bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inter-species geographic signatures for tracing horizontal gene transfer and long-term persistence of carbapenem resistance
Authors: Salamzade Rauf , Manson Abigail L. , Walker Bruce J. , Brennan-Krohn Thea , Worby Colin J. , Ma Peijun , He Lorrie L. , Shea Terrance P. , Qu James , Chapman Sinéad B. , Howe Whitney , Young Sarah K. , Wurster Jenna I. , Delaney Mary L. , Kanjilal Sanjat , Onderdonk Andrew B. , Pironti Alejandro , Bittencourt Cassiana E. , Gussin Gabrielle M. , Kim Diane , Peterson Ellena M. , Ferraro Mary Jane , Hooper David C. , Shenoy Erica S. , Cuomo Christina A. , Hung Deborah T. , Cosimi Lisa A. , Huang Susan S. , Kirby James E. , Pierce Virginia M. , Bhattacharyya Roby P. , Earl Ashlee M. 
Published: December 2021

AbstractBackgroundCarbapenem-resistant Enterobacterales (CRE) are an urgent global health threat. Inferring the dynamics of local CRE dissemination is currently limited by our inability to confidently trace the spread of resistance determinants to unrelated bacterial hosts. Whole genome sequence comparison is useful for identifying CRE clonal transmission and outbreaks, but high-frequency horizontal gene transfer (HGT) of carbapenem resistance genes and subsequent genome rearrangement complicate tracing the local persistence and mobilization of these genes across organisms.MethodsTo overcome this limitation, we developed a new approach to identify recent HGT of large, near-identical plasmid segments across species boundaries, which also allowed us to overcome technical challenges with genome assembly. We applied this to complete and near-complete genome assemblies to examine the local spread of CRE in a systematic, prospective collection of all CRE, as well as time- and species-matched carbapenem susceptible Enterobacterales, isolated from patients from four U.S. hospitals over nearly five years.ResultsOur CRE collection comprised a diverse range of species, lineages and carbapenem resistance mechanisms, many of which were encoded on a variety of promiscuous plasmid types. We found and quantified rearrangement, persistence, and repeated transfer of plasmid segments, including those harboring carbapenemases, between organisms over multiple years. Some plasmid segments were found to be strongly associated with specific locales, thus representing geographic signatures that make it possible to trace recent and localized HGT events.Functional analysis of these signatures revealed genes commonly found in plasmids of nosocomial pathogens, such as functions required for plasmid retention and spread, as well survival against a variety of antibiotic and antiseptics common to the hospital environment.ConclusionsCollectively, the framework we developed provides a clearer, high resolution picture of the epidemiology of antibiotic resistance importation, spread, and persistence in patients and healthcare networks.
The price of defence: toxins, visual signals and oxidative state in an aposematic butterfly
Authors: Blount Jonathan D. , Rowland Hannah M. , Mitchell Christopher , Speed Michael P. , Ruxton Graeme D. , Endler John A. , Brower Lincoln P. 
Published: December 2021

SUMMARYIn a variety of aposematic species, the conspicuousness of an individual’s warning signal and the quantity of its chemical defence are positively correlated. This apparent honest signalling is predicted by resource competition models which assume that the production and maintenance of aposematic defences compete for access to antioxidant molecules that have dual functions as pigments and in protecting against oxidative damage. We raised monarch butterflies (Danaus plexippus) on their milkweed host-plants (Apocynaceae) with increasing quantities of cardenolides to test whether (1) the sequestration of secondary defences is associated with costs in the form of oxidative lipid damage and reduced antioxidant defences; and (2) that reduced oxidative state can decrease the capacity of individuals to produce aposematic displays. In male monarchs conspicuousness was explained by an interaction between oxidative damage and sequestration: males with high levels of oxidative damage become less conspicuous with increased sequestration of cardenolides, whereas those with low oxidative damage become more conspicuous with increased levels of cardenolides. There was no significant effect of oxidative damage or concentration of sequestered cardenolides on female conspicuousness. Our results demonstrate a physiological linkage between the production of coloration and protection from autotoxicity, and differential costs of signalling in monarch butterflies.
Mutations in the spike RBD of SARS-CoV-2 omicron variant may increase infectivity without dramatically altering the efficacy of current multi-dosage vaccinations
Authors: Li Bingrui , Lu Xin , McAndrews Kathleen M. , Kalluri Raghu 
Published: December 2021

AbstractWith the continuous evolution of SARS-CoV-2, variants of concern (VOCs) and their mutations are a focus of rapid assessment. Vital mutations in the VOC are found in spike protein, particularly in the receptor binding domain (RBD), which directly interacts with ACE2 on the host cell membrane, a key determinant of the binding affinity and cell entry. With the reporting of the most recent VOC, omicron, we performed amino acid sequence alignment of the omicron spike protein with that of the wild type and other VOCs. Although it shares several conserved mutations with other variants, we found that omicron has a large number of unique mutations. We applied the Hopp-Woods scale to calculate the hydrophilicity scores of the amino acid stretches of the RBD and the entire spike protein, and found 3 new hydrophilic regions in the RBD of omicron, implying exposure to water, with the potential to bind proteins such as ACE2 increasing transmissibility and infectivity. However, careful analysis reveals that most of the exposed domains of spike protein can serve as antigenic epitopes for generating B cell and T cell-mediated immune responses. This suggests that in the collection of polyclonal antibodies to various epitopes generated after multiple doses of vaccination, some can likely still bind to the omicron spike protein and the RBD to prevent severe clinical disease. In summary, while the omicron variant might result in more infectivity, it can still bind to a reasonable repertoire of antibodies generated by multiple doses of current vaccines likely preventing severe disease. Effective vaccines may not universally prevent opportunistic infections but can prevent the sequelae of severe disease, as observed for the delta variant. This might still be the case with the omicron variant, albeit, with increased frequency of infection.
Role of anterior insula cortex in context-induced relapse of nicotine-seeking
Authors: Ghareh Hussein , Alonso-Lozares Isis , Schetters Dustin , Herman Rae J. , Heistek Tim S. , van Mourik Yvar , Jean-Richard-dit-Bressel Philip , Zernig Gerald , Mansvelder Huibert D. , de Vries Taco J. , Marchant Nathan J. 
Published: December 2021

AbstractTobacco use is the leading cause of preventable death worldwide, and relapse during abstinence remains the key barrier to successful treatment of tobacco addiction. During abstinence, environmental contexts associated with nicotine use can induce craving and contribute to relapse. The insular cortex (IC) is thought to be a critical substrate of nicotine addiction and relapse. However, its specific role in context-induced relapse of nicotine-seeking is not fully known. In this study, we report a novel rodent model of context-induced relapse to nicotine-seeking after punishment-imposed abstinence, which models self-imposed abstinence through increasing negative consequences of excessive drug use. Using the neuronal activity marker Fos we find that the anterior (aIC), but not the middle or posterior IC, shows increased activity during context-induced relapse. Combining Fos with retrograde labelling of aIC inputs, we show projections to aIC from contralateral aIC and basolateral amygdala exhibit increased activity during context-induced relapse. Next, we used fiber photometry in aIC and observed phasic increases in aIC activity around nicotine-seeking responses during self-administration, punishment, and the context-induced relapse tests. Next, we used chemogenetic inhibition in both male and female rats to determine whether activity in aIC is necessary for context-induced relapse. We found that chemogenetic inhibition of aIC decreased context-induced nicotine-seeking after either punishment- or extinction-imposed abstinence. These findings highlight the critical role nicotine-associated contexts play in promoting relapse, and they show that aIC activity is critical for this context-induced relapse following both punishment and extinction imposed abstinence.
Hierarchical length and sequence preferences establish a single major piRNA 3’-end
Authors: Stoyko Daniel , Genzor Pavol , Haase Astrid D. 
Published: December 2021

ABSTRACTPIWI-interacting RNAs (piRNAs) guard germline genomes against the deleterious action of retroviruses and other mobile genetic elements. How piRNAs faithfully discriminate between self and non-self to restrict all mobile elements while sparing essential genes remains a key outstanding question in genome biology. PiRNAs use extensive base-pairing to recognize their targets and variable 3’ends could change the specificity and efficacy of piRNA silencing. Here, we identify conserved rules that ensure the generation of a single major piRNA 3’end in flies and mice. Our data suggest that the PIWI proteins initially define a short interval on pre-piRNAs that grants access to the ZUC-processor complex. Within this Goldilocks zone, the preference of the ZUC-processor to cut in front of a Uridine determines the ultimate processing site. We observe a mouse-specific roadblock that relocates the Goldilocks zone and generates an opportunity for consecutive trimming by PNLDC1. Our data reveal a conserved hierarchy between length and sequence preferences that controls the piRNA sequence space. The unanticipated precision of 3’end formation bolsters the emerging understanding that the functional piRNA sequence space is tightly controlled to ensure effective defense.Key findingsEvery piRNA has a single major 3’endLength preference trumps sequence preference during 3’end formation.Relocation of the Goldilocks zone generates opportunity for trimming of mouse piRNAs.
scMARK an ‘MNIST’ like benchmark to evaluate and optimize models for unifying scRNA data
Authors: Swechha  , Mendonca Dylan , Focsa Octavian , Díaz-Mejía J. Javier , Cooper Samuel 
Published: December 2021

AbstractToday’s single-cell RNA analysis tools provide enormous value in enabling researchers to make sense of large single-cell RNA (scRNA) studies, yet their ability to integrate different studies at scale remains untested. Here we present a novel benchmark dataset (scMARK), that consists of 100,000 cells over 10 studies and can test how well models unify data from different scRNA studies. We also introduce a two-step framework that uses supervised models, to evaluate how well unsupervised models integrate scRNA data from the 10 studies. Using this framework, we show that the Variational Autoencoder, scVI, represents the only tool tested that can integrate scRNA studies at scale. Overall, this work paves the way to creating large scRNA atlases and ‘off-the-shelf’ analysis tools.
Label-free imaging to track reprogramming of human somatic cells
Authors: Molugu Kaivalya , Battistini Giovanni A. , Heaster Tiffany M. , Rouw Jacob , Guzman Emmanuel C. , Skala Melissa C. , Saha Krishanu 
Published: December 2021

AbstractThe process of reprogramming patient samples to human induced pluripotent stem cells (iPSCs) is stochastic, asynchronous, and inefficient leading to a heterogeneous population of cells. Here, we track the reprogramming status of single patient-derived cells during reprogramming with label-free live-cell imaging of cellular metabolism and nuclear morphometry to identify high-quality iPSCs. Erythroid progenitor cells (EPCs) isolated from human peripheral blood showed distinct patterns of autofluorescence lifetime for the reduced form of nicotinamide adenine dinucleotide (phosphate) [NAD(P)H] and flavin adenine dinucleotide (FAD) during reprogramming. Random forest models classified starting EPCs, partially-reprogrammed intermediate cells, and iPSCs with ∼95% accuracy. Reprogramming trajectories resolved at the single cell level indicated significant reprogramming heterogeneity along different branches of cell state. This combination of micropatterning, autofluorescence imaging, and machine learning provides a unique non-destructive method to assess the quality of iPSCs in real-time for various applications in regenerative medicine, cell therapy biomanufacturing, and disease modeling.
SV2A-Syt1 interaction controls surface nanoclustering and access to recycling synaptic vesicles
Authors: Small Christopher , Harper Callista , Kontaxi Christiana , Davenport Elizabeth , Wallis Tristan , Malapaka Anusha , Yak Nyakuoy , Joensuu Merja , Martínez-Mármol Ramon , Cousin Michael A. , Meunier Frédéric A. 
Published: December 2021

SummaryFollowing exocytosis, the recapture of vesicular proteins stranded at the plasma membrane in recycling synaptic vesicles (SVs) is essential to sustain neurotransmission. Nanoclustering is emerging as a mechanism through which proteins may be ‘pre-assembled’ prior to endocytosis, to ensure high fidelity of retrieval for subsequent rounds of vesicle fusion. Here, we used single molecule imaging to examine the nanoclustering of synaptotagmin-1 (Syt1) and synaptic vesicle protein 2A (SV2A). Syt1 forms surface nanoclusters through interaction of its C2B domain (K326/K328) with SV2A, as demonstrated by mutating Syt1 (K326A/K328A) and knocking down endogenous SV2A. Blocking cognate interaction with Syt1 (SV2AT84A) also decreased SV2A clustering. Impaired nanoclustering of Syt1 and SV2A leads to accelerated endocytosis of Syt1, altered intracellular sorting and decreased trafficking of Syt1 to a Rab5-positive endocytic pathway. We conclude that the interaction between SV2A and Syt1 locks both molecules into surface nanoclusters, controlling their entry into recycling SVs.
Primary infection by E. multilocularis induces distinct patterns of crosstalk between hepatic regulatory T and natural killer T cells in mice
Authors: Yarahmadov Tural , Wang Junhua , Sanchez-Taltavull Daniel , Alvarez Rojas Cristian A. , Brodie Tess , Büchi Isabel , Keogh Adrian , Gottstein Bruno , Stroka Deborah , Beldi Guido 
Published: December 2021

AbstractThe larval stage of the helminthic cestode Echinococcus multilocularis can inflict tumor-like hepatic lesions that cause the parasitic disease alveolar echinococcosis in humans, with high mortality in untreated patients. Recently, opportunistic properties of the disease have been proposed based on the increased incidence in immunocompromised patients and mouse models, indicating that an appropriate adaptive immune response is required for the control of the disease. However, little is known about how the local hepatic immune responses modulate the infection with E. multilocularis. In a mouse model of oral infection that mimics the normal infection route in human patients, the adaptive immune response in the liver was assessed using single-cell RNA sequencing of isolated hepatic CD3+ T cells at different infection stages. We observed an early significant increase in regulatory T and natural killer T cells in parallel with an active downregulation of CD4+ and CD8+ T cells. Early interactions between regulatory T cells and natural killer T cells indicate a promotion of the formation of hepatic lesions and later contribute to suppression of the resolution of parasite-induced pathology. The obtained data provides a fresh insight on the adaptive immune responses and local regulatory pathways at different infection stages of E. multilocularis in mice.Author summaryAlveolar echinococcosis is an endemic parasitic infection leading to slowly growing but potentially lethal liver lesions if untreated. Transmission by increasing populations of urban foxes and the raise of immunosuppressed patients in mainly industrializsed endemic zones are the main causes responsible for increased incidence of alveolar echinococcosis. Observations in humans and mice indicate that reactions of the adaptive immune system are required to control the disease and to protect from a chronic infection. Therefore, we analysed the responses of T cells in the liver at single-cell resolution in a murine model mimicking the typical route of infection in humans. This so called single-cell RNA sequencing revealed specific temporal changes of T cell subsets such as natural killer T cells and regulatory T cells, indicating that these two cell types are recruited in the early phase to try to protect from parasite proliferation and are subsequently inhibited in the late phase of infection thus indicating immune escape mechanisms of the parasite. This study shows temporal changes of the immune cell profile in the liver over the course of a natural infection with E. multilocularis at the single cell level and reveals putative targets for novel therapeutic approaches for human AE and possibly other (parasitic/helminthic) diseases.
Strain variation inClostridioides difficiletoxin activity associated with genomic variation at both PaLoc and non-PaLoc loci
Authors: Saund Katie , Pirani Ali , Lacy D. Borden , Hanna Philip C. , Snitkin Evan 
Published: December 2021

ABSTRACTClinical disease fromClostridioides difficileinfection can be mediated by two toxins and their neighboring regulatory genes encoded within the five-gene pathogenicity locus (PaLoc). We provide several lines of evidence that the toxin activity ofC. difficilemay be modulated by genomic variants outside of the PaLoc. We used a phylogenetic tree-based approach to demonstrate discordance between toxin activity and PaLoc evolutionary history, an elastic net method to show the insufficiency of PaLoc variants alone to model toxin activity, and a convergence-based bacterial genome-wide association study (GWAS) to identify correlations between non-PaLoc loci with changes in toxin activity. Combined, these data support a model ofC. difficiledisease wherein toxin activity may be strongly affected by many non-PaLoc loci. Additionally, we characterize multiple otherin vitrophenotypes relevant to human infections including germination and sporulation. These phenotypes vary greatly in their clonality, variability, convergence, and concordance with genomic variation. Lastly, we highlight the intersection of loci identified by GWAS for different phenotypes and clinical severity. This strategy to identify the overlapping loci can facilitate the identification of genetic variation linking phenotypic variation to clinical outcomes.IMPORTANCEClostridioides difficilehas two major disease mediating toxins, A and B, encoded within the pathogenicity locus (PaLoc). In this study we demonstrate via multiple approaches that genomic variants outside of the PaLoc are associated with changes in toxin activity. These genomic variants may provide new avenues of exploration in the hunt for novel disease modifying interventions. Additionally, we provide insight into the evolution of several additional phenotypes also critical to clinical infection such as sporulation, germination, and growth rate. Thesein vitrophenotypes display a range of responses to evolutionary pressures and as such vary in their appropriateness for certain bacterial genome wide association study approaches. We used a convergence-based association method to identify the genomic variants most correlated with both changes in these phenotypes and disease severity. These overlapping loci may be important to both bacterial function and human clinical disease.
Superspreading of SARS-CoV-2 infections: A Systematic Review and Meta-analysis
Authors: Du Zhanwei , Wang Chunyu , Liu Caifen , Bai Yuan , Pei Sen , Adam Dillon C. , Wang Lin , Wu Peng , Lau Eric H. Y. , Cowling Benjamin J. 
Published: December 2021

AbstractSuperspreading in transmission is a feature of SARS-CoV-2 transmission. We conducted a systematic review and meta-analysis on globally reported dispersion parameters of SARS-CoV-2. The pooled estimate was 0.55 (95% CI: 0.30, 0.79). The study location and method were found to be important drivers for its diversity.
Surveillance of COVID-19 vaccine effectiveness – a real-time case-control study in southern Sweden
Authors: Björk Jonas , Bonander Carl , Moghaddassi Mahnaz , Rasmussen Magnus , Malmqvist Ulf , Kahn Fredrik , Inghammar Malin 
Published: December 2021

AbstractThe extensive register infrastructure available for COVID-19 surveillance in Scania county, Sweden, makes it possible to classify cases with respect to hospitalization and disease severity, stratify on time since last dose and demographic factors, account for prior infection, and extract data for population controls automatically. Estimated vaccine effectiveness 0-3 months after the last dose remained stable during the study period but waned markedly 6 months after the last dose in older persons.