bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploiting Molecular Basis of Age and Gender Differences in Outcomes of SARS-CoV-2 Infections
Authors: Mercatelli Daniele , Pedace Elisabetta , Giorgi Federico M. , Guzzi Pietro Hiram
Published: May 2021

Motivation

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (coronavirus disease, 2019; COVID-19) is associated with adverse outcomes in patients. It has been observed that lethality seems to be related to the age of patients. Moreover, it has been demonstrated that ageing causes some modifications at a molecular level.

Objective

The study aims to shed out light on a possible link between the increased COVID-19 lethality and the molecular changes that occur in elderly people.

Methods

We considered public datasets on ageing-related genes and their expression at tissue level. We selected interactors that are known to be related to ageing process. Then, we performed a network-based analysis to identify interactors significantly related to both SARS-CoV-2 and ageing. Finally, we investigated changes on the expression level of coding genes at tissue, gender and age level.

Results

We observed a significant intersection between some SARS-CoV-2 interactors and ageing-related genes suggesting that those genes are particularly affected by COVID-19 infection. Our analysis evidenced that virus infection particularly affects ageing molecular mechanisms centred around proteins EEF2, NPM1, HMGA1, HMGA2, APEX1, CHEK1, PRKDC, and GPX4. We found that HMGA1, and NPM1 have a different expression in lung of males, while HMGA1, APEX1, CHEK1, EEF2, and NPM1 present changes in expression in males due to aging effects.

Conclusion

Our study generated a mechanistic framework to explaining the correlation between COVID-19 incidence in elderly patients and molecular mechanisms of ageing. This will provide testable hypotheses for future investigation and pharmacological solutions tailored on specific age ranges.
Cohort profile: Actionable Register of Geneva Out- and inpatients with SARS-CoV-2 (ARGOS)
Authors: Genecand Camille , Mongin Denis , Koegler Flora , Lebowitz Dan , Regard Simon , Nehme Mayssam , Braillard Olivia , Grira Marwène , Joubert Dominique , Chopard Pierre , Delaporte Elisabeth , Stirnemann Jerome , Guessous Idris , Tardin Aglaé , Courvoisier Delphine S.
Published: May 2021

Purpose

The Actionable Register of Geneva Out- and inpatients with SARS-CoV-2 (ARGOS) is an ongoing prospective cohort created by the Geneva Directorate of Health (GDH). It consists of an operational database compiling all SARS-CoV-2 test results conducted in the Geneva area since late February 2020. This article aims at presenting this comprehensive cohort, in light of some of the varying public health measures in Geneva, Switzerland, since March 2020.

Participants

As of June 1st, 2021, the database included 356’868 patients, among which 65’475 had at least one positive test result for SARS-CoV-2. Among all positive patients, 37.6% were contacted only once, 10.6 % had one follow-up call, 8.5% had two, and 27.7% had 3 or more follow-up calls. Participation rate among positive patients is 94%. Data collection is ongoing.

Findings to date

ARGOS data illustrates the magnitude of COVID-19 pandemic in Geneva, Switzerland, and details a variety of population factors and outcomes. The content of the cohort includes demographic data, comorbidities and risk factors for poor clinical outcome, self-reported COVID-19 symptoms, environmental and socio-economic factors, prospective and retrospective contact tracing data, travel quarantine data, and deaths. The registry has already been used in several publications focusing on symptoms and long COVID, infection fatality rate, and re-infection.

Future plans

The data of this large real-world registry provides a valuable resource for various types of research, such as clinical research, epidemiological research or policy assessment as it illustrates the impact of public health policies and overall disease burden of COVID-19.

STRENGTHS AND LIMITATIONS OF THIS STUDY

ARGOS’ main strength consists of its large number of cases, representative of all diagnosed cases on a regional level with the primary aim of assessing all cases.

ARGOS involves every individual who performed a SARS-CoV-2 test (PCR or antigenic) and is not limited to hospitalized patients, thus providing a valuable resource to assess the overall disease burden of COVID-19 in a geographically defined population.

To mitigate confounding effects and improve data analysis and interpretation, we present the data according to four policy periods.

This cohort is multicentric as it includes all tests performed in Geneva’s hospitals (both public and private), private practices and medical centers.

Due to operational needs, symptoms and comorbidities are self-reported, which may lead to measurement error or misclassification.
Nursing students’ attitudes, knowledge, and willingness to receive the COVID-19 vaccine: A cross-sectional study
Authors: Jiang Ning , Wei Baojian , Lin Hua , Wang Youjuan , Chai Shouxia , Liu Wei
Published: May 2021

Aim

To investigate nursing students’ konwledge, attitudes and willingness to receive the COVID-19 vaccine, and the influencing factors.

Background

Vaccination is one of the effective measures to prevent COVID-19, but the vaccination acceptance varies across countries and populations. As reserve nurses, nursing students have both the professionalism of medical personnel and the special characteristics of school students, their attitudes, knowledge, and willingness to receive the COVID-19 vaccine may greatly affect the vaccine acceptance of the population now and in the future. But little research has been done on vaccine acceptance among nursing students.

Design

A cross-sectional survey of nursing students was conducted via online questionnaires in March 2021.

Methods

Descriptive statistics, independent sample t tests/one-way ANOVA (normal distribution), Mann-Whitney U tests/Kruskal-Wallis H tests (skewness distribution) and multivariate linear regression were performed.

Results

The score rate of attitude, knowledge and vaccination willingness were 70.07%, 80.70% and 84.38% respectively. Attitude was significantly influenced by family economic conditions and whether a family member had been vaccinated. The main factors influencing knowledge were gender, grade and academic background. In terms of willingness, gender, academic background, visits to risk areas, whether family members were vaccinated, and whether they had side effects were significant influencing factors.

Conclusions

The vaccine acceptance of nursing students was fair. Greater focus needed to be placed on the males, those of younger age, with a science background, and having low grades, as well as on students whose family members had not received the COVID-19 vaccine or had side effects from the vaccine. Targeted intervention strategies were recommended to improve vaccination rates.
External Validation Of A Novel Signature Of Illness In Continuous Cardiorespiratory Monitoring To Detect Early Respiratory Deterioration Of ICU Patients
Authors: Callcut Rachael A. , Xu Yuan , Moorman J Randall , Tsai Christina , Villaroman Andrea , Robles Anamaria J. , Lake Douglas E , Hu Xiao , Clark Matthew T
Published: May 2021

The goal of predictive analytics monitoring is the early detection of patients at high risk of subacute potentially catastrophic illnesses. An excellent example of a targeted illness is respiratory failure leading to urgent unplanned intubation, where early detection might lead to interventions that improve patient outcomes. Previously, we identified signatures of this illness in the continuous cardiorespiratory monitoring data of Intensive Care Unit patients and devised algorithms to identify patients at rising risk. Here, we externally validated three logistic regression models to estimate the risk of emergency intubation developed in Medical and Surgical ICUs at the University of Virginia. We calculated the model outputs for more than 8000 patients in the University of California – San Francisco ICUs, 240 of whom underwent emergency intubation as determined by individual chart review. We found that the AUC of the models exceeded 0.75 in this external population, and that the risk rose appreciably over the 12 hours before the event. We conclude that there are generalizable physiological signatures of impending respiratory failure in the continuous cardiorespiratory monitoring data.
CBX4 regulates long-form thymic stromal lymphopoietin-mediated airway inflammation through SUMOylation in HDM-induced asthma
Authors: Liang Shixiu , Zhou Zicong , Zhou Zili , Liu Jieyi , Dong Hangming , Zou Fei , Zhao Haijin , Yu Changhui , Cai Shaoxi
Published: May 2021

Rationale

Thymic stromal lymphopoietin (TSLP) is present in two distinct isoforms, short-form (sfTSLP) and long-form (lfTSLP). lfTSLP promotes inflammation while sfTSLP inhibits inflammation in allergic asthma. However, little is known about the regulation of lfTSLP and sfTSLP during allergic attack in asthma airway epithelium.

Methods and Results

Here, we report that SUMOylation was enhanced in HDM-induced allergic asthma airway epithelium. Inhibition of SUMOylation significantly alleviated airway Th2 inflammation and lfTSLP expression. Mechanistically, CBX4, a SUMOylation E3 ligase, enhanced lfTSLP, but not sfTSLP, mRNA translation through the RNA binding protein, MEX-3B. MEX-3B promoted lfTSLP translation through binding of its KH domains to the lfTSLP mRNA. Furthermore, CBX4 regulated MEX-3B transcription in HBE through enhancing SUMOylation levels of the transcription factor, TFII-I.

Conclusion

We demonstrate an important mechanism whereby CBX4 promotes MEX-3B transcription through enhancing TFII-I SUMOylation, and MEX-3B enhances the expression of lfTSLP through binding to the lfTSLP mRNA and promoting its translation. Our findings uncover a novel target of CBX4 for therapeutic agents to lfTSLP-mediated asthma.
Evolutionary Inference Predicts Novel ACE2 Protein Interactions Relevant to COVID-19 Pathologies
Authors: Varela Austin A. , Cheng Sammy , Werren John H.
Published: May 2021

Angiotensin-converting enzyme 2 (ACE2) is the cell receptor that the coronavirus SARS-CoV-2 binds to and uses to enter and infect human cells. COVID-19, the pandemic disease caused by the coronavirus, involves diverse pathologies beyond those of a respiratory disease, including micro-thrombosis (micro-clotting), cytokine storms, and inflammatory responses affecting many organ systems. Longer-term chronic illness can persist for many months, often well after the pathogen is no longer detected. A better understanding of the proteins that ACE2 interacts with can reveal information relevant to these disease manifestations and possible avenues for treatment. We have undertaken an approach to predict candidate ACE2 interacting proteins which uses evolutionary inference to identify a set of mammalian proteins that “coevolve” with ACE2. The approach, called evolutionary rate correlation (ERC), detects proteins that show highly correlated evolutionary rates during mammalian evolution. Such proteins are candidates for biological interactions with the ACE2 receptor. The approach has uncovered a number of key ACE2 protein interactions of potential relevance to COVID-19 pathologies. Some proteins have previously been reported to be associated with severe COVID-19, but are not currently known to interact directly with ACE2, while additional predicted novel ACE2 interactors are of potential relevance to the disease. Using reciprocal rankings of protein ERCs, we have identified strongly interconnected ACE2 associated protein networks relevant to COVID-19 pathologies. ACE2 has clear connections to coagulation pathway proteins, such as Coagulation Factor V and fibrinogen components FGG, FGB, and FGA, the latter possibly mediated through ACE2 connections to Clusterin (which clears misfolded extracellular proteins) and GPR141 (whose functions are relatively unknown). ACE2 also connects to proteins involved in cytokine signaling and immune response (e.g. IFNAR2, XCR1, and TLR8), and to Androgen Receptor (AR). The ERC prescreening approach has also elucidated possible functions for previously uncharacterized proteins and possible new functions for well-characterized ones. Suggestions are made for the validation of ERC predicted ACE2 protein interactions. We propose that ACE2 has novel protein interactions that are disrupted during SARS-CoV-2 infection, contributing to the spectrum of COVID-19 pathologies.
Immunogenic Amino Acid Motifs and Linear Epitopes of COVID-19 mRNA Vaccines
Authors: Wisnewski Adam V , Redlich Carrie A , Kamath Kathy , Abad Queenie-Ann , Smith Richard F , Fazen Louis , Santiago Romero , Liu Jian , Luna Julian Campillo , Martinez Brian , Baum-Jones Elizabeth , Waitz Rebecca , Haynes Winston A , Shon John C
Published: May 2021

Reverse vaccinology is an evolving approach for improving vaccine effectiveness and minimizing adverse responses by limiting immunizations to critical epitopes. Towards this goal, we sought to identify immunogenic amino acid motifs and linear epitopes of the SARS-CoV-2 spike protein that elicit IgG in COVID-19 mRNA vaccine recipients. Paired pre/post vaccination samples from N=20 healthy adults, and post-vaccine samples from an additional N=13 individuals were used to immunoprecipitate IgG targets expressed by a bacterial display random peptide library, and preferentially recognized peptides were mapped to the spike primary sequence. The data identify several distinct amino acid motifs recognized by vaccine-induced IgG, a subset of those targeted by IgG from natural infection, which may mimic 3-dimensional conformation (mimotopes). Dominant linear epitopes were identified in the C-terminal domains of the S1 and S2 subunits (aa 558-569, 627-638, and 1148-1159) which have been previously associated with SARS-CoV-2 neutralization in vitro and demonstrate identity to bat coronavirus and SARS-CoV, but limited homology to non-pathogenic human coronavirus. The identified COVID-19 mRNA vaccine epitopes should be considered in the context of variants, immune escape and vaccine and therapy design moving forward.
Fear among Syrians: a Proposed Cutoff Score and Validation of the Arabic Fear of COVID-19 Scale- A National Survey
Authors: Mohsen Fatema , Bakkar Batoul , Alsrouji Salma Khadem , Abbas Esraa , Najjar Alma , Marrawi Marah , Latifeh Youssef
Published: May 2021

COVID-19 pandemic has led to psychological health issues one of which is fear. This study validates the Arabic version of the fear of COVID-19 scale and suggests a new cutoff score to measure fear of COVID-19 among the Syrian Population. A total of 3989 participants filled an online survey consisting of socio-demographic information, the fear of COVID-19 scale, the patient health questionnaire 9-item, and the generalized anxiety disorder 7-item. Receiver operating characteristic analysis was used to define cutoff scores for the fear of COVID-19 scale in relation to generalized anxiety disorder 7-item and the patient health questionnaire 9-item. The Cronbach α value of the Arabic fear of COVID-19 scale was 0.896, revealing good stability and internal consistency. The inter-item correlations were between [0.420 – 0.868] and the corrected item-total correlations were between [0.614 – 0.768]. A cutoff point of 17.5 was deduced from analysis. According to the deduced cutoff point, 2111(52.9%) were classified as cases with extreme fear. This cutoff score deduced from this study can be used for screening purposes to identify individuals that may be most vulnerable towards developing extreme fear of COVID-19. Therefore, early preventive and supportive measures can then be delivered.
Engagement with daily testing instead of self-isolating in contacts of confirmed cases of SARS-CoV-2: A qualitative analysis
Authors: Denford Sarah , Martin Alex F. , Love Nicola , Ready Derren , Oliver Isabel , Amlôt Richard , Yardley Lucy , Rubin G. James
Published: May 2021

Introduction

In December 2020 and January 2021 Public Health England (PHE) with NHS Test and Trace conducted a study to explore the feasibility and acceptability of daily testing as an alternative to self-isolation following close contact with a confirmed COVID-19 case. This qualitative paper aims to identify factors influencing uptake among those offered daily testing, and the subsequent impact on behaviour.

Methods

We conducted in-depth interviews with 52 participants who had taken part in the feasibility study. Participants were asked about their experiences of daily testing or self-isolating, their reasons for choosing to test or isolate, and their behaviour during the study period. Data were analysed using inductive thematic analysis.

Results

Results are presented under two main headings: 1) factors influencing acceptance of testing and 2) impact of test results. Participants appeared highly motivated to engage in behaviours that would protect others from the virus. Factors influencing the decision to accept testing included 1) needing to avoid self-isolation 2) concerns about test sensitivity and 3) perceived benefits of detecting infection. Participants who were taking tests reported:1) positive consequences following confirmation of COVID status 2) engaging in essential activities 3) uncertainty and 4) self-isolating whilst testing.

Conclusions

This study has identified a range of factors that appear to influence the decision to engage in daily testing or to self-isolate following close contact with a positive case, many of which could be addressed by clear communications. Covid-19 infection rates and government restrictions influenced experiences, and so further research is needed to explore perceptions of daily testing and behaviour following close contact with a positive case among a wider range of individuals, in the context of lower rates of COVID-19, few government restrictions on general population behaviour and more widespread testing.
Multiple drug arrests reported to the Maine Diversion Alert Program more frequently involved carisoprodol, amitriptyline, or quetiapine
Authors: Siddiqui Maaz , Piserchio John P. , Patel Misha , Park Jino , Foster Michelle , Desrosiers Clare E. , Herbert John , McCall Kenneth L. , Piper Brian J.
Published: May 2021

Background

Much of the blame of the increasing death toll by drug overdoses has justifiably been attributed to the United States’ current opioid epidemic. However, nearly 80% of overdoses related to opioids involve another drug substance or alcohol. The objective of this study was to elucidate overrepresentation of drugs in polypharmacy arrests by identifying drugs that were more likely to be found in conjunction with other substances, using the drug arrest data provided by the Maine Diversion Alert Program (DAP).

Methods

Single drug arrest and multiple drug arrest totals reported to the DAP were examined. Drugs involved in the arrests were classified by Drug Enforcement Administration Schedule (I-V or non-controlled prescription) and categorized into five drug families: hallucinogens, opioids, sedatives, stimulants, and miscellaneous. Multiple drug arrest totals were compared to single drug arrest totals to create a Multiple-to-Single Ratio (MSR) specific to each drug family and each drug. Chi-square approximations without Yates correction and two-tailed P values were used to determine statistical significance through GraphPad’s 2×2 contingency tables.

Results

Over three-fifths (63.8%) of all arrests involved a single drug. Opioids accounted for over-half (53.5%) of single arrests, followed by stimulants (27.7%) and hallucinogens (7.7%). Similarly, nearly two-fifths (39.6%) of multiple arrests were opioids, followed by stimulants (30.8%) and miscellaneous (13.0%). Miscellaneous family drugs were recorded with the highest Multiple-to-Single Ratio (1.51), followed by sedatives (1.09), stimulants (0.63), opioids (0.42), and hallucinogens (0.35). Carisoprodol (8.80), amitriptyline (6.34), and quetiapine (4.69) had the highest MSR values and therefore were the three most overrepresented drugs in polysubstance arrests.

Conclusion

The abuse of opioids, both alone and in conjunction with another drug, deserves continued surveillance in public health. In addition, common prescription drugs with lesser-known misuse potential, especially carisoprodol, amitriptyline, and quetiapine, require more attention by medical providers for their ability to enhance the effects of other drugs or to compensate for undesired drug effects.
Magnetic Field Mapping and Correction for Moving OP-MEG
Authors: Mellor Stephanie , Tierney Tim M. , O’Neill George C. , Alexander Nicholas , Seymour Robert A. , Holmes Niall , López José D. , Hill Ryan M. , Boto Elena , Rea Molly , Roberts Gillian , Leggett James , Bowtell Richard , Brookes Matthew J. , Maguire Eleanor A. , Walker Matthew C. , Barnes Gareth R.
Published: May 2021

Background

Optically pumped magnetometers (OPMs) have made moving, wearable magnetoencephalography (MEG) possible. The OPMs typically used for MEG require a low background magnetic field to operate, which is achieved using both passive and active magnetic shielding. However, the background magnetic field is never truly zero Tesla, and so the field at each of the OPMs changes as the participant moves. This leads to position and orientation dependent changes in the measurements, which manifest as low frequency artefacts in MEG data.

Objective

We modelled the spatial variation in the magnetic field and used the model to predict the movement artefact found in a dataset.

Methods

We demonstrate a method for modelling this field with a triaxial magnetometer, then showed that we can use the same technique to predict the movement artefact in a real OPM-based MEG (OP-MEG) dataset.

Results

Using an 86-channel OP-MEG system, we found that this modelling method maximally reduced the power spectral density of the data by 26.2 ± 0.6 dB at 0 Hz, when applied over 5 s non-overlapping windows.

Conclusion

The magnetic field inside our state-of-the art magnetically shielded room can be well described by low-order spherical harmonic functions. We achieved a large reduction in movement noise when we applied this model to OP-MEG data.

Significance

Real-time implementation of this method could reduce passive shielding requirements for OP-MEG recording and allow the measurement of low-frequency brain activity during natural participant movement.
Variation in upstream open reading frames contributes to allelic diversity in protein abundance
Authors: Gage Joseph L. , Mali Sujina , McLoughlin Fionn , Khaipho-Burch Merritt , Monier Brandon , Bailey-Serres Julia , Vierstra Richard D. , Buckler Edward S.
Published: May 2021

The 5’ untranslated region (UTR) sequence of eukaryotic mRNAs may contain upstream open reading frames (uORFs), which can regulate translation of the main open reading frame (mORF). The current model of translational regulation by uORFs posits that when a ribosome scans an mRNA and encounters a uORF, translation of that uORF can prevent ribosomes from reaching the mORF and cause decreased mORF translation. In this study, we first observed that rare variants in the 5’ UTR dysregulate protein abundance. Upon further investigation, we found that rare variants near the start codon of uORFs can repress or derepress mORF translation, causing allelic changes in protein abundance. This finding holds for common variants as well, and common variants that modify uORF start codons also contribute disproportionately to metabolic and whole-plant phenotypes, suggesting that translational regulation by uORFs serves an adaptive function. These results provide evidence for the mechanisms by which natural sequence variation modulates gene expression, and ultimately, phenotype.
Cooperative regulation of adherens junction elongation through Epidermal Growth Factor Receptor (EGFR) activation
Authors: Fu Chaoyu , Arora Aditya , Engl Wilfried , Sheetz Michael , Viasnoff Virgile
Published: May 2021

The mechanisms controlling the elongation rates of adherens junctions are poorly characterized and lag behind our understanding of those controlling their static properties. In suspended cell aggregates, we found that the speed of de novo junction formation between two cells increases with the number of junctions that the cells are already engaged in. This cooperative effect is driven by the transient activation of the Epidermal Growth Factor Receptor (EGFR) upon junction formation. EGFR activation then regulates the actin cytoskeleton turnover while cortical tension remains unaltered. Overall, we show that EGFR activation regulates the elongation speed of junctions (kinetype) without affecting their final size (phenotype) in such aggregates.
Peripheral Coupling Sites Formed by STIM1 Govern the Contractility of Vascular Smooth Muscle Cells
Authors: Krishnan Vivek , Ali Sher , Gonzales Albert L. , Thakore Pratish , Griffin Caoimhin S. , Yamasaki Evan , Alvarado Michael G. , Johnson Martin T. , Trebak Mohamed , Earley Scott
Published: May 2021

Peripheral coupling between the sarcoplasmic reticulum (SR) and plasma membrane (PM) forms signaling complexes that regulate the membrane potential and contractility of vascular smooth muscle cells (VSMCs), although the mechanisms responsible for these membrane interactions are poorly understood. In many cells, STIM1 (stromal-interaction molecule 1), a single transmembrane-domain protein that resides in the endoplasmic reticulum (ER), transiently moves to ER-PM junctions in response to depletion of ER Ca2+ stores and initiates store-operated Ca2+ entry (SOCE). Fully differentiated VSMCs express STIM1 but exhibit only marginal SOCE activity. We hypothesized that STIM1 is constitutively active in contractile VSMCs and maintains peripheral coupling. In support of this concept, we found that the number and size of SR-PM interacting sites were decreased and SR-dependent Ca2+ signaling processes were disrupted in freshly isolated cerebral artery SMCs from tamoxifen-inducible, SMC-specific STIM1-knockout (Stim1-smKO) mice. VSMCs from Stim1-smKO mice also exhibited a reduction in nanoscale colocalization between Ca2+-release sites on the SR and Ca2+-activated ion channels on the PM, accompanied by diminished channel activity. Stim1-smKO mice were hypotensive and resistance arteries isolated from them displayed blunted contractility. These data suggest that STIM1 – independent of SR Ca2+ store depletion – is critically important for stable peripheral coupling in contractile VSMCs.
Redundant and specific roles of EGFR ligands in the ERK activation waves during collective cell migration of MDCK cells
Authors: Lin Shuhao , Hirayama Daiki , Maryu Gembu , Matsuda Kimiya , Hino Naoya , Deguchi Eriko , Aoki Kazuhiro , Iwamoto Ryo , Terai Kenta , Matsuda Michiyuki
Published: May 2021

Epidermal growth factor receptor (EGFR) plays a pivotal role in collective cell migration by mediating cell-to-cell propagation of extracellular signal-regulated kinase (ERK) activation. Here, we aimed to determine which EGFR ligands mediate the ERK activation waves by gene knockout. Four of the seven known EGFR ligands are expressed in MDCK cells. We found that epidermal growth factor (EGF)-deficient cells exhibited lower basal ERK activity than the cells deficient in heparin-binding EGF (HBEGF), transforming growth factor alpha (TGFα) or epiregulin (EREG), but all cell lines deficient in a single EGFR ligand retained the ERK activation waves. Therefore, we knocked out the EGFR ligand genes in decreasing order of expression. ERK activation waves were markedly suppressed, albeit incompletely, only when all four EGFR ligands were knocked-out. Re-expression of the EGFR ligands revealed that all but HBEGF could restore the ERK activation waves. Aiming at complete elimination of the ERK activation waves, we further attempted to knockout Nrg1, a ligand for ErbB3 and ErbB4, and found that Nrg1 deficiency induced growth arrest in the absence of all four EGFR ligand genes expressed in MDCK cells. Collectively, these results showed that EGFR ligands exhibit remarkable redundancy in the propagation of ERK activation waves during collective cell migration.
The measure of spatial position within groups that best predicts predation risk depends on group movement
Authors: Lambert Poppy J. , Herbert-Read James E. , Ioannou Christos C.
Published: May 2021

Both empirical and theoretical studies show that an individual’s spatial position within a group can impact the risk of being targeted by predators. Spatial positions can be quantified in numerous ways, but there are no direct comparisons of different spatial measures in predicting the risk of being targeted by real predators. Here we assess these spatial measures in groups of stationary and moving virtual prey being attacked by three-spined sticklebacks (Gasterosteus aculeatus). In stationary groups, the limited domain of danger best predicted the likelihood of attack. In moving groups, the number of near neighbours was the best predictor but only over a limited range of distances within which other prey were counted. Otherwise, measures of proximity to the group’s edge outperformed measures of local crowding in moving groups. There was no evidence that predators preferentially attacked the front or back of the moving groups. Domains of danger without any limit, as originally used in the selfish herd model, were also a poor predictor of risk. These findings reveal that the collective properties of prey can influence how spatial position affects predation risk, via effects on predators’ targeting, hence selection may act differently on prey positioning behaviour depending on group movement.
Building the cytokinetic contractile ring in an early embryo: initiation as clusters of myosin II, anillin and septin, and visualization of a septin filament network
Authors: Garno Chelsea , Irons Zoe H. , Gamache Courtney M. , Wu Xufeng , Shuster Charles B. , Henson John H.
Published: May 2021

The cytokinetic contractile ring (CR) was first described some 50 years ago, however our understanding of the assembly and structure of the animal cell CR remains incomplete. We recently reported that mature CRs in sea urchin embryos contain myosin II mini-filaments organized into aligned concatenated arrays, and that in early CRs myosin II formed discrete clusters that transformed into the linearized structure over time. The present study extends our previous work by addressing the hypothesis that these myosin II clusters also contain the crucial scaffolding proteins anillin and septin, known to help link actin, myosin II, RhoA, and the membrane during cytokinesis. Super-resolution imaging of cortices from dividing embryos indicates that within each cluster, anillin and septin2 occupy a centralized position relative to the myosin II mini-filaments. As CR formation progresses, the myosin II, septin and anillin containing clusters enlarge and coalesce into patchy and faintly linear patterns. Our super-resolution images provide the initial visualization of anillin and septin nanostructure within an animal cell CR, including evidence of a septin filament network. Furthermore, Latrunculin-treated embryos indicated that the localization of septin or anillin to the myosin II clusters in the early CR was not dependent on actin filaments. These results highlight the structural progression of the CR in sea urchin embryos from an array of clusters to a linearized purse string, the association of anillin and septin with this process, and provide, for the first time, the visualization of septin filament higher order structure in an animal cell CR.
Survey and Molecular Detection of Sri Lankan Cassava Mosaic Virus in Thailand
Authors: Saokham Kingkan , Hemniam Nuannapa , Roekwan Sukanya , Hunsawattanakul Sirikan , Thawinampan Jutathip , Siriwan Wanwisa
Published: May 2021

Cassava plantations in an area of 458 ha spanning five provinces along the Thailand– Cambodia border were surveyed from October 2018 to July 2019 to determine the prevalence of cassava mosaic disease (CMD) caused by Sri Lankan cassava mosaic virus (SLCMV) in the region. CMD prevalence was 40% in the whole area and 80% in Prachinburi, 43% in Sakaeo, 37% in Burium, 25% in Surin, and 19% in Sisaket provinces. Disease severity was generally scored as 2–3. The highest average disease severity was in Sakaeo province (3.7), followed by Buriram (3.6), Prachinburi (2.88), Surin (2.5), and Sisaket (2.4) provinces. Asymptomatic plants were identified in Surin (12%), Prachinburi (5%), Sakaeo (0.2%), and Buriram (0.1%) by PCR analysis. Interestingly, cassava cultivars CMR-89 and Rayong 11 were susceptible to CMD. In approximately 95% of cases, the infection was transmitted by whitefly (Bemisia tabaci), which had a high population density in Prachinburi but was sparse in Surin, with the largest populations observed in May and June. Nucleotide sequencing of the mitochondrial cytochrome oxidase 1 (mtCO1) gene of whitefly (Bemisia tabaci) in Thailand revealed a similarity to the Asia II 1 whitefly gene. Furthermore, the AV1 gene—which encodes the capsid protein—showed 90% nucleotide identity with SLCMV. Phylogenetic analysis of completed nucleotide sequences of DNA-A and DNA-B components of the SLCMV genome determined by rolling circle amplification (RCA) indicated that they were similar to the nucleotide sequence of SLCMV isolates from Thailand, Vietnam, and Cambodia. These results provide important insights into the distribution, impact, and spread of CMD and SLCMV in Thailand.
Functional characterization of RELN missense mutations involved in recessive and dominant forms of Neuronal Migration Disorders
Authors: Riva Martina , Ferreira Sofia , Medvedeva Vera P. , Causeret Frédéric , Henry Olivia J. , Roux Charles-Joris , Bellesme Céline , Freri Elena , Parrini Elena , Josifova Dragana , Guerrini Renzo , Bahi-Buisson Nadia , Pierani Alessandra
Published: May 2021

RELN is a large secreted glycoprotein that acts at multiple steps of cerebral cortex development, including neuronal migration. Only recessive mutations of the Reelin gene (RELN) have been associated with human cortical malformations and none has been functionally characterized. We identified novel missense RELN mutations in both compound and de novo heterozygous patients exhibiting an array of neuronal migration disorders (NMDs) as diverse as pachygyria, polymicrogyria and heterotopia. Most mutations caused defective RELN secretion in vitro and, when ectopically expressed in the embryonic mouse cortex, affected neuronal aggregation and/or migration in vivo. We determined the de novo heterozygous mutations acted as dominant negative and demonstrated that RELN mutations mediate not only recessive, but also dominant NMDs. This work assesses for the first time the pathogenicity of RELN mutations showing a strong genotype-phenotype correlation. In particular, the behavior of the mutant proteins in vitro and in vivo predicts the severity of cortical malformations and provides valuable insight into the pathogenesis of these disorders.
Fabrication and Characterization Methods for Investigating Cell-Matrix Interactions in Environments Possessing Spatial Orientation Heterogeneity
Authors: Potter Michael J. , Richardson William J.
Published: May 2021

Fibrillar collagen is a ubiquitous structural protein that plays a significant role in determining the mechanical properties of various tissues. The constituent collagen architecture can give direct insight into the respective functional role of the tissue due to the strong structure-function relationship that is exhibited. In such tissues, matrix structure can vary across local subregions contributing to mechanical heterogeneity which can be implicated in tissue function or failure. The post-myocardial infarction scar environment is an example of note where mechanically insufficient collagen can result in impaired cardiac function and possibly tissue rupture due to post-MI cellular response and matrix interactions. In order to further develop the understanding of cell-matrix and cell-cell interactions within heterogeneous environments, we developed a method of heterogeneous collagen gel fabrication which produces a region of randomly oriented fibers directly adjacent to an interconnected region of anisotropic alignment. To fully capture and evaluate the degree of alignment and spatial orientation heterogeneity, several image processing and automated analysis methods were employed. Our analysis revealed the successful fabrication of an interconnected spatially heterogeneous collagen gel possessing distinct regions of random or preferential alignment. Additionally, embedded cell populations were observed to recognize and reorient with their underlying and surrounding architectures through our cell-centric analysis techniques.
Structural basis for target-site selection in RNA-guided DNA transposition systems
Authors: Park Jung-Un , Tsai Amy , Mehrotra Eshan , Petassi Michael T. , Hsieh Shan-Chi , Ke Ailong , Peters Joseph E. , Kellogg Elizabeth H.
Published: May 2021

CRISPR-associated transposition systems allow guide RNA-directed integration of a single DNA insertion in one orientation at a fixed distance from a programmable target sequence. We define the mechanism explaining this process by characterizing the transposition regulator, TnsC, from a Type V-K CRISPR-transposase system using cryo-EM. Polymerization of ATP-bound TnsC helical filaments explains how polarity information is passed to the transposase. Our Cryo-EM structure of TniQ-TnsC reveals that TniQ caps the TnsC filament, establishing a universal mechanism for target information transfer in Tn7/Tn7-like elements. Transposase-driven disassembly establishes delivery of the element only to unused protospacers. Finally, structures with the transition state mimic, ADP·AlF3, reveals how TnsC transitions to define the fixed point of insertion. These mechanistic findings provide the underpinnings for engineering CRISPR-associated transposition systems for research and therapeutic applications.

One Sentence Summary

Cryo-EM studies reveals the role of the AAA+ regulator TnsC for target-site selection in CRISPR-associated transposition systems.
Locus-associated R-loop repression in cis
Authors: Khosraviani Negin , Abraham Karan J. , Chan Janet N.Y. , Mekhail Karim
Published: May 2021

R-loops exert varied beneficial or detrimental effects. To assess the function of an R-loop at a specific genetic locus, we had developed an inducible RNaseH1-EGFP-dCas9 (RED) protein chimaera as part of a locus-associated R-loop-modulating system (LasR). LasR is compatible with R-loop modulation in trans, which targets RED to one locus to repress R-loops at another spatially proximal site. Here we use the LasR system for R-loop modulation in cis, which consists of targeting RED directly to an R-loop. The combination of LasR in cis and trans will be essential to ascribe functions to specific R-loops within varied molecular contexts and study designs.
Topographical relocation of adolescent sleep spindles reveals a new maturational pattern in the human brain
Authors: Gombos Ferenc , Bódizs Róbert , Pótári Adrián , Bocskai Gábor , Berencsi Andrea , Szakács Hanna , Kovács Ilona
Published: May 2021

Current theories of human neural development emphasize the posterior-to-anterior pattern of brain maturation. However, this scenario leaves out significant brain areas not directly involved with sensory input and behavioral control. Suggesting the relevance of cortical activity unrelated to sensory stimulation, such as sleep, we investigated adolescent transformations in the topography of sleep spindles. Sleep spindles are known to be involved in neural plasticity and in adults have a bimodal topography: slow spindles are frontally dominant, while fast spindles have a parietal/precuneal origin. The late functional segregation of the precuneus from the frontoparietal network during adolescence suggests that spindle topography might approach the adult state relatively late in development, and it may not be a result of the posterior-to-anterior maturational pattern. We analyzed the topographical distribution of spindle parameters in HD-EEG polysomnographic sleep recordings of adolescents and found that slow spindle duration maxima traveled from central to anterior brain regions, while fast spindle density, amplitude and frequency peaks traveled from central to more posterior brain regions. These results provide evidence for the gradual posteriorization of the anatomical localization of fast sleep spindles during adolescence and indicate the existence of an anterior-to posterior pattern of human brain maturation.
μ opioid receptors acutely regulate adenosine signaling in a thalamo-striatal circuit
Authors: Adhikary Sweta , Birdsong William T.
Published: May 2021

Endogenous adenosine plays a crucial role in maintaining energy homeostasis and adenosine levels are tightly regulated across neural circuits. In the dorsal medial striatum (DMS) adenosine inhibits neurotransmitter release, but the source and mechanism underlying its accumulation are largely unknown. Opioids also inhibit neurotransmitter release in the DMS and influences adenosine accumulation after prolonged exposure. However, how these two neurotransmitter systems interact acutely is also largely unknown. This study demonstrates that activation of opioid receptors (MORs), but not δ opioid receptors (DORs) or κ opioid receptors (KORs), inhibits tonic activation of adenosine A1Rs via a cyclic adenosine monophosphate (cAMP) dependent mechanism in both male and female mice. Further, selectively knocking-out MORs from presynaptic terminals and postsynaptic medium spiny neurons (MSNs) revealed that activation of MORs on D1R positive MSNs, but not D2R positive MSNs, is necessary to inhibit tonic adenosine signaling on presynaptic terminals. Given the role of D1R positive MSNs in movement and motivated behaviors, these findings reveal a novel mechanism by which these neurons regulate their own synaptic inputs.

Significance Statement

Understanding interactions between neuromodulatory systems within brain circuits is a fundamental question in neuroscience. The present work uncovers a novel role of opioids in acutely inhibiting adenosine accumulation and subsequent adenosine receptor signaling in the striatum by inhibiting the production of cAMP. Adenosine receptor signaling regulates striatal neurotransmitters including glutamate, GABA, dopamine and acetylcholine. Furthermore, interactions between adenosine2A receptors and numerous other GPCRs, including D2 dopamine and CB1 cannabinoid receptors, suggest that endogenous adenosine broadly modulates striatal GPCR signaling. Additionally, this work discovered that resting endogenous adenosine is released by D1, but not D2 receptor positive MSNs, suggesting that opioid signaling and manipulation of D1R-expressing MSN cAMP activity can broadly affect striatal function and behavior.
Adaptive phenotypic plasticity stabilizes evolution in fluctuating environments
Authors: Lalejini Alexander , Ferguson Austin J. , Grant Nkrumah A. , Ofria Charles
Published: May 2021

Fluctuating environmental conditions are ubiquitous in natural systems, and populations have evolved various strategies to cope with such fluctuations. The particular mechanisms that evolve profoundly influence subsequent evolutionary dynamics. One such mechanism is phenotypic plasticity, which is the ability of a single genotype to produce alternate phenotypes in an environmentally dependent context. Here, we use digital organisms (self-replicating computer programs) to investigate how adaptive phenotypic plasticity alters evolutionary dynamics and influences evolutionary outcomes in cyclically changing environments. Specifically, we examined the evolutionary histories of both plastic populations and non-plastic populations to ask: (1) Does adaptive plasticity promote or constrain evolutionary change? (2) Are plastic populations better able to evolve and then maintain novel traits? And (3), how does adaptive plasticity affect the potential for maladaptive alleles to accumulate in evolving genomes? We find that populations with adaptive phenotypic plasticity undergo less evolutionary change than non-plastic populations, which must rely on genetic variation from de novo mutations to continuously readapt to environmental fluctuations. Indeed, the non-plastic populations undergo more frequent selective sweeps and accumulate many more genetic changes. We find that the repeated selective sweeps in non-plastic populations drive the loss of beneficial traits and accumulation of maladaptive alleles via deleterious hitchhiking, whereas phenotypic plasticity can stabilize populations against environmental fluctuations. This stabilization allows plastic populations to more easily retain novel adaptive traits than their non-plastic counterparts. In general, the evolution of adaptive phenotypic plasticity shifted evolutionary dynamics to be more similar to that of populations evolving in a static environment than to non-plastic populations evolving in an identical fluctuating environment. All natural environments subject populations to some form of change; our findings suggest that the stabilizing effect of phenotypic plasticity plays an important role in subsequent adaptive evolution.
Conditional immobilization for live imaging C. elegans using auxin-dependent protein depletion
Authors: Cahoon Cori K. , Libuda Diana E.
Published: May 2021

The visualization of biological processes using fluorescent proteins and dyes in living organisms has enabled numerous scientific discoveries. The nematode Caenorhabditis elegans is a widely used model organism for live imaging studies since the transparent nature of the worm enables imaging of nearly all tissues within a whole, intact animal. While current techniques are optimized to enable the immobilization of hermaphrodite worms for live imaging, many of these approaches fail to successfully restrain the smaller male worms. To enable live imaging of worms of both sexes, we developed a new genetic, conditional immobilization tool that uses the auxin inducible degron (AID) system to immobilize both hermaphrodites and male worms for live imaging. Based on chromosome location, mutant phenotype, and predicted germline consequence, we identified and AID-tagged three candidate genes (unc-18, unc-104, and unc-52). Strains with these AID-tagged genes were placed on auxin and tested for mobility and germline defects. Among the candidate genes, auxin-mediated depletion of UNC-18 caused significant immobilization of both hermaphrodite and male worms that was also partially reversible upon removal from auxin. Notably, we found that male worms require a higher concentration of auxin for a similar amount of immobilization as hermaphrodites, thereby suggesting a potential sex-specific difference in auxin absorption and/or processing. In both males and hermaphrodites, depletion of UNC-18 did not largely alter fertility, germline progression, nor meiotic recombination. Finally, we demonstrate that this new genetic tool can successfully immobilize both sexes enabling live imaging studies of sexually dimorphic features in C. elegans.

ARTICLE SUMMARY

C. elegans is a powerful model system for visualizing biological processes in live cells. In addition to the challenge of suppressing the worm movement for live imaging, most immobilization techniques only work with hermaphrodites. Here, we describe a new genetic immobilization tool that conditionally immobilizes both worm sexes for live imaging studies. Additionally, we demonstrate that this tool can be used for live imaging the C. elegans germline without causing large defects to germline progression or fertility in either sex.