bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vaccines against Covid-19, venous thromboembolism, and thrombocytopenia. A population-based retrospective cohort study
Authors: Laporte Joan-Ramon , Coma Ermengol , Fina Francesc , García-Eroles Luís , Vidal Xavier , Medina Manuel 
Published: July 2021

AbstractBackgroundWe aimed at estimating the risk of venous thromboembolism (VTE), thrombocytopenia (TCP), and VTE associated with TCP, by age and sex, after the first dose of both adenovirus vector-based and mRNA-based Covid-19 vaccines, and after the second dose of m-RNA vaccines.MethodsIn this population-based retrospective cohort study in the national health care databases in Catalonia, we examined three groups: 1 662 719 people 10 years of age and over vaccinated with the first dose of a Covid-19 vaccine, 622 778 with the second dose, and 190 616 diagnosed of Covid-19 in the same period (between1 January 2021 and 18 April 2021). The rates of various clinical presentations of VTE and TCP were compared with those in the reference population (7 013 040 people served by the health care system in 2019). The two primary outcomes were the observed 21 day rate of a composite variable of cerebral venous sinus thrombosis, mesenteric thrombosis, portal vein thrombosis, or any venous thromboembolism (VTE) associated with thrombocytopenia (TCP), and the rate of any VTE associated with TCP (VTE+TCP). Analyses were standardised by age and sex.ResultsThe 21 day rate per 100 000 of the primary composite variable was 2.15 in the reference population, 5.65 following the first vaccine dose (standardised difference, 2.53 (95% CI [CI], 1.04 to 4.00), and 7.23 following the second dose (standardised difference, 4.07 (95% CI, 1.43 to 6.70). The event rates of VTE+TCP and of all the secondary variables showed the same patterns.Excess event rates were higher in men than in women, and they were not especially increased in any particular age group. All Covid-19 vaccines were associated with increased rates of the outcome variables.Excess event rates were much higher in the Covid-19 cohort (35.60 per 100 000 (95% CI, 26.15 to 45.06).ConclusionsWe observed increases of rates of venous thromboembolism in usual and unusual anatomical sites and of thrombocytopenia in recipients of both adenovirus vector and mRNA vaccines against Covid-19. Excess rates were higher in men than in women and they were not particularly elevated in any specific age group.
Bayesian Inference of Joint Coalescence Times for Sampled Sequences
Authors: Simon Helmut , Huttley Gavin 
Published: July 2021

ABSTRACTThe site frequency spectrum (SFS) is a commonly used statistic to summarize genetic variation in a sample of genomic sequences from a population. Such a genomic sample is associated with an imputed genealogical history with attributes such as branch lengths, coalescence times and the time to the most recent common ancestor (TMRCA) as well as topological and combinatorial properties. We present a Bayesian model for sampling from the joint posterior distribution of coalescence times conditional on the SFS associated with a sample of sequences in the absence of selection. In this model, the combinatorial properties of a genealogy, which is represented as a coalescent tree, are expressed as matrices. This facilitates the calculation of likelihoods and the effective sampling of the entire space of tree structures according to the Equal Rates Markov (or Yule-type) measure. Unlike previous methods, assumptions as to the type of stochastic process that generated the genealogical tree are not required. Novel approaches to defining both uninformative and informative prior distributions are employed. The uncertainty in inference due to the stochastic nature of mutation and the unknown tree structure is expressed by the shape of the posterior distributions. The method is implemented using the general purpose Markov Chain Monte Carlo software PyMC3. From the sampled posterior distribution of coalescence times, one can also infer related quantities such as the number of ancestors of a sample at a given time in the past (ancestral distribution) and the probability of specific relationships between branch lengths (for example, that the most recent branch is longer than all the others). The performance of the method is evaluated against simulated data and is also applied to historic mitochondrial data from the Nuu-Chah-Nulth people of North America. The method can be used to obtain estimates of the TMRCA of the sample. The relationship of these estimates to those given by “Thomson’s estimator” is explored.
ETAS®50 Attenuates SARS-CoV-2 Spike Protein-Induced IL-6 and IL-1β Production by Suppressing p44/42 MAPK and Akt Phosphorylation in Murine Primary Macrophages
Authors: Shirato Ken , Takanari Jun , Kizaki Takako 
Published: July 2021

AbstractExcessive host inflammation following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with severity and mortality in coronavirus disease 2019 (COVID-19). We recently reported that the SARS-CoV-2 spike protein S1 subunit (S1) induces pro-inflammatory responses by activating toll-like receptor 4 (TLR4) signaling in macrophages. ETAS®50, a standardized extract ofAsparagus officinalisstem, is a unique functional food that elicits anti-photoaging effects by suppressing pro-inflammatory signaling in hydrogen peroxide- and ultraviolet B-exposed skin fibroblasts. To elucidate its potential in preventing excessive inflammation in COVID-19, we examined the effects of ETAS®50 on pro-inflammatory responses in S1-stimulated murine peritoneal exudate macrophages. Co-treatment of the cells with ETAS®50 significantly attenuated S1-induced secretion of interleukin (IL)-6 in a concentration-dependent manner without reducing cell viability. ETAS®50 also markedly suppressed the S1-induced transcription of IL-6 and IL-1β. However, among the TLR4 signaling proteins, ETAS®50 did not affect the degradation of inhibitor κBα, nuclear translocation of nuclear factor-κB p65 subunit, and phosphorylation of c-Jun N-terminal kinase p54 subunit after S1 exposure. In contrast, ETAS®50 significantly suppressed S1-induced phosphorylation of p44/42 mitogen-activated protein kinase (MAPK) and Akt. Attenuation of S1-induced transcription of IL-6 and IL-1β by the MAPK kinase inhibitor U0126 was greater than that by the Akt inhibitor perifosine, and the effects were potentiated by simultaneous treatment with both inhibitors. These results suggest that ETAS®50 attenuates S1-induced IL-6 and IL-1β production by suppressing p44/42 MAPK and Akt signaling in macrophages. Therefore, ETAS®50 may be beneficial in regulating excessive inflammation in patients with COVID-19.
Plasmid supercoiling decreases during the dark phase in cyanobacteria: a clarification of the interpretation of chloroquine-agarose gels
Authors: Rüdiger Salima , Rediger Anne , Kölsch Adrian , Dienst Dennis , Axmann Ilka M. , Machné Rainer 
Published: July 2021

AbstractIn cyanobacteria DNA supercoiling varies over the diurnal light/dark cycle and is integrated with the circadian transcription program and (Woelfle et al. [2007], Vijayan et al. [2009], PNAS). Specifically, Woelfle et al. have reported that DNA supercoiling of an endogenous plasmid became progressively higher during prolonged dark phases in Synechococcus elongatus PCC 7942. This is counterintuitive, since higher levels of negative DNA supercoiling are commonly associated with exponential growth and high metabolic flux. Vijayan et al. then have reverted the interpretation of plasmid mobility on agarose gels supplemented with chloroquine diphosphate (CQ), but not further discussed the differences. Here, we set out to clarify this open issue in cyanobacterial DNA supercoiling dynamics. We first re-capitulate Keller’s band counting method (1975, PNAS) using CQ instead of ethidium bromide as the intercalating agent. A 500x–1000x higher CQ concentration is required in the DNA relaxation reaction (topoisomerase I) than in the agarose gel buffer to quench all negative supercoiling of pUC19 extracted from Escherichia coli. This is likely due to the dependence of both, the DNA binding affinity of CQ and the induced DNA unwinding angle, on the ionic strength of the buffer. Lower levels of CQ were required to fully relax in vivo pUC19 supercoiling than were used by Woelfle et al. Next, we analyzed the in vivo supercoiling of endogenous plasmids of Synechocystis sp. PCC 6803, at two different CQ concentrations. These experiments indicate that negative supercoiling of plasmids does not increase but decreases in the dark phase, and progressively decreases further in prolonged darkness.
The structural role of bacterial eDNA in the formation of biofilm streamers
Authors: Secchi Eleonora , Savorana Giovanni , Vitale Alessandra , Eberl Leo , Stocker Roman , Rusconi Roberto 
Published: July 2021

AbstractAcross diverse habitats, bacteria are mainly found as biofilms, surface-attached communities embedded in a self-secreted matrix of extracellular polymeric substances (EPS), which enhances bacterial resistance to antimicrobial treatment and mechanical stresses. In the presence of flow and geometric constraints such as corners or constrictions, biofilms take the form of long, suspended threads known as streamers, which bear important consequences in industrial and clinical settings by causing clogging and fouling. The formation of streamers is thought to be driven by the viscoelastic nature of the biofilm matrix. Yet, little is known about the structural composition of streamers and how it affects their mechanical properties. Here, using a microfluidic platform that allows growing and precisely examining biofilm streamers, we show that extracellular DNA (eDNA) constitutes the backbone and is essential for the mechanical stability ofPseudomonas aeruginosa’ s streamers. This finding is supported by the observations that DNA-degrading enzymes prevent the formation of streamers and clear already formed ones, and that the antibiotic ciprofloxacin promotes their formation by increasing the release of eDNA. Furthermore, using mutants for production of the exopolysaccharide Pel, an important component ofP. aeruginosa’ s EPS, we reveal a new, although indirect role of Pel, in tuning the mechanical properties of the streamers. Taken together, these results highlight the importance of eDNA and of its interplay with Pel in determining the mechanical properties ofP. aeruginosastreamers, and suggest that targeting the composition of streamers can be an effective approach to control the formation of these biofilm structures.
A bacterial dynamin-like protein confers a novel phage resistance strategy on the population level in Bacillus subtilis
Authors: Guo Lijun , Sattler Laura , Graumann Peter , Bramkamp Marc 
Published: July 2021

SummaryBacillus subtilis DynA is a member of the dynamin superfamily, involved in membrane remodeling processes. DynA was shown to catalyze full membrane fusion and it plays a role in membrane surveillance against antibiotics. We show here that DynA also provides a novel resistance mechanism against phage infection. Cells lacking DynA are efficiently lysed after phage infection and virus replication. DynA does not prevent phage infection and replication in individual cells, but significantly delays host cell lysis, thereby slowing down the release of phage progeny from the host cells. During the process, DynA forms large, almost immobile clusters on the cell membrane that seem to support membrane integrity. Single molecule tracking revealed a shift of freely diffusive molecules within the cytosol towards extended, confined motion at the cell membrane following phage induction. Thus, the bacterial dynamins are the first anti-phage system reported to delay host cell lysis and the last line of defense of a multilayered antiviral defense. DynA is therefore providing protective effects on the population, but not on single cell level.
FH loss in RPE cells causes retinal degeneration in a human RPE-porcine retinal explant co-culture model
Authors: Armento Angela , Murali Aparna , Marzi Julia , Arrango-Gonzalez Blanca , Kilger Ellen , Clark Simon J , Schenke-Layland Katja , Ramlogan-Steel Charmaine A , Steel Jason C , Ueffing Marius 
Published: July 2021

AbstractAge-related Macular degeneration (AMD) is a degenerative disease of the macula affecting the elderly population. Treatment options are limited, partly due to the lack of understanding of AMD pathology and the sparse availability of research models, that replicate the complexity of the human macula and the intricate interplay of the genetic, aging and life-style risk factors contributing to AMD. One of the main genetic risks associated with AMD is located on Complement Factor H (CFH) gene, leading to an amino acid substitution in the FH protein (Y402H). However, the mechanism of how this FH variant promotes the onset of AMD remains unclear. Previously, we have shown that FH deprivation in RPE cells, via CFH silencing, leads to increased inflammation, metabolic impairment and vulnerability towards oxidative stress. In this study, we established a novel co-culture model comprised of CFH silenced RPE cells and porcine retinal explants derived from the visual streak of the porcine eyes, closely resembling the human macula. We show that retinae exposed to FH-deprived RPE cells show signs of retinal degeneration, with rod cells being the first cells to undergo degeneration. Moreover, via Raman analyses, we observe that the main changes involve the mitochondria and lipid composition of the co-cultured retinae upon FH loss. Interestingly, the detrimental effects of FH loss in RPE cells on the neuroretina were independent of glial cell activation and external complement sources. Moreover, we show that the co-culture model is also suitable for human retinal explants, and we observed a similar trend when RPE cells deprived of FH were co-cultured with human retinal explants from a single donor eye. Our findings highlight the importance of RPE derived FH for retinal homeostasis and provide a valuable model for AMD research.
N-glycosylation profiles of the SARS-CoV-2 spike D614G mutant and its ancestral protein characterized by advanced mass spectrometry
Authors: Wang Dongxia , Zhou Bin , Keppel Theodore , Solano Maria , Baudys Jakub , Goldstein Jason , Finn M.G. , Fan Xiaoyu , Chapman Asheley P. , Bundy Jonathan L. , Woolfitt Adrian R. , Osman Sarah , Pirkle James L. , Wentworth David E. , Barr John R. 
Published: July 2021

AbstractN-glycosylation plays an important role in the structure and function of membrane and secreted proteins. The spike protein on the surface of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, is heavily glycosylated and the major target for developing vaccines, therapeutic drugs and diagnostic tests. The first major SARS-CoV-2 variant carries a D614G substitution in the spike (S-D614G) that has been associated with altered conformation, enhanced ACE2 binding, and increased infectivity and transmission. In this report, we used mass spectrometry techniques to characterize and compare the N-glycosylation of the wild type (S-614D) or variant (S-614G) SARS-CoV-2 spike glycoproteins prepared under identical conditions. The data showed that half of the N-glycosylation sequons changed their distribution of glycans in the S-614G variant. The S-614G variant showed a decrease in the relative abundance of complex-type glycans (up to 45%) and an increase in oligomannose glycans (up to 33%) on all altered sequons. These changes led to a reduction in the overall complexity of the total N-glycosylation profile. All the glycosylation sites with altered patterns were in the spike head while the glycosylation of three sites in the stalk remained unchanged between S-614G and S-614D proteins.
African Swine Fever Virus and host response - transcriptome profiling of the Georgia 2007/1 strain and porcine macrophages
Authors: Cackett Gwenny , Portugal Raquel , Matelska Dorota , Dixon Linda , Werner Finn 
Published: July 2021

AbstractAfrican swine fever virus (ASFV) has a major global economic impact. With a case fatality in domestic pigs approaching 100%, it currently presents the largest threat to animal farming. Although genomic differences between attenuated and highly virulent ASFV strains have been identified, the molecular determinants for virulence at the level of gene expression have remained opaque. Here we characterise the transcriptome of ASFV genotype II Georgia 2007/1 (GRG) during infection of the physiologically relevant host cells, porcine macrophages. In this study we applied Cap Analysis Gene Expression sequencing (CAGE-seq) to map the 5’ ends of viral mRNAs at 5 and 16 hours post-infection. A bioinformatics analysis of the sequence context surrounding the transcription start sites (TSSs) enabled us to characterise the global early and late promoter landscape of GRG. We compared transcriptome maps of the GRG isolate and the lab-attenuated BA71V strain that highlighted GRG virulent-specific transcripts belonging to multigene families, including two predicted MGF 100 genes I7L and I8L. In parallel, we monitored transcriptome changes in the infected host macrophage cells. Of the 9,384 macrophage genes studied, transcripts for 652 host genes were differentially regulated between 5 and 16 hours-post-infection compared with only 25 between uninfected cells and 5 hours post-infection. NF-kB activated genes and lysosome components like S100 were upregulated, and chemokines such as CCL24, CXCL2, CXCL5 and CXCL8 downregulated.ImportanceAfrican swine fever virus (ASFV) causes haemorrhagic fever in domestic pigs with case fatality rates approaching 100%, and no approved vaccines or antivirals. The highly-virulent ASFV Georgia 2007/1 strain (GRG) was the first isolated when ASFV spread from Africa to the Caucasus region in 2007. Then spreading through Eastern Europe, and more recently across Asia. We used an RNA-based next generation sequencing technique called CAGE-seq to map the starts of viral genes across the GRG DNA genome. This has allowed us to investigate which viral genes are expressed during early or late stages of infection and how this is controlled, comparing their expression to the non-virulent ASFV-BA71V strain to identify key genes that play a role in virulence. In parallel we investigated how host cells respond to infection, which revealed how the ASFV suppresses components of the host immune response to ultimately win the arms race against its porcine host.
The benefits of merging passive and active tracking approaches: new insights into riverine migration by salmonid smolts
Authors: Chavarie Louise , Honkanen Hannele M. , Newton Matthew , Lilly Jessie M. , Greetham Hannah R. , Adams Colin E. 
Published: July 2021

AbstractThe process of smolting is a critical phase in the life-cycle of anadromous salmonids and it has been associated with substantial rates of mortality. Survival during freshwater and marine migration is known to have population level effects, thus an understanding of the patterns of mortality has the potential to yield important insights into population bottlenecks. Despite important advancements in tracking techniques, the specifics of mortality events in anadromous salmonids during their initial migration to sea remains somewhat elusive. Here, we develop a framework combining spatial and temporal detections of smolt riverine migration from two tracking techniques, which enable inferences to be made about mortality locations, causes, and rates. In this study, we demonstrate that during their initial riverine transitional phase, smolts were particularly vulnerable to predators. Specifically, avian predation appeared to be the main cause of mortality (42%), although piscine predation events were not trivial (14%). Our results suggested some direct and indirect tagging-induced mortality (e.g., through increased predation vulnerability), which highlights the importance of determining tagging mortality in a telemetry study to ensure adequate interpretation of migration success. Overall, by estimating migration loss and its variability, our study framework should help to guide management actions to mitigate the widespread population declines these species are currently facing.
A dual barcoding approach to bacterial strain nomenclature: Genomic taxonomy ofKlebsiella pneumoniaestrains
Authors: Hennart Melanie , Guglielmini Julien , Maiden Martin C.J. , Jolley Keith A. , Criscuolo Alexis , Brisse Sylvain 
Published: July 2021

AbstractSublineages within microbial species can differ widely in their ecology and pathogenicity, and their precise definition is important in basic research and industrial or public health applications. Whereas the classification and naming of prokaryotes is unified at the species level and higher taxonomic ranks, universally accepted definitions of sublineages within species are largely missing, which introduces confusion in population biology and epidemiological surveillance.Here we propose a broadly applicable genomic classification and nomenclature approach for bacterial strains, using the prominent public health threatKlebsiella pneumoniaeas a model. Based on a 629-gene core genome multilocus sequence typing (cgMLST) scheme, we devised a dual barcoding system that combines multilevel single linkage (MLSL) clustering and life identification numbers (LIN). Phylogenetic and clustering analyses of >7,000 genome sequences captured population structure discontinuities, which were used to guide the definition of 10 infra-specific genetic dissimilarity thresholds. The widely used 7-gene multilocus sequence typing (MLST) nomenclature was mapped onto MLSL sublineages (threshold: 190 allelic mismatches) and clonal group (threshold: 43) identifiers for backwards nomenclature compatibility. The taxonomy is publicly accessible through a community-curated platform (https://bigsdb.pasteur.fr/klebsiella), which also enables external users’ genomic sequences identification.The proposed strain taxonomy combines two phylogenetically informative barcodes systems that provide full stability (LIN codes) and nomenclatural continuity with previous nomenclature (MLSL). This species-specific dual barcoding strategy for the genomic taxonomy of microbial strains is broadly applicable and should contribute to unify global and cross-sector collaborative knowledge on the emergence and microevolution of bacterial pathogens.
Correcting machine learning models using calibrated ensembles with ‘mlensemble’
Authors: Konopka Tomasz 
Published: July 2021

AbstractMachine learning models in bioinformatics are often trained and used within the scope of a single project, but some models are also reused across projects and deployed in translational settings. Over time, trained models may turn out to be maladjusted to the properties of new data. This creates the need to improve their performance under various constraints. This work explores correcting models without retraining from scratch and without accessing the original training data. It uses a taxonomy of strategies to guide the development of a software package, ‘mlensemble’. Key features include joining heterogeneous models into ensembles and calibrating ensembles to the properties of new data. These are well-established techniques but are often hidden within more complex tools. By exposing them to the application level, the package enables analysts to use expert knowledge to adjust models whenever needed. Calculations with imaging data show benefits when the noise characteristics of the training and the application datasets differ. An example using genomic single-cell data demonstrates model portability despite batch effects. The generality of the framework makes it applicable also in other subject domains.