bluuebunny/crossref_metadata_2025_split huggingface dataset:
Excessive matrix metalloproteinase-1 and hyperactivation of endothelial cells occurred in COVID-19 patients and were associated with the severity of COVID-19
Authors: Syed Fahim , Li Wei , Relich Ryan F. , Russell Patrick M. , Zhang Shanxiang , Zimmerman Michelle K. , Yu Qigui 
Published: January 2021

AbstractCOVID-19 starts as a respiratory disease that can progress to pneumonia, severe acute respiratory syndrome (SARS), and multi-organ failure. Growing evidence suggests that COVID-19 is a systemic illness that primarily injures the vascular endothelium, yet the underlying mechanisms remain unknown. SARS-CoV-2 infection is believed to trigger a cytokine storm that plays a critical role in the pathogenesis of endothelialitis and vascular injury, eventually leading to respiratory and multi-organ failure in COVID-19 patients. We used a multiplex immunoassay to systematically profile and compare 65 inflammatory cytokines/chemokines/growth factors in plasma samples from 24 hospitalized (severe/critical) COVID-19 patients, 14 mild/moderate cases, and 13 healthy controls (HCs). Patients with severe/critical and mild/moderate COVID-19 had significantly higher plasma levels of 20 analytes than HCs. Surprisingly, only one cytokine (MIF) was among these altered analytes, while the rest were chemokines and growth factors. In addition, only MMP-1 and VEGF-A were significantly elevated in hospitalized COVID-19 patients when compared to mild/moderate cases. Given that excessive MMP-1 plays a central role in tissue destruction in a wide variety of vascular diseases and that elevated VEGF-A, an EC activation marker, increases vascular permeability, we further studied MMP-1 enzymatic activity and other EC activation markers such as soluble forms of CD146, ICAM-1, and VCAM-1. We found that plasma MMP-1 enzymatic activity and plasma levels of MMP-1 and EC activation markers were highly dysregulated in COVID-19 patients. Some dysregulations were associated with patients’ age or gender, but not with race. Our results demonstrate that COVID-19 patients have distinct inflammatory profiles that are distinguished from the cytokine storms in other human diseases. Excessive MMP-1 and hyperactivation of ECs occur in COVID-19 patients and are associated with the severity of COVID-19.
Deficient hand washing facilities in public toilets in the time of the COVID-19 pandemic: A survey in one high-income country
Authors: Wilson Nick , Thomson George 
Published: January 2021

ABSTRACTAimsTo identify the extent of the provision of water and soap for hand washing in public toilets at the time of the COVID-19 pandemic. To also make comparisons with a pre-pandemic survey that included a sample of the same facilities.MethodsWe collected data from 400 toilets that were open to the public; all those in three contiguous city council territories (228) and a further convenience sample of 172 around the rest of New Zealand. Comparisons were made with the data on the same facilities included in a 2012/2013 survey.ResultsFor all the toilets in this survey, 2.5% had no water for hand washing and 14.8% had no soap. There was COVID-19 related health messaging signage in 19.5% of toilets, with posters of the COVID-19 QR code used to facilitate contact tracing in 12.3%, and generic hand washing signage in 1.8%. The hand washing water had “no touch” activation at 28.0% of toilets and at 18.5% for toilet bowl flushing. Toilet bowl lids were not present at 32.8%, and 2.3% of toilets had damage which would impair their functionality (eg, broken toilet seats). For the 128 sites that had also been examined in the previous survey, this new survey found significantly increased provision of soap (risk ratio = 1.47; 95%CI: 1.25 to 1.72), but no increased provision of water.ConclusionsDespite the serious threat of the COVID-19 pandemic, the majority of hand washing facilities in public toilets sampled required tap touching, and did not have health messaging. Nevertheless there has been some modest improvements in soap (but not water) provision since the previous survey eight years before.
Sleep in Frontline Healthcare Workers on Social Media During the COVID-19 Pandemic
Authors: Stewart Nancy H , Koza Anya L , Dhaon Serena , Shoushtari Christiana , Martinez Maylyn , Arora Vineet M 
Published: January 2021

AbstractImportanceDuring the pandemic, healthcare workers on social media are sharing their challenges, including sleep disturbances.ObjectiveTo assess sleep using validated measures among frontline healthcare workers on social mediaDesignA self-selection survey was distributed on Facebook, Twitter, and Instagram for 16 days (August 31-September 15, 2020) targeting healthcare workers (HCW) who were clinically active during the pandemic. Study participants completed the Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI), and reported demographic/career information. Poor sleep quality was defined as PSQI>5. Moderate-to-severe insomnia was defined as an ISI>14. The mini-Z was used to measure burnout. Multivariate logistic regression tested associations between demographics, career characteristics, and sleep outcomes.SettingOnline self-selection survey on social mediaParticipants963 surveys were completed. Participants were predominantly White (92.8%), female (73.4%), aged 30-49 (71.9%), and physicians (64.4%). Mean sleep duration was 6.1 (SD 1.2) hours. Nearly 90% reported poor sleep (PSQI). One third (33.0%) reported moderate or severe insomnia. Many (60%) experienced sleep disruptions due to device usage or had bad dreams at least once per week (45%). Over 50% reported burnout. In multivariable logistic regressions, non-physician (OR 2.4; CI: 1.7, 3.4), caring for COVID-19 patients (OR 1.8; CI 1.2, 2.8), Hispanic ethnicity (OR 2.2; CI: 1.4, 3.5), being female (OR 1.6; CI 1.1, 2.4), and having a sleep disorder (OR 4.3; CI 2.7,6.9) were associated with increased odds of insomnia. In open-ended comments (n=310), poor sleep mapped to four categories: children and family, work demands, personal health, and pandemic-related sleep disturbances.ConclusionDuring the COVID-19 pandemic, 90% of frontline healthcare workers surveyed on social media reported poor sleep, over one-third reported insomnia, and over half reported burnout. Many also reported sleep disruptions due to device usage and nightmares. Sleep interventions for frontline healthcare workers are urgently needed.Key pointsQuestionHow are frontline healthcare workers on social media sleeping during the pandemic?FindingsDuring the COVID-19 pandemic, 90% of frontline healthcare workers on social media are reporting poor sleep, and one third are reporting insomnia. Those who report sleep disturbances were more likely to report burnout.MeaningInterventions aimed at improving the sleep of frontline healthcare workers are warranted.
A SARS-CoV-2 Label-Free Surrogate Virus Neutralization Test and a Longitudinal Study of Antibody Characteristics in COVID-19 Patients
Authors: Luo Yiqi Ruben , Yun Cassandra , Chakraborty Indrani , Wu Alan H.B. , Lynch Kara L. 
Published: January 2021

AbstractBackgroundThe laboratory-based methods to measure the SARS-CoV-2 humoral response include virus neutralization tests (VNTs) to determine antibody neutralization potency. For ease of use and universal applicability, surrogate virus neutralization tests (sVNTs) based on antibody-mediated blockage of molecular interactions have been proposed.MethodsA surrogate virus neutralization test established on a label-free immunoassay platform (LF-sVNT). The LF-sVNT analyzes the binding ability of RBD to ACE2 after neutralizing RBD with antibodies in serum.ResultsThe LF-sVNT neutralizing antibody titers (IC50) were determined from serum samples (n=246) from COVID-19 patients (n=113), as well as the IgG concentrations and the IgG avidity indices. Although there is variability in the kinetics of the IgG concentrations and neutralizing antibody titers between individuals, there is an initial rise, plateau and then in some cases a gradual decline at later timepoints after 40 days post-symptom onset. The IgG avidity indices, in the same cases, plateau after the initial rise and did not show a decline.ConclusionsThe LF-sVNT can be a valuable tool in clinical laboratories for the assessment of the presence of neutralizing antibodies to COVID-19. This study is the first to provide longitudinal neutralizing antibody titers beyond 200 days post-symptom onset. Despite the decline of IgG concentration and neutralizing antibody titer, IgG avidity index increases, reaches a plateau and then remains constant up to 8 months post-infection. The decline of antibody neutralization potency can be attributed to the reduction in antibody quantity rather than the deterioration of antibody avidity, a measure of antibody quality.SummaryA surrogate virus neutralization test established on a label-free immunoassay platform (LF-sVNT). Using the LF-sVNT and other assays, 246 serum samples from 113 COVID-19 patients were measured. We observed the time course of antibody characteristics beyond 200 days post-symptom onset.
Analysis of HIV Reservoirs in Cellular Conjugates from Peripheral Blood
Authors: Pérez Liliana , Crespo-Vélez Daniel , Lee Max , Zakaria Saami , Poole April , Bell Jennifer , Migueles Stephen A. , Chun Tae-Wook , Moir Susan , Maldarelli Frank , Boritz Eli A. 
Published: January 2021

AbstractDefining distinctive attributes of HIV-infected cells will inform development of HIV cure-directed therapies. Priorex vivostudies of blood and tissue have suggested that some HIV-infected CD4 T cells are found in conjugates with other cell types. Here, we analyzed levels and sequences of HIV nucleic acids in sorted cellular conjugates from PBMC. Compared to single CD4 T cells, conjugates containing CD4 T cells showed no enrichment for HIV DNA or RNA. However, in several HIV controllers, HIV DNA sequences from sorted conjugates were enriched for sequences closely related to plasma viruses. In ART-treated people, although subgenomic HIV DNA sequences in sorted conjugates and single cells were genetically intermingled, intact proviruses were more frequent in whole blood cells than in magnetically-purified CD4 T cells. We conclude that some HIV-infected cells have attributes that predict preferential loss during sample processing, and that may also reflect vulnerability to therapeutic targetingin vivo.
Welfare at group and individual level: optical flow patterns of broiler chicken flocks are correlated with the behaviour of individual birds
Authors: Gebhardt-Henrich Sabine , Stratmann Ariane , Dawkins Marian Stamp 
Published: January 2021

AbstractGroup level measures of welfare such as the optical flow patterns made by broiler chicken flocks have been criticized on the grounds that they give only average measures and overlook the welfare of individual animals. However, we here show that by using the skew and kurtosis in addition to the mean, optical flow patterns can be used to deliver information not just about the flock average but also about the proportion of individuals in different movement categories. We correlated flock optical flow patterns with the behaviour of a sample of 16 birds per flock in two runway tests and a water (latency-to-lie) test. In the runway tests, there was a positive correlation between the time taken to complete the runway and the skew and kurtosis of optical flow on day 28 of flock life (slow individuals came from flocks with a high skew and kurtosis). In the water test, there was a positive correlation between the length of time the birds remained standing and the mean and variance of flock optical flow (the most mobile individuals came from flocks with the highest mean). Patterns at flock level thus contain valuable information about the welfare of the individuals that compose the flock.Simple SummaryTechnology on farms potentially brings benefits of improved animal health, welfare and productivity as well as reduction in disease, waste and environmental impact. However, it also raises public concern about the welfare of individual animals, particularly when applied to large groups such as broiler (meat) chickens. We here address this issue by showing that camera technology can both provide life-long continuous monitoring of the welfare of whole flocks and also give crucial information about the individuals making up the flock. The cameras detect variation between individuals and are also sensitive to birds moving abnormally. By testing birds individually, we show that slow-moving birds tended to come from flocks that moved slowly overall and showed large variation between individuals whereas fast-moving birds were more likely to come from more active flocks that moved more uniformly. Properly used, camera technology can thus monitor the welfare of flocks continuously throughout their lives while reflecting the behaviour of individual birds.
Translation Inhibitory Elements from Hox a3 and a11 mRNAs use uORFs for translation inhibition
Authors: Alghoul Fatima , Schaeffer Laure , Eriani Gilbert , Martin Franck 
Published: January 2021

AbstractDuring embryogenesis, Hox mRNA translation is tightly regulated by a sophisticated molecular mechanism that combines two RNA regulons located in their 5’UTR. First, an Internal Ribosome Entry Site (IRES) enables cap-independent translation. The second regulon is a Translation Inhibitory Element or TIE, which ensures concomitant cap-dependent translation inhibition. In this study, we deciphered the molecular mechanisms of Hox a3 and a11 TIE elements. Both TIEs possess an upstream Open Reading Frame (uORF) that is critical to inhibit cap-dependent translation. However, the molecular mechanisms used are different. In TIE a3, we identify a uORF which inhibits cap-dependent translation and we show the requirement of the non-canonical initiation factor eIF2D for this process. The mode of action of TIE a11 is different, it also contains a uORF but it is a minimal uORF formed by an uAUG followed immediately by a stop codon, namely a ‘start-stop’. The a11 ‘start-stop’ sequence is located upstream of a highly stable stem loop structure which stalls the 80S ribosome and thereby inhibits cap-dependent translation of Hox a11 main ORF.
Topological analysis of single-cell data reveals shared glial landscape of macular degeneration and neurodegenerative diseases
Authors: Kuchroo Manik , DiStasio Marcello , Calapkulu Eda , Ige Maryam , Zhang Le , Sheth Amar H. , Menon Madhvi , Xing Yu , Gigante Scott , Huang Jessie , Dhodapkar Rahul M. , Rieck Bastian , Wolf Guy , Krishnaswamy Smita , Hafler Brian P. 
Published: January 2021

1One Sentence SummaryA novel topological machine learning approach applied to single-nucleus RNA sequencing from human retinas with age-related macular degeneration identifies interacting disease phase-specific glial activation states shared with Alzheimer’s disease and multiple sclerosis.2AbstractNeurodegeneration occurs in a wide range of diseases, including age-related macular degeneration (AMD), Alzheimer’s disease (AD), and multiple sclerosis (MS), each with distinct inciting events. To determine whether glial transcriptional states are shared across phases of degeneration, we sequenced 50,498 nuclei from the retinas of seven AMD patients and six healthy controls, generating the first single-cell transcriptomic atlas of AMD. We identified groupings of cells implicated in disease pathogenesis by applying a novel topologically-inspired machine learning approach called ‘diffusion condensation.’ By calculating diffusion homology features and performing persistence analysis, diffusion condensation identified activated glial states enriched in the early phases of AMD, AD, and MS as well as an AMD-specific proangiogenic astrocyte state promoting pathogenic neovascularization in advanced AMD. Finally, by mapping the expression of disease-associated genes to glial states, we identified key signaling interactions creating hypotheses for therapeutic intervention. Our topological analysis identified an integrated disease-phase specific glial landscape that is shared across neurodegenerative conditions affecting the central nervous system.
Quickomics: exploring omics data in an intuitive, interactive and informative manner
Authors: Gao Benbo , Zhu Jing , Negi Soumya , Zhang Xinmin , Gyoneva Stefka , Casey Fergal , Wei Ru , Zhang Baohong 
Published: January 2021

AbstractSummaryWe developed Quickomics, a feature-rich R Shiny-powered tool to enable biologists to fully explore complex omics statistical analysis results and perform advanced analysis in an easy-to-use interactive interface. It covers a broad range of secondary and tertiary analytical tasks after primary analysis of omics data is completed. Each functional module is equipped with customizable options and generates both interactive and publication-ready plots to uncover biological insights from data. The modular design makes the tool extensible with ease.AvailabilityResearchers can experience the functionalities with their own data or demo RNA-Seq and proteomics datasets by using the app hosted athttp://quickomics.bxgenomics.comand following the tutorial,https://bit.ly/3rXIyhL. The source code under GPLv3 license is provided athttps://github.com/interactivereport/Quickomicsfor local installation.Supplementary informationSupplementary materials are available athttps://bit.ly/37HP17g.
Extreme C-to-A Hypermutation at a Site of Cytosine-N4 Methylation
Authors: Cherry Joshua L. 
Published: January 2021

ABSTRACTMethylation of cytosine in DNA at position C5 increases the rate of C→T mutations in bacteria and eukaryotes. Methylation at the N4 position, employed by some restriction-modification systems, is not known to increase the mutation rate. Here I report that aSalmonella entericaType III restriction-modification system that includes a cytosine-N4 methyltransferase causes an enormous increase in the rate of mutation of the methylated cytosines, which occur at the overlined C in the motif. Mutations consist mainly of C→A transversions, the rate of which is increased ~500-fold by the restriction-modification system. The rate of C→T transitions is also increased, and somewhat exceeds that at C5-methylated cytosines inDcmsites. Two otherSalmonellaN4 methyltransferases investigated do not have such dramatic effects, although in one case there is a modest increase in C→A mutations along with an increase in C→T mutations. Sensitivity of the C→A rate to orientation with respect to both DNA replication and transcription is higher at hypermutable sites than at other cytosines, suggesting a fundamental mechanistic difference between hypermutation and ordinary mutation.IMPORTANCEMutation produces the raw material for adaptive evolution, but also imposes a burden because most mutations are deleterious. The rate of mutation at a particular site is affected by a variety of factors. In both prokaryotes and eukaryotes, methylation of C at the C5 position, a naturally-occurring DNA modification, greatly increases the rate of C→T mutation. A distinct C modification that occurs in prokaryotes, methylation at N4, is not known to increase mutation rate. Here I report that a bacterial restriction-modification system, found in someSalmonella, increases the rate of C→A mutation by a factor of 500 at sites that it methylates at N4. This rate increase is much greater than that caused by C5 methylation. Although fewer than one in 1600 positions analyzed are methylation sites, over 10% of all mutations occur at these sites. Like other examples of extremely high mutation rate, whether naturally-occurring or the result of laboratory mutation, this phenomenon may shed light on the mechanism of mutation in general.
Tandem-Cleavage Linkers Improve the In Vivo Stability and Tolerability of Antibody-Drug Conjugates
Authors: Chuprakov Stepan , Ogunkoya Ayodele O. , Barfield Robyn M. , Bauzon Maxine , Hickle Colin , Kim Yun Cheol , Yeo Dominick , Zhang Fangjiu , Rabuka David , Drake Penelope M. 
Published: January 2021

ABSTRACTAlthough peptide motifs represent the majority of cleavable linkers used in clinical-stage antibody-drug conjugates (ADCs), the sequences are often sensitive to cleavage by extracellular enzymes, such as elastase, leading to systemic release of the cytotoxic payload. This action reduces the therapeutic index by causing off-target toxicities that can be dose-limiting. For example, a common side-effect of ADCs made using peptide-cleavable linkers is myelosuppression, including neutropenia. Only a few reports describe methods for optimizing peptide linkers to maintain efficient and potent tumor payload delivery while enhancing circulating stability. Herein, we address these critical limitations through the development of a tandem-cleavage linker strategy, where two sequential enzymatic cleavage events mediate payload release. We prepared dipeptides that are protected from degradation in the circulation by a sterically-encumbering glucuronide moiety. Upon ADC internalization and lysosomal degradation, the monosaccharide is removed and the exposed dipeptide is degraded, liberating the attached payload inside the target cell. We used CD79b-targeted monomethyl auristatin E (MMAE) conjugates as our model system, and compared the stability, efficacy, and tolerability of ADCs made with tandem-cleavage linkers to ADCs made using standard technology with the vedotin linker. The results—where rat studies showed dramatically improved tolerability in the hematopoietic compartment—highlight the role that linker stability plays in efficacy and tolerability, and offer a means of improving an ADC’s therapeutic index for improved patient outcomes.
Cooperative and aggressive behaviours vary between ranks in anemonefish social hierarchies
Authors: Rueger T , Heatwole SJ , Wong MY 
Published: January 2021

AbstractMany animal groups consist of individuals organised in dominance hierarchies, based on age, size or fighting ability. Lower ranked individuals often do not reproduce themselves but perform cooperative behaviours to help the reproductive output of dominant individuals or the group as a whole. Theoretical models suggest that individuals of higher rank should show increased amounts of aggressive behaviours, such as aggressions towards other group members, but should decrease the amount of cooperative behaviours, such as brood care or territory maintenance. Most empirical tests of these models focus on insect or mammalian systems where kin selection plays a large role, rather than animals that live in groups of unrelated individuals. Here we use two anemonefish species to test hypotheses of variation in cooperation and aggression with respect to social rank and species, for social systems where group members are unrelated. We assessed the behaviours of each rank in 20 groups ofAmphiprion perculaand 12 groups ofA. perideraionin Kimbe Bay, Papua New Guinea. We also performed a removal experiment to test if cooperative and aggressive behaviours are likely adaptive, i.e., if they change as an individual ascends in rank. Our results show differences between the two species, withA. perculashowing more cooperative behaviours andA. perideraionshowing more aggressive behaviours, despite them being closely related and sharing a very similar ecology. With respect to both cooperation and aggression we found consistent differences between ranks in both species, with higher ranks performing more aggressive as well as more cooperative behaviours. When we experimentally provided lower ranked individuals (rank 4) an opportunity to ascend in the hierarchy, they showed more aggression and more cooperation in line with our observations for rank 3 individuals. Thus, we show that rank specific behavioural patterns are likely adaptive in anemonefishes and that some model predictions do not hold in systems where kin selection benefits are absent. Rather, future fitness benefits through territory inheritance and group augmentation likely motivate cooperative and aggressive behaviours by subordinates in groups of unrelated vertebrates.