA barcoding seeds and pulp in bat faeces. These interactions were recorded in the dry forest and rainforest of Costa Rica, during the dry and the wet seasons of an extreme El Niño year. From these we constructed seasonal and whole‐year bat–plant networks and analysed their structures and dissimilarities. In general, networks had low nestedness, had high modularity, and were dominated by one large compartment which included most species and interactions. Contrary to our expectations, networks were less nested and more modular in drier conditions, both in the comparison between forest types and between seasons. We suggest that increased competition, when resources are scarce during drier seasons and habitats, lead to higher resource partitioning among bats and thus higher modularity. Moreover, we have found similar network structures between dry and rainforests during El Niño and non‐El Niño years. Finally, most interaction dissimilarity among networks occurred due to interaction rewiring among species, potentially driven by seasonal changes in resource availability.
Brexit and multilingualism in the European Union
Authors: Ginsburgh Victor , Moreno‐Ternero Juan D. 
Published: January 2022

AbstractThe European Union (EU) spends more than one billion euros per year ensuring translation and interpretation of 24 languages to preserve multilingualism. We examine how this budget should be fairly allocated, taking into account linguistic and economic realities of each member country. Our analysis tries to estimate the value of keeping English as a procedural language (in fact, almost a lingua franca) in the post‐Brexit EU, where, today, just about one percent of the population speaks it as native language.