bluuebunny/crossref_metadata_2025_split huggingface dataset:
Quantifying behavior change during the first year of the COVID-19 pandemic in the United States
Authors: Chao Dennis L , Cho Victor , Izzo Amanda S , Proctor Joshua L , Zimmermann Marita 
Published: January 2022

AbstractBackgroundDuring the first year of the COVID-19 pandemic, the most effective way to reduce transmission and to protect oneself was to reduce contact with others. However, it is unclear how behavior changed, despite numerous surveys about peoples’ attitudes and actions during the pandemic and public health efforts to influence behavior.MethodsWe used two sources of data to quantify changes in behavior at the county level during the first year of the pandemic in the United States: aggregated mobile device (smartphone) location data to approximate the fraction of people staying at home each day and digital invitation data to capture the number and size of social gatherings.ResultsBetween mid-March to early April 2020, the number of events fell and the fraction of devices staying at home peaked, independently of when states issued emergency orders or stay-at-home recommendations. Activity began to recover in May or June, with later rebounds in counties that suffered an early spring wave of reported COVID-19 cases. Counties with high incidence in the summer had more events, higher mobility, and less stringent state-level COVID-related restrictions the month before than counties with low incidence. Counties with high incidence in early fall stayed at home less and had less stringent state-level COVID-related restrictions in October, when cases began to rise in some parts of the US. During the early months of the pandemic, the number of events was inversely correlated with the fraction of devices staying at home, but after the fall of 2020 mobility appeared to stay constant as the number of events fell. Greater changes in behavior were observed in counties where a larger fraction voted for Biden in the 2020 US Presidential election. The number of people invited per event dropped gradually throughout the first year of the pandemic.ConclusionsThe mobility and events datasets uncovered different kinds of behavioral responses to the pandemic. Our results indicate that people did in fact change their behavior in ways that likely reduced COVID exposure and transmission, though the degree of change appeared to be affected by political views. Though the mobility data captured the initial massive behavior changes in the first months of the pandemic, the digital invitation data, presented here for the first time, continued to show large changes in behavior later in the first year of the pandemic.
Plasma sgp130 is an independent predictor of non-alcoholic fatty liver disease severity
Authors: Gunes Aysim , Bilodeau Laurent , Huet Catherine , Belblidia Assia , Baldwin Cindy , Giard Jeanne-Marie , Biertho Laurent , Lafortune Annie , Couture Christian Yves , Nguyen Bich N , Galun Eithan , Bémeur Chantal , Bilodeau Marc , Laplante Mathieu , Tang An , Faraj May , Estall Jennifer L. 
Published: January 2022

ABSTRACTBackgroundInterleukin-6 (IL-6) plays important and dynamic roles in inflammation associated with fatty liver disease over all stages, from simple steatosis to steatohepatitis, cirrhosis and cancer. IL-6 signals locally, but also circulates with multiple co-factors that control paracrine and endocrine signaling. As inflammation is a main driver of liver fibrosis, we investigated relationships between circulating components of the interleukin-6 signaling pathway (IL-6, sIL-6R and sgp130) and liver pathology in subjects with metabolically associated fatty liver disease (MAFLD) or steatohepatitis (MASH).MethodsPredictive performances of plasma IL-6, sIL-6R and sgp130 were investigated in two independent cohorts: 1) patients with biopsy-confirmed MASH (n=49), where magnetic resonance spectroscopy (MRS), imaging (MRI) and elastography (MRE) assessed liver fat, volume and stiffness; and 2) patients with morbid obesity (n=245) undergoing bariatric surgery where histological staging of steatosis, activity, and fibrosis determined MASH severity. Correlations were evaluated between IL-6, sIL-6R and sgp130 and anthropomorphic characteristics, plasma markers of metabolic disease or liver pathology.ResultsIn patients with MASH, plasma IL-6 and sgp130 strongly correlated with liver stiffness, which for sgp130 was independent of age, sex, BMI, diabetes, hyperlipidemia, hypertension or history of HCC. Plasma sgp130 was the strongest predictor of liver stiffness compared to common predictors and risk scores. Plasma sIL-6R correlated with liver volume independent of age, sex, and BMI. In patients with morbid obesity, circulating sgp130 correlated with advanced liver fibrosis.ConclusionLevels of circulating sgp130 can predict progressing MASH and may be used alone or in combination with other predictors as a non-invasive measure of liver disease severity.GRAPHICAL ABSTRACT
A Coupled Experimental and Statistical Approach for an Assessment of the Airborne Infection Risk in Event Locations
Authors: Siebler Lukas , Rathje Torben , Calandri Maurizio , Stergiaropoulos Konstantinos , Richter Bernhard , Nusseck Manfred , Spahn Claudia 
Published: January 2022

AbstractOperators of event locations are particularly affected by a pandemic. Resulting restrictions may cause uneconomical business. With previous models, only an incomplete quantitative risk assessments is possible, whereby no suitable restrictions can be derived. Hence, a mathematical and statistical model has been developed in order to link measurement data of substance dispersion in rooms with epidemiological data like incidences, reproduction numbers, vaccination rates and test qualities. This allows a first time overall assessment of airborne infection risks in large event locations. In these venues displacement ventilation concepts are often implemented. In this case simplified theoretical assumptions fail for the prediction of relevant airflows for infection processes. Thus, with locally resolving trace gas measurements and specific data of infection processes, individual risks can be computed more detailed. Via inclusion of many measurement positions, an assessment of entire event locations is possible. Embedding the overall model in a flexible application, daily updated epidemiological data allow latest calculations of expected new infections and individual risks of single visitors for a certain event. With this model, an instrument has been created that can help policymakers and operators to take appropriate measures and to check restrictions for their effect.
A simple bypass assay for DNA polymerases shows hypermutating variants associated with cancer show mechanistic differences in vitro
Authors: Crevel Gilles , Kearsey Stephen , Cotterill Sue 
Published: January 2022

ABSTRACTErrors made by DNA polymerases contribute to both natural variation and, in extreme cases, to genome instability and its associated diseases. Recently the importance of polymerase misincorporation in disease has been highlighted by the identification of cancer-associated polymerase variants and the recognition that a subgroup of these variants have a hypermutation phenotype in tumours. We have developed a bypass assay to rapidly determine the tendency of a polymerase to misincorporate in vitro. We have used the assay to compare misincorporation by wild-type, exonuclease defective and two hypermutating DNA polymerase e variants, P286R and V411L. The assay clearly distinguished between the misincorporation rates of wild type, exonuclease dead and P286R polymerases. However, the V411L polymerase showed different misincorporation characteristics to P286R, suggesting that these variants cause hypermutation by different mechanisms. Using this assay misincorporation opposite a templated C nucleotide was consistently higher than for other nucleotides, and this caused predominantly C to T transitions. This is consistent with the observation that C to T transitions are commonly seen in POLE mutant tumours.
Membrane interactions and uncoating of Aichi virus, a picornavirus that lacks a VP4
Authors: Kelly James T. , Swanson Jessica , Newman Joseph , Groppelli Elisabetta , Stonehouse Nicola J. , Tuthill Tobias J. 
Published: January 2022

AbstractKobuviruses are an unusual and poorly characterised genus within the picornavirus family, and can cause gastrointestinal enteric disease in humans, livestock and pets. The human Kobuvirus, Aichi virus (AiV) can cause severe gastroenteritis and deaths in children below the age of five years, however this is a very rare occurrence. During the assembly of most picornaviruses (e.g. poliovirus, rhinovirus and foot-and-mouth disease virus), the capsid precursor protein VP0 is cleaved into VP4 and VP2. However, Kobuviruses retain an uncleaved VP0. From studies with other picornaviruses, it is known that VP4 performs the essential function of pore formation in membranes, which facilitates transfer of the viral genome across the endosomal membrane and into the cytoplasm for replication. Here, we employ genome exposure and membrane interaction assays to demonstrate that pH plays a critical role in AiV uncoating and membrane interactions. We demonstrate that incubation at low pH alters the exposure of hydrophobic residues within the capsid, enhances genome exposure and enhances permeabilisation of model membranes. Furthermore, using peptides we demonstrate that the N-terminus of VP0 mediates membrane pore formation in model membranes, indicating that this plays an analogous function to VP4.ImportanceTo initiate infection, viruses must enter a host cell and deliver their genome into the appropriate location. The picornavirus family of small non-enveloped RNA viruses includes significant human and animal pathogens and are also models to understand the process of cell entry. Most picornavirus capsids contain the internal protein VP4, generated from cleavage of a VP0 precursor. During entry, VP4 is released from the capsid. In enteroviruses this forms a membrane pore, which facilitates genome release into the cytoplasm. Due to high levels of sequence similarity, it is expected to play the same role for other picornaviruses. Some picornaviruses, such as Aichi virus, retain an intact VP0, and it is unknown how these viruses re-arrange their capsids and induce membrane permeability in the absence of VP4. Here we have used Aichi virus as a model VP0 virus to test for conservation of function between VP0 and VP4. This could enhance understanding of pore function and lead to development of novel therapeutic agents that block entry.
Molecular basis of SARS-CoV-2 Omicron variant receptor engagement and antibody evasion and neutralization
Authors: Hong Qin , Han Wenyu , Li Jiawei , Xu Shiqi , Wang Yifan , Li Zuyang , Wang Yanxing , Zhang Chao , Huang Zhong , Cong Yao 
Published: January 2022

AbstractThe SARS-CoV-2 Omicron variant exhibits striking immune evasion and is spreading globally at an unprecedented speed. Understanding the underlying structural basis of the high transmissibility and greatly enhanced immune evasion of Omicron is of high importance. Here through cryo-EM analysis, we present both the closed and open states of the Omicron spike, which appear more compact than the counterparts of the G614 strain, potentially related to the Omicron substitution induced enhanced protomer-protomer and S1-S2 interactions. The closed state showing dominant population may indicate a conformational masking mechanism of immune evasion for Omicron spike. Moreover, we capture two states for the Omicron S/ACE2 complex with S binding one or two ACE2s, revealing that the substitutions on the Omicron RBM result in new salt bridges/H-bonds and more favorable electrostatic surface properties, together strengthened interaction with ACE2, in line with the higher ACE2 affinity of the Omicron relative to the G614 strain. Furthermore, we determine cryo-EM structures of the Omicron S/S3H3 Fab, an antibody able to cross-neutralize major variants of concern including Omicron, elucidating the structural basis for S3H3-mediated broad-spectrum neutralization. Our findings shed new lights on the high transmissibility and immune evasion of the Omicron variant and may also inform design of broadly effective vaccines against emerging variants.
Uncertainty-guided learning with scaled prediction errors in the basal ganglia
Authors: Moeller Moritz , Manohar Sanjay , Bogacz Rafal 
Published: January 2022

AbstractTo accurately predict rewards associated with states or actions, the variability of observations has to be taken into account. In particular, when the observations are noisy, the individual rewards should have less influence on tracking of average reward, and the estimate of the mean reward should be updated to a smaller extent after each observation. However, it is not known how the magnitude of the observation noise might be tracked and used to control prediction updates in the brain reward system. Here, we introduce a new model that uses simple, tractable learning rules that track the mean and standard deviation of reward, and leverages prediction errors scaled by uncertainty as the central feedback signal. We provide a normative analysis, comparing the performance of the new model with that of conventional models in a value tracking task. We find that the new model has an advantage over conventional models when tested across various levels of observation noise. Further, we propose a possible biological implementation of the model in the basal ganglia circuit. The scaled prediction error feedback signal is consistent with experimental findings concerning dopamine prediction error scaling relative to reward magnitude, and the update rules are found to be consistent with many features of striatal plasticity. Our results span across the levels of implementation, algorithm, and computation, and might have important implications for understanding the dopaminergic prediction error signal and its relation to adaptive and effective learning.Author SummaryThe basal ganglia system is a collection of subcortical nuclei in the mammalian brain. This system and its dopaminergic inputs are associated with learning from rewards. Here, dopamine is thought to signal errors in reward prediction. The structure and function of the basal ganglia system are not fully understood yet—for example, the basal ganglia are split into two antagonistic pathways, but the reason for this split and the role of the two pathways are unknown. Further, it has been found that under some circumstances, rewards of different sizes lead to dopamine responses of similar size, which cannot be explained with the reward prediction error theory. Here, we propose a new model of learning in the basal ganglia—the scaled prediction error model. According to our model, both reward average and reward uncertainty are tracked and represented in the two basal ganglia pathways. The learned reward uncertainty is then used to scale dopaminergic reward prediction errors, which effectively renders learning adaptive to reward noise. We show that such learning is more robust than learning from unscaled prediction errors and that it explains several physiological features of the basal ganglia system.
Nrf2 attenuates the innate immune response after experimental myocardial infarction
Authors: Bromage Daniel I. , Trevelin Silvia , Huntington Josef , Yang Victoria X. , Muthukumar Ananya , Mackie Sarah J. , Sawyer Greta , Zhang Xiaohong , Santos Celio X.C. , Safinia Niloufar , Smyrnias Ioannis , Giacca Mauro , Ivetic Alex , Shah Ajay M. 
Published: January 2022

AbstractObjectivesWe aimed to investigate the contribution of the transcription factor nuclear factor erythroid-derived 2-like 2 (Nrf2) to the inflammatory response after experimental myocardial infarction (MI).BackgroundThere is compelling evidence implicating dysregulated inflammation in the mechanism of ventricular remodeling and heart failure (HF) after MI. The transcription factor Nrf2 (encoded by Nfe2l2) is a promising target in this context. It impedes transcriptional upregulation of pro-inflammatory cytokines and is anti-inflammatory in various murine models.MethodsWe subjected Nrf2-/- mice and wild type (WT) controls to permanent left coronary artery (LCA) ligation. The inflammatory response was investigated with fluorescence-activated cell sorting (FACS) analysis of peripheral blood and heart cell suspensions, together with qRT-PCR of infarcted tissue for chemokines and their receptors. To investigate whether Nrf2-mediated transcription is a dedicated function of leukocytes, we interrogated publicly available RNA-sequencing (RNA-seq) data from mouse hearts after permanent LCA ligation for Nrf2-regulated gene (NRG) expression.ResultsFACS analysis demonstrated a profoundly inflamed phenotype in the hearts of global Nrf2-/- mice as compared to WT mice after MI. Moreover, infarcted tissue from Nrf2-/- mice displayed higher expression of inflammatory cytokines, chemokines, and their receptors, including IL6, Ccl2, and Cxcr4. RNA-seq analysis showed upregulated NRG expression in WT mice after MI compared to untreated mice, which was significantly higher in bioinformatically isolated CCR2+ cells.ConclusionsTaken together, the results suggest that Nrf2 signalling in leukocytes, and possibly CCR2+ monocyte-derived cardiac resident macrophages, may be potential targets to prevent post-MI ventricular remodeling.
Strong SARS-CoV-2 N-specific CD8+ T immunity induced by engineered extracellular vesicles associates with protection from lethal infection in mice
Authors: Ferrantelli Flavia , Chiozzini Chiara , Manfredi Francesco , Leone Patrizia , Spada Massimo , Virgilio Antonio Di , Giovannelli Andrea , Sanchez Massimo , Cara Andrea , Michelini Zuleika , Federico Maurizio 
Published: January 2022

ABSTRACTSARS-CoV-2-specific CD8+ T cell immunity is expected to counteract viral variants in both efficient and durable ways. We recently described a way to induce a potent SARS-CoV-2 CD8+ T immune response through the generation of engineered extracellular vesicles (EVs) emerging from muscle cells. This method relies on intramuscular injection of DNA vectors expressing different SARS-CoV-2 antigens fused at their N-terminus with Nefmut protein, i.e., a very efficient EV-anchoring protein. However, quality, tissue distribution, and efficacy of these SARS-CoV-2-specific CD8+ T cells remained uninvestigated. To fill the gaps, antigen-specific CD8+ T lymphocytes induced by the immunization through the Nefmut-based method were characterized in terms of their polyfunctionality and localization at lung airways, i.e., the primary targets of SARS-CoV-2 infection. We found that injection of vectors expressing Nefmut/S1 and Nefmut/N generated polyfunctional CD8+ T lymphocytes in both spleens and bronchoalveolar lavage fluids (BALFs). When immunized mice were infected with 4.4 lethal doses 50% of SARS-CoV-2, all S1-immunized mice succumbed, whereas those developing the highest percentages of N-specific CD8+ T lymphocytes resisted the lethal challenge. We also provide evidence that the N-specific immunization coupled with the development of antigen-specific CD8+ T-resident memory cells in lungs, supporting the idea that the Nefmut- based immunization can confer a long-lasting, lung-specific immune memory. In view of the limitations of current anti-SARS-CoV-2 vaccines in terms of antibody waning and efficiency against variants, our CD8+ T cell-based platform could be considered for a new combination prophylactic strategy.
Actin-microtubule dynamic composite forms responsive active matter with memory
Authors: Kučera Ondřej , Gaillard Jérémie , Guérin Christophe , Théry Manuel , Blanchoin Laurent 
Published: January 2022

AbstractActive cytoskeletal materials in vitro demonstrate self-organising properties similar to those observed in their counterparts in cells. However, the search to emulate phenomena observed in the living matter has fallen short of producing a cytoskeletal network that would be structurally stable yet possessing adaptive plasticity. Here, we address this challenge by combining cytoskeletal polymers in a composite, where self-assembling microtubules and actin filaments collectively self-organise due to the activity of microtubules-percolating molecular motors. We demonstrate that microtubules spatially organise actin filaments that in turn guide microtubules. The two networks align in an ordered fashion using this feedback loop. In this composite, actin filaments can act as structural memory and, depending on the concentration of the components, microtubules either write this memory or get guided by it. The system is sensitive to external stimuli suggesting possible autoregulatory behaviour in changing mechanochemical environment. We thus establish artificial active actin-microtubule composite as a system demonstrating architectural stability and plasticity.
Choice of medium affects PBMC quantification, cell size, and downstream respiratory analysis
Authors: Christensen Ida Bager , Ribas Lucas , Larsen Steen , Dela Flemming , Gillberg Linn 
Published: January 2022

AbstractHigh-resolution respirometry (HRR) can assess PBMC bioenergetics, but no standardized medium for PBMC preparation and HRR analysis exist. Here, we study the effect of four different media (MiR05, PBS, RPMI, Plasmax) on quantification, size, and HRR analysis (Oxygraph-O2k) of intact PBMCs. Remarkably, PBMC quantification was 21% higher in MiR05 than PBS and Plasmax, and 28% higher than in RPMI, causing O2flux underestimation during HRR due to inherent adjustments. Moreover, smaller cell size of PBMCs and aggregation was observed in MiR05. We suggest optimization of HRR with a standardized, plasma-like medium for future HRR analysis of intact PBMCs.
TRF2 rescues telomere attrition and prolongs cell survival in Duchenne muscular dystrophy cardiomyocytes derived from human iPSCs
Authors: Eguchi Asuka , Torres-Bigio Sofía I. , Koleckar Kassie , Gonzalez Adriana Fernanda G. S. , Birnbaum Foster , Blau Helen M. 
Published: January 2022

AbstractDuchenne muscular dystrophy (DMD) is a severe muscle wasting disease caused by the lack of dystrophin. Heart failure, driven by cardiomyocyte death, fibrosis, and the development of dilated cardiomyopathy, is the leading cause of death in DMD patients. Current treatments decrease the mechanical load on the heart, but do not address the root cause of dilated cardiomyopathy: cardiomyocyte death. Previously, we showed that telomere shortening is a hallmark of cardiomyocytes in DMD patient cardiac tissues and in a mouse model of DMD we generated that manifests dilated cardiomyopathy. We also found that this telomere shortening is recapitulated in DMD cardiomyocytes differentiated from patient-derived induced pluripotent stem cells (iPSCs). Here we further characterize that DMD cardiomyocytes exhibit reduced cell size, nuclear size, and sarcomere density compared to healthy isogenic controls. The telomere-binding protein, TRF2, is a core component of the shelterin complex, which protects chromosome ends and is expressed at lower levels in DMD cardiomyocytes compared to controls. We investigated whether preservation of telomere length could be achieved with upregulation of TRF2. We found that TRF2 upregulation in DMD cardiomyocytes increased telomere lengths, cell size, nuclear size, sarcomere density, and cell survival. These data suggest TRF2 gene therapy has the potential to delay the onset of dilated cardiomyopathy.