bluuebunny/crossref_metadata_2025 huggingface dataset:
Atrial Fibrillation Drivers: Redefining the Electrophysiological Substrate
Authors: Rottmann Markus , Pfenniger Anna , Yoo Shin , Johnson David , Geist Gail Elizabeth , Mandava Suman , Burrell Amy , Knight Bradley P , Passman Rod , Arora Rishi
Published: December 2020

Background:
We performed high-density mapping of persistent atrial fibrillation (AF) in animals and patients (1) to test that AF is due to greater than or equal 1 reentry, and (2) to characterize activation delay and reentries pre/ post pulmonary vein isolation (PVI). We determined electrophysiological characteristics that may predispose to the induction, maintenance, and reduction of AF.
Methods and Results:
This study includes 48 dogs and nine patients. 43 AF- and five sinus/ paced rhythm dogs (3-14 weeks rapid atrial pacing) were studied at open chest surgery with 117 epicardial electrograms (EGMs) (2.5mm dist.) in 6 bi-atrial regions. Rotational activity automatically detected with a new algorithm tracking the earliest and latest activation in all regions (5+/-2 per region) were stable over 424+/-505ms [120-4940ms]. Reentry stability was highest in the right atrial appendage (RAA) (405+/-219ms) and the posterior left atrium (PLA) (267+/-115ms) and anchored between >=3 zones of activation delay (15+/-5ms, median 13ms) defined as >10ms per 2.5mm. Cycle length (CL) and degree of focal fibrosis were highest in the PLA and left atrial free wall (LAFW) with 94+/-7ms, 96+/-5ms, and 49+/-14%, 47+/-19%. Fiber crossing density correlated with the stability of rotational activity (R=0.6, P<0.05). Activation delay was 2x higher in AF compared to sinus rhythm/paced rhythm (interval 200-500ms). Activation delay zones > 10ms were at the same locations, but increased 4x during AF vs. SR and were located at fiber crossings, fibrosis/ fat zones. Stability of rotational activity correlated with Organization Index (OI), Fraction Index (FI), Shannon's Entropy (ShEn), and CL (R>0.5, p< 0.0001). PVI in five hearts increased CL [2-14%] and reduced stability of rotational activity in nearly all regions remote to the pulmonary veins (PVs). Also in the clinical evaluation in nine patients using the HD-catheter (16 electrodes, 3mm dist.) activation delay at the reentrant trajectory was 2x higher at edges with maximal delay (20.5+/-8.1ms, median 19.6ms) vs (9.3+/-8.8ms, median 9.2ms) and 1.4 x higher during AF (13.0+/-18.7ms, median 7.2ms) compared to SR/ CS-pacing (18.0+/-11.6ms, median 17.7ms).
Conclusion:
Rotational activities in all bi-atrial regions anchored between small frequency-dependent activation delay zones in AF. PVI led to beneficial remodeling in bi-atrial regions remote to the PVs. These data may identify a new paradigm for persistent AF.
Uncertainty reduction in logistic regressions: a COVID-19 case-study using surrogate locations' asymptotic values
Authors: Hebling Vieira Bruno , Hiar Nathalia Hanna , Cardoso George Cunha
Published: December 2020

Logistic regressions are subject to high uncertainty when the data are not past the inflection point. For example, for logistic regressions estimated with data up to or before inflection point, uncertainties in the upper asymptotic value $K$ can be of the same order of magnitude of the population under analysis. This paper presents a method for uncertainty reduction in logistic regression using data from a surrogate logistic process. We illustrate the procedure using the Richards' growth function (Generalized Logistic Function) to make predictions for COVID-19 evolution in Brazilian cities at stages before and during their epidemic inflection points. We constrain the logistic function regression with $K$ calculated from selected surrogate international cities where the epidemic is clearly past its inflection point. Information gained with this constraint stabilizes the logistic regression, reducing the uncertainty in the curves' parameters, including the rate of growth at the inflection point. The uncertainty is reduced even when the actual surrogate $K$ is used just as an anchor to simulate different epidemic scenarios. Results predicted for COVID-19 trajectories within Brazil agree with actual data. These results suggest that in the absence of big data, a simple logistic regression may provide low uncertainty if surrogate cities have been identified for estimates of $K$, even if the specifics of the evolution in the surrogate cities are different. The method may be used for other logistic models and for other logistic processes in other areas such as economics and biology, if surrogate processes can be identified.
A Comprehensive Clinical Description of Pediatric SARS-CoV-2 Infection in Western Pennsylvania
Authors: Freeman Megan Culler , Gaietto Kristina , DiCicco Leigh Anne , Rauenswinter Sherry , Squire Joseph R , Aldewereld Zachary , Rapsinski Glenn , Iagnemma Jennifer , Campfield Brian T. , Wolfson David , Kazmerski Traci M. , Forno Erick
Published: December 2020

Objective: We sought to characterize clinical presentation and healthcare utilization for pediatric COVID-19 in Western Pennsylvania (PA).
Methods: We established and analyzed a registry of pediatric COVID-19 in Western PA that includes cases in patients <22 years of age cared for by the pediatric quaternary medical center in the area and its associated pediatric primary care network from March 11 through August 20, 2020.
Results: Our cohort included 424 pediatric COVID-19 cases (mean age 12.5 years, 47.4% female); 65% reported exposure and 79% presented with symptoms. The most common initial healthcare contact was through telehealth (45%). Most cases were followed as outpatients, but twenty-two patients (4.5%) were hospitalized: 19 with acute COVID-19 disease, and three for multisystem inflammatory syndrome of children (MIS-C). Admitted patients were younger (p<0.001) and more likely to have pre-existing conditions (p<0.001). Black/Hispanic patients were 5.8 times more likely to be hospitalized than white patients (p=0.012). Five patients (1.2%) were admitted to the PICU, including all three MIS-C cases; two required BiPAP and one mechanical ventilation. All patients survived.
Conclusions: We provide a comprehensive snapshot of pediatric COVID-19 disease in an area with low to moderate incidence. In this cohort, COVID-19 was generally a mild disease; however, ~5% of children were hospitalized. Pediatric patients can be critically ill with this infection, including those presenting with MIS-C.
Economic Burden of Viral Acute Respiratory Infections in Upper-Middle-Income Countries: Protocol For A Systematic Review
Authors: Rocha-Filho Cesar Ramos , Rocha Aline Pereira , Reis Felipe Sebastiao de Assis , Pinto Ana Carolina Pereira Nunes , Ramalho Gabriel Sodre , Trevisani Giulia Fernandes Moca , Ferla Laura Jantsch , Puga Maria Eduarda Santos , Correa Luci , Trevisani Virginia Fernandes Moca , De Liberal Marcia Mello Costa , Atallah Alvaro Nagib
Published: December 2020

Objective: To synthesize the available data on the economic burden of Coronavirus Diseases 2019 (COVID-19), Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS), Influenza-Like Illness (ILI), Respiratory Syncytial Virus (RSV)-related Acute Respiratory Infection (ARI), and Parainfluenza Virus type III (PIV3)-related ARI in Upper-Middle-Income Countries (UMIC), highlighting its major causes and comparing direct costs among nations. Study design: Systematic review, following the recommendations proposed in the Cochrane Handbook, but with some adaptations from previous economic studies. Review question: Is there any economic cost of viral ARI in UMIC? Types of studies to be included: Partial economic evaluation, such as Cost-of-Illness (COI) studies and burden of illness/diseases, database analysis, observational reports (cross-sectional studies, and prospective and retrospective cohort), and economic modelling studies that discuss one of the viral ARI in UMIC. No year of publication filter or language limit will be applied. Search databases: MEDLINE, EMBASE, LILACS, CINAHL, EconLit, CRD Library, MedRxiv, and Research Square. Moreover, hand searches of the bibliographies of included studies and relevant reviews identified during the screening process will be undertaken to identify any additional relevant study for inclusion in our review. Synthesis of results: Qualitative analysis. We will focus on the overall economic burden of the diseases on health systems and population; total direct cost; the contribution of different cost components to the economic burden (e.g. pharmacological therapy, hospitalization); comparative assessments of costs analysis across geographical location and time horizon; and current research gaps. Moreover, we intend to identify, when presented, prevalence and incidence rates of each disease. PROSPERO registration number: CRD42020225757.
The Presence of Ambulatory Hypoxia as an Early Predictor of Moderate to Severe COVID-19 Disease
Authors: Bhasin Ajay , Bregger Melissa , Kluk Mark , Park Peter , Feinglass Joe , Barsuk Jeffrey
Published: December 2020

Background

The importance of ambulatory hypoxia without resting hypoxia in COVID-19 is unknown. Ambulatory hypoxia without resting hypoxia may help objectively identify high-risk patients hospitalized with COVID-19. Interventions may be initiated earlier with sufficient lead-time between development of ambulatory hypoxia and other outcome measures.

Methods

We performed a retrospective study of adult patients hospitalized with COVID-19 from March 1, 2020 to October 30, 2020 in ten hospitals in an integrated academic medical system in the Chicagoland area. We analyzed patients who had daily ambulatory oximetry measurements, excluding patients who had first ambulatory oximetry measurements after the use of oxygen therapies (nasal cannula or advanced oxygen therapies). We determined the association of ambulatory hypoxia without resting hypoxia with the eventual need for nasal cannula or advanced oxygen therapies (defined as high flow nasal cannula, Bi-PAP, ventilator, or extracorporeal membrane oxygenation). We also calculated the time between development of ambulatory hypoxia and the need for oxygen therapies.

Results

Of 531 patients included in the study, 132 (24.9%) had ambulatory hypoxia. Presence of ambulatory hypoxia was strongly associated with subsequent use of nasal cannula (OR 4.8, 95% CI 2.8 – 8.4) and advanced oxygen therapy (IRR 7.7, 95% CI 3.4 – 17.5). Ambulatory hypoxia preceded nasal cannula use by a median 12.5 hours [IQR 3.25, 29.25] and advanced oxygenation therapies by 54 hours [IQR 25, 82].

Conclusion

Ambulatory hypoxia without resting hypoxia may serve as an early, non-invasive physiologic marker for the likelihood of developing moderate to severe COVID-19 and help clinicians triage patients and initiate earlier interventions.
A Systematic High-throughput Phenotyping Assay for Sugarcane Stalk Quality Characterization by Near-infrared Spectroscopy
Authors: Wang Maoyao , Li Xinru , Shen Yinjuan , Adnan Muhammad , Mao Le , Lu Pan , Hu Qian , Jiang Fuhong , Khan Muhammad Tahir , Deng Zuhu , Huang Jiangfeng , Zhang Muqing
Published: December 2020

Stalk quality improvement is deemed a promising strategy to enhance sugarcane production. However, the lack of efficient approaches for a systematic evaluation of sugarcane germplasm limited stalk quality improvement. In this study, 628 sugarcane samples were employed to take a high-throughput assay for determining the sugarcane stalk quality. Based on the high-performance anion chromatography method, large sugarcane stalk quality variations were detected in biomass composition and the corresponding fundamental ratio values. Online and offline Near-infrared Spectroscopy (NIRS) modeling strategies were applied for multiple purpose calibration. Consequently, 25 equations were generated with the excellent determination coefficient (R2) and ratio performance deviation (RPD) values. Notably, for some observations, RPD values as high as 6.3 were observed that indicated their exceptional performance potential and prediction capacity. Hence, this study provides a feasible way for high-throughput assessment of stalk quality, permitting large-scale screening of optimal sugarcane germplasm.
Pathogenic and Indigenous Denitrifying Bacteria are Transcriptionally Active and Key Multi-Antibiotic Resistant Players in Wastewater Treatment Plants
Authors: Yuan Ling , Wang Yubo , Zhang Lu , Palomo Alejandro , Zhou Jizhong , Smets Barth F. , Bürgmann Helmut , Ju Feng
Published: December 2020

The global rise and spread of antibiotic resistance greatly challenge the treatment of bacterial infections. Wastewater treatment plants (WWTPs) harbor and discharge antibiotic resistance genes (ARGs) as environmental contaminants. However, the knowledge gap on the host identity, activity and functionality of ARGs limits transmission and health risk assessment of WWTPs resistome. Hereby, a genome-centric quantitative metatranscriptomic approach was exploited to realize high-resolution qualitative and quantitative analyses of bacterial hosts of ARGs (i.e., multi-resistance, pathogenicity, activity and niches) throughout 12 urban WWTPs. We found that ∼45% of 248 recovered genomes expressed ARGs against multiple classes of antibiotics, among which bacitracin and aminoglycoside resistance genes inProteobacteriawas the most prevalent scenario. Both potential pathogens and indigenous denitrifying bacteria were transcriptionally active hosts of ARGs. The almost unchanged relative expression levels of ARGs in the most resistant populations (66.9%) and the surviving ARG hosts including globally emerging pathogens (e.g.,Aliarcobacter cryaerophilus) in treated WWTP effluent prioritizes future examination on the health risks related with resistance propagation and human exposure in the receiving environment.
Paracrine behaviors arbitrate parasite-like interactions between tumor subclones
Authors: Noble Robert J. , Walther Viola , Roumestand Christian , Hibner Urszula , Hochberg Michael E. , Lassus Patrice
Published: December 2020

Explaining the emergence and maintenance of intratumor heterogeneity is an important question in cancer biology. Tumor cells can generate considerable subclonal diversity, which influences tumor growth rate, treatment resistance, and metastasis, yet we know remarkably little about how cells from different subclones interact. Here, we confronted two murine mammary cancer cell lines to determine both the nature and mechanisms of subclonal cellular interactionsin vitro.Surprisingly, we found that, compared to monoculture, growth of the ‘winner’ was enhanced by the presence of the ‘loser’ cell line, whereas growth of the latter was reduced. Mathematical modeling and laboratory assays indicated that these interactions are mediated by the production of paracrine metabolites resulting in the winner subclone effectively ‘farming’ the loser. Our findings add a new level of complexity to the mechanisms underlying subclonal growth dynamics.
Activity-dependent refinement of nasal retinal projections drives topographic map sharpening in the teleost visual system
Authors: Spead Olivia , Poulain Fabienne E.
Published: December 2020

Topographic maps in the brain are essential for processing information. Yet, our understanding of topographic mapping has remained limited by our inability to observe maps forming and refining directly in vivo. Here, we used Cre-mediated recombination of a new colorswitch reporter in zebrafish to generate the first transgenic model allowing the dynamic analysis of retinotopic mapping in vivo. We found that the antero-posterior retinotopic map forms early but remains dynamic, with nasal and temporal retinal axons expanding their projection domains over time. Nasal projections initially arborize in the anterior tectum but progressively refine their projection domain to the posterior tectum in an activity-dependent manner. This activity-dependent refinement drives retinotopic map sharpening along the antero-posterior axis. Altogether, our study provides the first analysis of a topographic map maturing in real-time in a live animal and opens new strategies for dissecting the intricate mechanisms of precise topographic mapping in vertebrates.
A cytokine network balance influences the fate ofLeishmania (Viannia) braziliensisinfection in a cutaneous leishmaniasis hamster model
Authors: Paiva MB , Ribeiro-Romão RP , Resende-Vieira L , Braga-Gomes T , Oliveira MP , Saavedra AF , Silva-Couto L , Albuquerque HG , Moreira OC , Pinto EF , Da-Cruz AM , Gomes-Silva A
Published: December 2020

The golden hamster is a suitable model for studying cutaneous leishmaniasis (CL) due toLeishmania (Viannia) braziliensis. Immunopathological mechanismsare wellstablished intheL. (L.) major-mousemodel, in which IL-4 instructs a Th2 response towards progressive infection. In the present study, we evaluatedthe natural history ofL. braziliensisinfection from its first stagesup to lesion establishment, with the aim ofidentifyingimmunological parameters associated with the disease outcome and parasitismfate. To this end, hamsters infected with 104, 105,or 106promastigoteswere monitored duringthe first hours (4h, 24h), early (15, 30 days) and late (50 days) post-infection (pi) phases. Cytokines, iNOS and arginasegene expression were quantified in the established lesions by RT-PCR. Compared to the 105or 106groups, 104animals presented lower lesions sizes, less tissue damage,and lower IgG levels. Basal gene expression in normal skin was high for TGF-β, and intermediary for TNF, IL-6, and IL-4.At 4hpi, no cytokine induction was observed in the 104group, while an upregulation of IL-6, IL-10, and IL-4 was observed in the 106group. At 15dpi, lesion appearance was accompanied byan increasedexpression of all assessed cytokines, markedly in the 105and 106groups. Upregulation of all investigated cytokines was observed in the late phase, although less expressive in the 104group. IFN-γ was the depending variable influencing tissue damage, while IL-6 was associatedto parasite load. The network correlating gene expression and clinical and laboratorial parameters indicated inoculum-independent associations at 15 and 30dpi.A strong positive network correlation was observed in the 104group, but not in the105or 106groups. In conclusion, IL-4, IL-6, IL-10, and TGF-β are linkedtoL. braziliensisprogression. However, a balanced cytokine network is the key for an immune response able to reduce the ongoing infection and reduce pathological damage.
Selective human tau protein expression in different clock circuits of theDrosophilabrain disrupts different aspects of sleep and circadian rhythms
Authors: Jaciuch David , Munns Jack , Chawla Sangeeta , Davis Seth J. , Juusola Mikko
Published: December 2020

Circadian behavioural deficits, such as increased daytime naps and reduced night-time sleep, are common in Alzheimer’s disease and other tauopathies. But it has remained unclear whether these circadian abnormalities arise from tau pathology in either the master pacemaker or downstream neurons. Here we study this question by selectively expressing different human tau proteins in specificDrosophilabrain circuits and monitoring locomotor activity under light-dark (LD) and in “free-running” dark-dark (DD) conditions. We show that expressing human tau proteins in the fly brain recapitulates faithfully several behavioural changes found in tauopathies. We identify discrete neuronal subpopulations within the clock network as the primary target of distinct circadian behavioural disturbances in different environmental conditions. Specifically, we show that the PDF-positive pacemaker neurons are the main site for night-activity gain and -sleep loss, whereas the non-PDF clock-neurons are the main site of reduced intrinsic behavioural rhythmicity. Bioluminescence measurements revealed that the molecular clock is intact despite the behavioural arrhythmia. Our results establish that dysfunction in both the central clock- and afferent clock-neurons jointly contribute to the circadian locomotor activity rhythm disruption inDrosophilaexpressing human tau.

Significance Statement

This study directly linksin vivohuman tau protein expression in region-specificDrosophilaclock-neurons with the resulting sleep and circadian rhythm deficits to extract new knowledge of how Alzheimer’s disease and other tauopathies perturb the balance of activity and sleep. We anticipate that this novel approach will provide a useful general template for other studies of neurodegeneration in model organisms, seeking to dissect the impact of neurodegenerative disease on circadian behaviour, and further deepening our understanding of how the clock-neuron network works.
Decomposing the sources of SARS-CoV-2 fitness variation in the United States
Authors: Kepler Lenora , Hamins-Puertolas Marco , Rasmussen David A.
Published: December 2020

The fitness of a pathogen is a composite phenotype determined by many different factors influencing growth rates both within and between hosts. Determining what factors shape fitness at the host population-level is especially challenging because both intrinsic factors like pathogen genetics and extrinsic factors such as host behaviour influence between-host transmission potential. These challenges have been highlighted by controversy surrounding the population-level fitness effects of mutations in the SARS-CoV-2 genome and their relative importance when compared against non-genetic factors shaping transmission dynamics. Building upon phylodynamic birth-death models, we develop a new framework to learn how hundreds of genetic and non-genetic factors have shaped the fitness of SARS-CoV-2. We estimate the fitness effects of all amino acid variants and several structural variants that have circulated in the United States between February 2020 and March 2021 from viral phylogenies. We also estimate how much fitness variation among pathogen lineages is attributable to genetic versus non-genetic factors such as spatial heterogeneity in transmission rates. Before September 2020, most fitness variation between lineages can be explained by background spatial heterogeneity in transmission rates across geographic regions. Starting in late 2020, genetic variation in fitness increased dramatically with the emergence of several new lineages including B.1.1.7, B.1.427, B.1.429 and B.1.526. Our analysis also indicates that genetic variants in less well-explored genomic regions outside of Spike may be contributing significantly to overall fitness variation in the viral population.
Exploring the microbiome-wide lysine acetylation, succinylation and propionylation in human gut microbiota
Authors: Zhang Xu , Cheng Kai , Ning Zhibin , Mayne Janice , Walker Krystal , Chi Hao , Farnsworth Charles L. , Lee Kimberly , Figeys Daniel
Published: December 2020

Background

Lysine acylations are important post-translational modifications that are present in both eukaryotes and prokaryotes, regulating diverse cellular functions. Our knowledge of the microbiome lysine acylation remains limited due to the lack of efficient analytical and bioinformatics methods for complex microbial communities.

Results

We show that serial enrichment using motif antibodies successfully captures peptides containing lysine acetylation, propionylation and succinylation from human gut microbiome samples. A new bioinformatic workflow consisting of unrestricted database search confidently identified >60,000 acetylated, and ~20,000 propionylated and succinylated gut microbial peptides. Characterization of these identified modification-specific metaproteomes, i.e. meta-PTMomes, demonstrates that lysine acylations are differentially distributed in microbial species with different metabolic capabilities.

Conclusion

This study provides an analytical framework, consisting of a serial immunoaffinity enrichment and an open database search strategy, for the study of lysine acylations in microbiome, which enables functional microbiome studies at the post-translational level.
Soft sweeps predominate recent positive selection in bonobos (Pan paniscus) and chimpanzees (Pan troglodytes)
Authors: Brand Colin M. , White Frances J. , Ting Nelson , Webster Timothy H.
Published: December 2020

Two modes of positive selection have been recognized: 1) hard sweeps that result in the rapid fixation of a beneficial allele typically from ade novomutation and 2) soft sweeps that are characterized by intermediate frequencies of at least two haplotypes that stem from standing genetic variation or recurrentde novomutations. While many populations exhibit both hard and soft sweeps throughout the genome, there is increasing evidence that soft sweeps, rather than hard sweeps, are the predominant mode of adaptation in many species, including humans. Here, we use a supervised machine learning approach to assess the extent of completed hard and soft sweeps in the closest living relatives of humans: bonobos and chimpanzees (genusPan). We trained convolutional neural network classifiers using simulated data and applied these classifiers to population genomic data for 71 individuals representing all five extantPanlineages, of which we successfully analyzed 60 individuals from four lineages. We found that recent adaptation inPanis largely the result of soft sweeps, ranging from 73.1 to 97.7% of all identified sweeps. While few hard sweeps were shared among lineages, we found that between 19 and 267 soft sweep windows were shared by at least two lineages. We also identify novel candidate genes subject to recent positive selection. This study emphasizes the importance of shifts in the physical and social environment, rather than novel mutation, in shaping recent adaptations in bonobos and chimpanzees.
More than Words: Neurophysiological Correlates of Semantic Dissimilarity Depend on Comprehension of the Speech Narrative
Authors: Broderick Michael P. , Zuk Nathaniel J. , Anderson Andrew J. , Lalor Edmund C.
Published: December 2020

Speech comprehension relies on the ability to understand the meaning of words within a coherent context. Recent studies have attempted to obtain electrophysiological indices of this process by modelling how brain activity is affected by a word’s semantic dissimilarity to preceding words. While the resulting indices appear robust and are strongly modulated by attention, it remains possible that, rather than capturing the contextual understanding of words, they may actually reflect word-to-word changes in semantic content without the need for a narrative-level understanding on the part of the listener. To test this possibility, we recorded EEG from subjects who listened to speech presented in either its original, narrative form, or after scrambling the word order by varying amounts. This manipulation affected the ability of subjects to comprehend the narrative content of the speech, but not the ability to recognize the individual words. Neural indices of semantic understanding and low-level acoustic processing were derived for each scrambling condition using the temporal response function (TRF) approach. Signatures of semantic processing were observed for conditions where speech was unscrambled or minimally scrambled and subjects were able to understand the speech. The same markers were absent for higher levels of scrambling when speech comprehension dropped below chance. In contrast, word recognition remained high and neural measures related to envelope tracking did not vary significantly across the different scrambling conditions. This supports the previous claim that electrophysiological indices based on the semantic dissimilarity of words to their context reflect a listener’s understanding of those words relative to that context. It also highlights the relative insensitivity of neural measures of low-level speech processing to speech comprehension.
ImuA participates in SOS mutagenesis by interacting with RecA1 and ImuB inMyxococcus xanthus
Authors: Sheng Duohong , Wang Ye , Jiang Zhiwei , Liu Dongkai , Li Yuezhong
Published: December 2020

Bacteria have two pathways to restart stalled replication forks caused by environmental stresses, error-prone translesion DNA synthesis (TLS) catalyzed by TLS polymerase and error-free template switching catalyzed by RecA, and their competition on the arrested fork affects bacterial SOS mutagenesis. DnaE2 is an error-prone TLS polymerase, and its functions require ImuA and ImuB. Here we investigated the function ofimuA,imuBanddnaE2inMyxococcus xanthusand found thatimuAshowed differences fromimuBanddnaE2in bacterial growth, resistance and mutation frequency. Transcriptomics analysis found that ImuA were associated with bacterial SOS response. Yeast-two-hybrid scanning revealed that ImuA interacted with RecA1 besides ImuB. Protein activity analysis proved that ImuA had no DNA binding activity, but inhibited the DNA binding and recombinase activity of RecA1. These findings highlight that ImuA not only participates in TLS by binding ImuB, but also inhibits the recombinase activity of RecA1 inM. xanthus, suggesting a role of ImuA in the two replication restart pathways.

Importance

DnaE2 is responsible for bacterial SOS mutagenesis in nearly one third of sequenced bacterial strains. However, its mechanism, especially the function of its accessory protein ImuA, is still unclear. Here we reported thatM. xanthusImuA might facilitate DnaE2 TLS by inhibiting the recombinase activity of RecA1, which helps to explain the mechanism of DnaE2-dependent TLS and the scientific problem of choosing one of the two restart pathways to repair the stalled replication fork.
IMPACT OF A SARS-COV-2 INFECTION IN PATIENTS WITH CELIAC DISEASE
Authors: Elli Luca , Facciotti Federica , Lombardo Vincenza , Scricciolo Alice , Sanders David S , Vaira Valentina , Barisani Donatella , Vecchi Maurizio , Costantino Andrea , Scaramella Lucia , Dell'Osso Bernardo , Doneda Luisa , Roncoroni Leda
Published: December 2020

Objective. The SARS-CoV-2 pandemic has spread across the world causing a dramatic number of infections and deaths. No data are available about the effects of an infection in patients affected by celiac disease (CD) in terms of the development of related symptoms and antibodies. We aimed to investigate the impact of the SARS-CoV-2 pandemic in celiac patients.
Design. During a lockdown, the celiac patients living in the Milan area were contacted and interviewed about the development of COVID-19 symptoms as well as adherence to an anti-virus lifestyle and a gluten-free diet (GFD). They were also given a stress questionnaire to fill in. The development of anti-SARS-CoV-2 IgG and IgA (anti-RBD and N proteins) and the expression of the duodenal ACE2 receptor were investigated. When available, duodenal histology, anti-tissue transglutaminase IgA (tTGA), presence of immunologic comorbidities and adherence to the GFD were analysed as possible risk factors.
Results. 362 celiac patients have been interviewed and 42 (11%) presented with COVID-19 symptoms. The presence of symptoms was not influenced by tTGA positivity, presence of duodenal atrophy or adherence to GFD. 37% of the symptomatic patients presented anti-SARS-CoV-2 immunoglobulins (Ig). Globally, 18% of celiac patients showed anti-SARS-CoV-2 Ig vs 25% of the non-celiac control (p=0.18). The values of anti-RBD IgG/IgA and anti-N IgG did not differ from the non-celiac controls. Celiac patients had a significant lower level of anti-N IgA. The ACE2 receptor was detected in the non-atrophic duodenal mucosa of celiac patients; atrophy was associated with a lower expression of the ACE2 receptor.
Conclusion. CD patients have an anti-SARS-CoV-2 Ig positiveness and profile similar to non-celiac controls, except for anti-N IgA. The main celiac parameters and adherence to the GFD do not influence the development of a different Ig profile.
It makes you realise your own mortality: A qualitative study on mental health of older adults in the UK during COVID-19
Authors: McKinlay Alison Ruth , Fancourt Daisy , Burton Alexandra
Published: December 2020

Background: Older adults have been disproportionately affected by COVID-19, with high fatalities and health complications reported. Adults over the age of 70 in the UK were advised to self-isolate for 3 months early during the pandemic and it is unclear which factors influenced their experiences during this time.
Objective: The aim of this qualitative study was to explore factors that threatened and protected the wellbeing of older adults living in the UK during the COVID-19 pandemic.
Methods: We undertook semi-structured interviews with 20 adults aged over 70. Purposive sampling methods were used to increase diversity within the group. Transcripts were analysed using thematic analysis.
Results: Participants were aged 72-93, 9 women and 11 men, 80% were White British, 40% lived alone. We identified 2 superordinate themes, including (1) Threats to wellbeing: mortality concerns, grief and loss of normal life, restricted health service access, COVID-19 concerns, and restricted access to activities that protect wellbeing. (2) Factors protective of wellbeing: slower pace of life, maintaining routine, socialising, and use of past coping skills. Many participants drew on their resilience and life experience to self-manage fear and uncertainty associated with the pandemic, using their time during lockdown to reflect or organise end-of-life affairs.
Conclusions: This study provides evidence that while older adults experienced challenges, many were resilient against COVID-19 restrictions despite early concerns of mental health consequences. Our findings highlight the importance of maintaining access to essentials to promote feelings of normality and social support to help reduce uncertainty in times of pandemics.
REACT-1 round 7 updated report: regional heterogeneity in changes in prevalence of SARS-CoV-2 infection during the second national COVID-19 lockdown in England
Authors: Riley Steven , Walters Caroline E. , Wang Haowei , Eales Oliver , Ainslie Kylie E. C. , Atchinson Christina , Fronterre Claudio , Diggle Peter J. , Ashby Deborah , Donnelly Christl A , Cooke Graham , Barclay Wendy , Ward Helen , Darzi Ara , Elliott Paul
Published: December 2020

Background
England exited a four-week second national lockdown on 2nd December 2020 initiated in response to the COVID-19 pandemic. Prior results showed that prevalence dropped during the first half of lockdown, with greater reductions in higher-prevalence northern regions.

Methods
REACT-1 is a series of community surveys of SARS-CoV-2 RT-PCR swab-positivity in England, designed to monitor the spread of the epidemic and thus increase situational awareness. Round 7 of REACT-1 commenced swab-collection on 13th November 2020. A prior interim report included data from 13th to 24th November 2020 for 105,122 participants. Here, we report data for the entire round with swab results obtained up to 3rd December 2020.

Results
Between 13th November and 3rd December (round 7) there were 1,299 positive swabs out of 168,181 giving a weighted prevalence of 0.94% (95% CI 0.87%, 1.01%) or 94 per 10,000 people infected in the community in England. This compares with a prevalence of 1.30% (1.21%, 1.39%) from 16th October to 2nd November 2020 (round 6), a decline of 28%. Prevalence during the latter half of round 7 was 0.91% (95% CI, 0.81%, 1.03%) compared with 0.96% (0.87%, 1.05%) in the first half. The national R number in round 7 was estimated at 0.96 (0.88, 1.03) with a decline in prevalence observed during the first half of this period no longer apparent during the second half at the end of lockdown. During round 7 there was a marked fall in prevalence in West Midlands, a levelling off in some regions and a rise in London. R numbers at regional level ranged from 0.60 (0.41, 0.80) in West Midlands up to 1.27 (1.04, 1.54) in London, where prevalence was highest in the east and south-east of the city. Nationally, between 13th November and 3rd December, the highest prevalence was in school-aged children especially at ages 13-17 years at 2.04% (1.69%, 2.46%), or approximately 1 in 50.

Conclusion
Between the previous round and round 7 (during lockdown), there was a fall in prevalence of SARS-CoV-2 swab-positivity nationally, but it did not fall uniformly over time or by geography. Continued vigilance is required to reduce rates of infection until effective immunity at the population level can be achieved through the vaccination programme.
Architectures of epidemic models: accommodating constraints from empirical and clinical data
Authors: TURINICI Gabriel
Published: December 2020

Deterministic compartmental models have been used extensively in modeling epidemic propagation.
These models are required to fit available data and numerical procedures are often implemented to this end. But not every model architecture is able to fit the data because the structure of the model imposes hard constraints on the solutions. We investigate in this work two such situations: first the distribution of transition times from a compartment to another may impose a variable number of intermediary states; secondly, a non-linear relationship between time-dependent measures of compartments sizes may indicate the need for structurations (i.e., considering several groups of individuals of heterogeneous characteristics).
Risk of Stress/Depression and Functional Impairment in Denmark Immediately Following a COVID-19 Shutdown
Authors: Andersen Lars H. , Fallesen Peter , Bruckner Tim-Allen
Published: December 2020

Background
This study aimed to investigate the impact of the first COVID-19 lockdown (March-April 2020) on risk for stress/depression and functional impairment in a representative sample of adult individuals in Denmark, and whether the impact of lockdown was heterogeneous across living situation.

Methods:
Using a representative, randomly drawn sample from the complete Danish adult population interviewed in March 2 to April 13, 2020 (n=2,836) and again in July 2020 (n=1,526, 54% retention rate), we study how the imposed lockdown announced March 11 following the onset of the first Danish wave of COVID-19 infections affected mental wellbeing. We use the World Health Organization Five Well-being Index (WHO-5) and the Work and Social Adjustment Scale (WSAS) to capture wellbeing and functioning. Using covariate adjusted ordinary least squares linear probability models and exploiting variation in the timing of responses occurring just before and just after the introduction of lockdown, we compare respondents before lockdown to respondents that answered during lockdown, as well to answers in re-interviews in July.

Results:
We find reduced depressive symptoms among adults immediately after the shutdown, concentrated in adults with children living at home. Measures of functional impairment also decline immediately after the March shutdown among adults with children living at home. Impairment intensified for the entire sample between March and July, but depressive symptoms remained at lower rate in July.

Conclusions:
Findings in Denmark indicate that living with children at home may have, in the short term, buffered the potential mental health sequelae of the COVID-19 shutdown.
Increased connectivity among sensory and motor regions during visual and audiovisual speech perception
Authors: Peelle Jonathan E. , Spehar Brent , Jones Michael S. , McConkey Sarah , Myerson Joel , Hale Sandra , Sommers Mitchell S. , Tye-Murray Nancy
Published: December 2020

In everyday conversation, we usually process the talker’s face as well as the sound of their voice. Access to visual speech information is particularly useful when the auditory signal is degraded. Here we used fMRI to monitor brain activity while adult humans (n = 60) were presented with visual-only, auditory-only, and audiovisual words. The audiovisual words were presented in quiet and several signal-to-noise ratios. As expected, audiovisual speech perception recruited both auditory and visual cortex, with some evidence for increased recruitment of premotor cortex in some conditions (including in substantial background noise). We then investigated neural connectivity using psychophysiological interaction (PPI) analysis with seed regions in both primary auditory cortex and primary visual cortex. Connectivity between auditory and visual cortices was stronger in audiovisual conditions than in unimodal conditions, including a wide network of regions in posterior temporal cortex and prefrontal cortex. In addition to whole-brain analyses, we also conducted a region-of-interest analysis on the left posterior superior temporal sulcus (pSTS), implicated in many previous studies of audiovisual speech perception. We found evidence for both activity and effective connectivity in pSTS for visual-only and audiovisual speech, although these were not significant in whole-brain analyses. Taken together, our results suggest a prominent role for cross-region synchronization in understanding both visual-only and audiovisual speech that complements activity in “integrative” brain regions like pSTS.
Ranked Choice Voting for Representative Transcripts with TRaCE
Authors: Olson Andrew J. , Ware Doreen
Published: December 2020

Genome sequencing projects annotate protein-coding gene models with multiple transcripts, aiming to represent all of the available transcript evidence. However, downstream analyses often operate on only one representative transcript per gene locus, sometimes known as the canonical transcript. To choose canonical transcripts, TRaCE (Transcript Ranking and Canonical Election) holds an ‘election’ in which a set of RNA-seq samples rank transcripts by annotation edit distance. These sample-specific votes are tallied along with other criteria such as protein length and InterPro domain coverage. The winner is selected as the canonical transcript, but the election proceeds through multiple rounds of voting to order all the transcripts by relevance. Based on the set of expression data provided, TRaCE can identify the most common isoforms from a broad expression atlas or prioritize alternative transcripts expressed in specific contexts.

Availability and Implementation

Transcript ranking code can be found on GitHub at {{https://github.com/warelab/TRaCE}}

Contact

olson@cshl.edu,ware@cshl.edu

Supplementary information

Additional data are available in the github repository.
Experiencing surprise: the temporal dynamics of its impact on memory
Authors: Frank Darya , Kafkas Alex , Montaldi Daniela
Published: December 2020

To efficiently process information, the brain shifts between encoding and retrieval states, prioritising bottom-up or top-down processing accordingly. Expectation violation before or during learning has been shown to trigger an adaptive encoding mechanism, resulting in better memory for unexpected events. Using fMRI we explored (1) whether this encoding mechanism is also triggered during retrieval, and if so, (2) what the temporal dynamics of its mnemonic consequences are. Male and female participants studied object images, then, with new objects, they learned a contingency between a cue and a semantic category. Rule-abiding (expected) and violating (unexpected) targets and similar foils were used at test. We found interactions between previous and current similar events’ expectation, such that when an expected event followed a similar but unexpected event, its performance was boosted, underpinned by activation in the hippocampus, midbrain, and occipital cortex. In contrast, a sequence of two unexpected similar events also triggered occipital engagement, however, this did not enhance memory performance. Taken together, our findings suggest that when the goal is to retrieve, encountering surprising events engages an encoding mechanism, supported by bottom-up processing, that may enhance memory for future related events.

Significance statement

Optimising the balance between new learning and the retrieval of existing knowledge is an ongoing process, at the core of human cognition. Previous research into memory encoding suggests experiencing surprise leads to the prioritisation of the leaning of new memories, forming an adaptive encoding mechanism. We examined whether this mechanism is also engaged when the current goal is to retrieve information. Our results demonstrate that an expectation-driven shift towards an encoding state, supported by enhanced perceptual processing, is beneficial for the correct identification of subsequent expected similar events. These findings have important implications for our understanding of the temporal dynamics of the adaptive encoding of information into memory.
The ratio versus difference optimization and its implications for optimality theory
Authors: Shinde Sonali , Patwardhan Ankur , Watve Milind
Published: December 2020

Among the classical models of optimization, some models maximize the ratio of returns per investment, others maximize the difference between returns and investment. However, the question under what conditions use of the ratio model is appropriate and under what conditions a difference model should be used remained unaddressed until recently. The question is important because the strategies indicated by ratio optimum can be substantially different than the ones suggested by difference optimum. We make a general case here for the set of conditions for appropriate use of ratio versus difference optimum. When the investable amount is perceived as limiting but not the investment opportunities a ratio optimum is appropriate and when the investment opportunities are perceived to be limiting but not the investable amount, difference optimum is appropriate. Taking examples of Concorde fallacy, parental investment, r and K selection, nectar production, pollinator behavior, protein synthesis and stability, viral burst size and human economic behavior we show that the ratiodifference distinction in optimization models resolves many long standing debates and conundrums in evolution, behavior and economics.
ICM cells can be partitioned robustly through transient synchronization using secreted FGF4
Authors: Xu Xiaochan , Trusina Ala , Sneppen Kim
Published: December 2020

The differentiation of ICM cells into epiblast (EPI) and primitive endoderm (PE) is central in embryonic development. It is known that FGF4 signaling is important in this process, but it remains unclear how cells can be correctly partitioned. Here we model the NANOG-GATA6-FGF4 network, and test all 64 logical regulatory combinations for their ability to partition a group of cells. We found that nearly all the logic combinations allowed for correct partitioning, including a minimal network where self-activation of NANOG and GATA6 was inactivated. However such self-activation increased the robustness of the system. Furthermore, the model also captured the reported changes in cell proportions in response to FGF perturbations. This constrains the possible regulatory logic and predicts the presence of an “OR” gate in cell-cell communication. We repeatedly found that FGF4 coordinated the decision in two phases: A convergence and a bifurcation phase. First FGF4 negative feedback drives the cells to a balanced “battle” state where most cells have intermediate levels of both regulators, thus being double positive. Subsequent bifurcation happens at constant FGF4 level. Together our results suggest that the frequently observed state of multipotency during differentiation may be an emergent phenomenon resulting from inter-cellular negative feedbacks.