bluuebunny/crossref_metadata_2025 huggingface dataset:
A Hybrid Catheter Localisation Framework in Echocardiography Based on Electromagnetic Tracking and Deep Learning Segmentation
Authors: Jia Fei , Wang Shu , Pham V. T.
Published: December 2020

Interventional cardiology procedure is an important type of minimally invasive surgery that deals with the catheter-based treatment of cardiovascular diseases, such as coronary artery diseases, strokes, peripheral arterial diseases and aortic diseases. Ultrasound imaging, also called echocardiography, is a typical imaging tool that monitors catheter puncturing. Localising a medical device accurately during cardiac interventions can help improve the procedure’s safety and reliability under ultrasound imaging. However, external device tracking and image-based tracking methods can only provide a partial solution. Thus, we proposed a hybrid framework, with the combination of both methods to localise the catheter tip target in an automatic way. The external device used was an electromagnetic tracking system from North Digital Inc (NDI) and the ultrasound image analysis was based on UNet, a deep learning network for semantic segmentation. From the external method, the tip’s location was determined precisely, and the deep learning platform segmented the exact catheter tip automatically.
Bias measurement in, bias results out: how an assumption free height adjusted weight model outperforms body mass index
Authors: Shuey Megan M. , Huang Shi , Levinson Rebecca T. , Farber-Eger Eric , Cahill Katherine N. , Beckman Joshua A. , Koethe John R. , Silver Heidi J. , Niswender Kevin D. , Cox Nancy J. , Harrell Frank E. , Wells Quinn S.
Published: December 2020

Objective

Body mass index (BMI) is the most commonly used predictor of weight-related comorbidities and outcomes. However, the presumed relationship between height and weight intrinsic to BMI may introduce bias with respect to prediction of clinical outcomes. Using Vanderbilt University Medical Center’s deidentified electronic health records and landmark methodology, we performed a series of analyses comparing the performance of models representing weight and height as separate interacting variables to models using BMI.

Methods

Model prediction was evaluated with respect to established weight-related cardiometabolic traits, metabolic syndrome and its components hypertension, diabetes mellitus, low high-density lipoprotein, and elevated triglycerides, as well as cardiovascular outcomes, atrial fibrillation, coronary artery disease, heart failure, and peripheral artery disease. Model performance was evaluated using likelihood ratio, R2, and Somers’ Dxy rank correlation. Differences in model predictions were visualized using heatmaps.

Results

Regardless of outcome, the maximally flexible model had a higher likelihood ratio, R2, and Somers’ Dxy rank correlation for event-free prediction probability compared to the BMI model. Performance differed based on the outcome and across the height and weight range.

Conclusions

Compared to BMI, modeling height and weight as independent, interacting variables results in less bias and improved predictive accuracy for all tested traits.

Study Importance Questions

What is already known about this subject?

Body mass index, derived from collected height and weight measures, is an imperfect proxy measure of body fat composition often used in medical research.

What are the new findings in your manuscript?

We demonstrate how BMI introduces complex non-uniform biases across outcome and height-weight space.

How might your results change the direction of research or the focus of clinical practice?

Modeling height and weight as separate, non-linear, interacting variables improves clinical prediction across the complete spectrum of heights and weights for all clinical out-comes.
On an optimal testing strategy for workplace settings operating during the COVID-19 pandemic
Authors: Hernandez X. , Valentinotti S.
Published: December 2020

High quality daily testing for the presence of the SARS-CoV-2 in workplace settings has become part of the standard and mandatory protection measures implemented widely in response to the current pandemic. Such tests are often limited to a small fraction of the attending personnel due to cost considerations, limited availability and processing capabilities and the often cumbersome requirements of the test itself. A maximally efficient use of such an important and frequently scarce resource is clearly required. We here present an optimal testing strategy which minimises the presence of pre-symptomatic and asymptomatic members of the population, derived under a series of simplifying assumptions, which however retain many of the generalities of the problem and yield robust results, as verified through a number of numerical simulations. We show that reduction in overall infected-person-days, IPD, by significant percentages can be achieved, for fixed numbers of tests per day of 5% and 10% of the population, of 30% and 50% in the IPD numbers, respectively.
Ferritin nanoparticle based SARS-CoV-2 RBD vaccine induces persistent antibody response and long-term memory in mice
Authors: Wang Wenjun , Huang Baoying , Zhu Yanping , Tan Wenjie , Zhu Mingzhao
Published: December 2020

Since the outbreak of COVID-19, over 200 vaccine candidates have been documented and some of them have advanced to clinical trials with encouraging results. However, the antibody persistence over 3 months post immunization and the long-term memory have been rarely reported. Here, we report that a ferritin nanoparticle based SARS-CoV-2 RBD vaccine induced in mice an efficient antibody response which lasts for at least 7 months post immunization. Significantly higher number of memory B cells were maintained and a significantly higher level of recall response was induced upon antigen challenge. Thus, we believe our current study provide the first information about the long-term antibody persistence and memory response of a COVID-19 vaccine. This information would be also timely useful for the development and evaluation of other vaccines.
Cell-intrinsic effects of TorsinA(ΔE) disrupt dopamine release in a mouse model ofDYT1-TOR1Adystonia
Authors: Downs Anthony M. , Fan Xueliang , Kadakia Radhika , Donsante Yuping , Jinnah H.A. , Hess Ellen J.
Published: December 2020

DYT1-TOR1Adystonia is an inherited dystonia caused by a three base-pair deletion in theTOR1Agene (TOR1AΔE). Although the mechanisms underlying the dystonic movements are largely unknown, abnormalities in striatal dopamine and acetylcholine neurotransmission are consistently implicated whereby dopamine release is reduced while cholinergic tone is increased. Because striatal cholinergic neurotransmission mediates dopamine release, it is not known if the dopamine release deficit is mediated indirectly by abnormal acetylcholine neurotransmission or ifTor1a(ΔE)acts directly within dopaminergic neurons to attenuate release. To dissect the microcircuit that governs the deficit in dopamine release, we conditionally expressedTor1a(ΔE)in either dopamine neurons or cholinergic interneurons in mice and assessed striatal dopamine release usingex vivofast scan cyclic voltammetry or dopamine efflux usingin vivomicrodialysis. Conditional expression ofTor1a(ΔE)in cholinergic neurons did not affect striatal dopamine release. In contrast, conditional expression ofTor1a(ΔE)in dopamine neurons reduced dopamine release to 50% of normal, which is comparable to the deficit inTor1a+/ΔEknockin mice that express the mutation ubiquitously. Despite the deficit in dopamine release, we found that theTor1a(ΔE)mutation does not cause obvious nerve terminal dysfunction as other presynaptic mechanisms, including electrical excitability, vesicle recycling/refilling, Ca2+signaling, D2 dopamine autoreceptor function and GABABreceptor function, are intact. Although the mechanistic link betweenTor1a(ΔE)and dopamine release is unclear, these results clearly demonstrate that the defect in dopamine release is caused by the action of theTor1a(ΔE)mutation within dopamine neurons.
A role for cerebral cortex in the suppression of innate defensive behavior
Authors: Natale Silvia , Masferrer Maria Esteban , Deivasigamani Senthilkumar , Gross Cornelius T.
Published: December 2020

The cerebral cortex is involved in the control of cognition and the processing of learned information and it appears to have a role in the adaptation of behavior in response to unpredictable circumstances. In addition, the cortex may have a role in the regulation of innate responses since rodents, cats or primates with surgical removal or accidental destruction of cortical regions show excessive irritability, aggression and rage elicited by threatening stimuli. However, it remains unclear whether cortex has an acute role in suppressing innate threat responses because the imprecision and chronic nature of these lesions leaves open the possibility that compensatory processes may underlie some of these phenotypes. In the present study we used pharmacogenetic inhibition to precisely, rapidly and reversibly suppress cortical pyramidal neuron function and examine its contribution to defensive behaviors elicited by a variety of innately aversive stimuli. Inhibition of cortex caused an increase of defensive responses elicited by an aggressive conspecific, a novel prey, and a physically stressful stimulus. These findings are consistent with a role of cortex in the acute inhibition of innate defensive behaviors.
InVivoPharmacokinetic Study of Remdesivir Dry Powder for Inhalation in Hamsters
Authors: Sahakijpijarn Sawittree , Moon Chaeho , Warnken Zachary N. , Maier Esther Y. , DeVore Jennie E. , Christensen Dale J. , Koleng John J. , Williams Robert O.
Published: December 2020

Remdesivir dry powder for inhalation was previously developed using thin film freezing (TFF). A single-dose 24-hour pharmacokinetic study in hamsters, a small animal model for SARS-CoV-2, demonstrated that pulmonary delivery of TFF remdesivir can achieve plasma remdesivir and GS-441524 levels higher than the reported EC50s of both remdesivir and GS-441524 (in human epithelial cells) over 20 hours. The half-life of GS-4412524 following dry powder insufflation was about 7 hours, suggesting the dosing regimen would be twice daily administration. Although the remdesivir-Captisol®(80/20 w/w) formulation showed faster and greater absorption of remdesivir and GS-4412524 in the lung, remdesivir-leucine (80/20 w/w) exhibited a greater Cmaxwith shorter Tmaxand lower AUC of GS-441524, indicating lower total drug exposure is required to achieve a high effective concentration against SAR-CoV-2. In conclusion, remdesivir dry powder for inhalation would be a promising alternative dosage form for the treatment of COVID-19 disease.
Multi-scale annotations of chromatin states in 127 human cell-types
Authors: Kai Yan , Tsoucas Stephanos , Suo Shengbao , Yuan Guo-Cheng
Published: December 2020

Genome-wide profiling of chromatin states has been widely used to characterize the biological function of non-coding genomic sequences in a cell-type specific manner. However, the systematic, comprehensive annotations of chromatin states from experimental data are challenging and require not just extensive biological knowledge but also sophisticated computational modeling. Previously we developed a hierarchical hidden Markov model, named diHMM, to systematically annotate chromatin states at multiple scales based on the combination of histone mark and chromatin regulator binding profiles. Here, we have improved the method by optimizing computational efficiency and using an ensemble-clustering approach to achieve a unified annotation by integrating information from cell-type-specific models. We then applied this improved method to generate a unified multi-scale chromatin state map in 127 human cell types, based on public data generated by the Epigenome Roadmap and ENCODE consortia. We found cell types with similar origin are typically associated with similar chromatin states, but cultured cell lines have distinct structures than primary cells. The contribution of enhancer elements to gene regulation is mediated by the broader context of domain-state organization. Distinct domain-state patterns are associated with various 3D chromatin structures. As such, we have demonstrated the utility of the multi-scale chromatin state map in characterizing the biological function of the human genome.
Hydrating the Respiratory Tract: An Alternative Explanation Why Masks Lower Severity of COVID-19 Disease
Authors: Courtney Joseph M. , Bax Ad
Published: December 2020

Seasonality of respiratory diseases has been linked, among other factors, to low outdoor absolute humidity and low relative humidity in indoor environments, which increase evaporation of water in the mucosal layer lining the respiratory tract. We demonstrate that normal breathing results in an absorption-desorption cycle inside facemasks, where super-saturated air is absorbed by the mask fibers during expiration, followed by evaporation during inspiration of dry environmental air. For double-layered cotton masks, which have considerable heat capacity, the temperature of inspired air rises above room temperature, and the effective increase in relative humidity can exceed 100%. We propose that the recently reported, disease-attenuating effect of generic facemasks is dominated by the strong humidity increase of inspired air.

SIGNIFICANCE STATEMENT

Facemasks are the most widely used tool for mitigating the spread of the COVID-19 pandemic. Decreased disease severity by the wearer has also been linked to the use of cloth facemasks. This well-documented finding is surprising considering that such masks are poor at filtering the smallest aerosol particles, which can reach the lower respiratory tract and have been associated with severe disease. We show that facemasks strongly increase the effective humidity of inhaled air, thereby promoting hydration of the respiratory epithelium which is known to be beneficial to the immune system. Increased humidity of inspired air could be an alternate explanation for the now well-established link between mask wearing and lower disease severity.
Assessing the usage of indirect motor pathways following a hemiparetic stroke
Authors: Tian Runfeng , Dewald Julius P.A. , Yang Yuan
Published: December 2020

A hallmark impairment in a hemiparetic stroke is a loss of independent joint control resulting in abnormal co-activation of shoulder abductor and elbow flexor muscles in their paretic arm, clinically known as the flexion synergy. The flexion synergy appears while generating shoulder abduction (SABD) torques as lifting the paretic arm. This likely be caused by an increased reliance on contralesional indirect motor pathways following damage to direct corticospinal projections. The assessment of functional connectivity between brain and muscle signals, i.e., brain-muscle connectivity (BMC), may provide insight into such changes to the usage of motor pathways. Our previous model simulation shows that multi-synaptic connections along the indirect motor pathway can generate nonlinear connectivity. We hypothesize that increased usage of indirect motor pathways (as increasing SABD load) will lead to an increase of nonlinear BMC. To test this hypothesis, we measured brain activity, muscle activity from shoulder abductors when stroke participants generate 20% and 40% of maximum SABD torque with their paretic arm. We computed both linear and nonlinear BMC between EEG and EMG. We found dominant nonlinear BMC at contralesional/ipsilateral hemisphere for stroke, whose magnitude increased with the SABD load. These results supported our hypothesis and indicated that nonlinear BMC could provide a quantitative indicator for determining the usage of indirect motor pathways following a hemiparetic stroke.
Engineered CRISPR/Cas12a Enables Rapid SARS-CoV-2 Detection
Authors: Nguyen Long T. , Rananaware Santosh R. , Pizzano Brianna L.M. , Stone Brandon T. , Jain Piyush K.
Published: December 2020

The coronavirus disease (COVID-19) caused by SARS-CoV-2 has swept through the globe at an unprecedented rate. CRISPR-based detection technologies such as DETECTR, SHERLOCK, and STOPCovid have emerged as a rapid and affordable platform that can shape the future of diagnostics. Recently, we reported engineered crRNAs for Cas12a, called ENHANCE, that enables enhanced detection of nucleic acids. Here we report development, clinical validation, and advancement of ENHANCE platform for detecting SARS-CoV-2. With an RT-LAMP pre-amplification step, ENHANCE detects samples down to a single copy with 95% accuracy and shows high specificity towards various isolates of SARS-CoV-2 against 31 highly similar and common respiratory pathogens. Utilizing LbCas12a-mediated trans-cleavage activity, ENHANCE works robustly in a wide range of magnesium concentration (3 mM-13 mM), allowing for further assay optimization. Additionally, ENHANCEv2 is developed to further improve the previously reported ENHANCE. ENHANCEv2 employs mutated LbCas12aD156R, engineered chimeric DNA-extended crRNA, and a dual reporter for both fluorescence-based reporter assay and lateral flow assay. Both ENHANCE and ENHANCEv2 are validated in 62 clinical nasopharyngeal swabs, showing 60/62 (96.7%) agreement with RT-qPCR results, and using only 5 μL of sample and 20 minutes of CRISPR reaction. Lateral flow assay on paper strips displays 100% agreement with fluorescence-based reporter assay in the clinical validation. Following a 30-minute pre-amplification RT-LAMP step, the lyophilized ENHANCEv2 is shown to achieve high sensitivity and specificity while reducing CRISPR reaction time to as low as 3 minutes and maintaining its detection capability upon storage at room temperature for several weeks.
The spatial spread of HIV in Malawi: An individual-based mathematical model
Authors: Estill Janne , Ng’ambi Wingston , Rozanova Liudmila , Keiser Olivia
Published: December 2020

The prevalence of HIV varies greatly between and within countries. We therefore developed a flexible individual-based mathematical model for HIV transmission, that comprises a spatial representation and individual-level determinants. We tested this model by calibrating it to the HIV epidemic in Malawi and exploring whether the heterogeneity in HIV prevalence could be caused without accounting for heterogeneity in behaviour. We ran the model for Malawi between years 1975-2030 with five alternative realizations of the geographical structure and mobility: (I) no geographical structure; 28 administrative districts including (II) only permanent relocations between districts, (III) permanent relocations and between-district casual sexual relationships, or (IV) permanent relocations between districts and to/from abroad and between-district casual sex; and (V) a grid of 10×10km2 cells, with permanent relocations and between-cell casual relationships. We assumed HIV was present in 1975 in the districts with >10% prevalence in 2010. We calibrated the models to national and district-level prevalence estimates.

Reaching the national prevalence required all adults to have at least 20 casual sex acts/year until 1990. Models II, III and V reproduced the geographical heterogeneity in prevalence to some extent if between-district relationships were either excluded (Model II) or restricted to minimum (Models III, V). Long-distance casual partnership mixing (Models III-V) mitigated the differences in prevalence substantially; with international migration the differences disappeared completely (Model IV). National prevalence was projected to decrease to 4-5% by 2030. Our model sustained the major differences in HIV prevalence across Malawi, if casual relationships between districts were kept at sufficiently low level. An earlier introduction of HIV into the Southern part of Malawi may thus be one of the explanations to the present heterogeneity in HIV prevalence.

Author summary

The prevalence of HIV varies greatly across the settings, both globally and within countries. The ability of the commonly used compartmental models to account for the geographical structure and individual-level determinants that cause this heterogeneity is limited. In this project, we developed an individual-based simulation framework for modelling HIV transmission in a real setting. We built the model to take into account an unlimited number of individual-level characteristics, and a geographical representation of the setting that can be defined using an arbitrary resolution and distance matrices. We demonstrate the use of this model by simulating the HIV epidemic of Malawi 1975-2030 and exploring whether the observed heterogeneity could be preserved without taking into account any spatial heterogeneity in sexual behaviour. A relatively simple version of the model reproduced the broad-scale differences in HIV prevalence, but the detailed differences will need further investigation.
Introduction into the Marseille geographical area of a mild SARS-CoV-2 variant originating from sub-Saharan Africa
Authors: Colson Philippe , Levasseur Anthony , Gautret Philippe , Fenollar Florence , Hoang Van Thuan , Delerce Jeremy , Bitam Idir , Saile Rachid , Maaloum Mossaab , Padane Abdou , Bedotto Marielle , Brechard Ludivine , Bossi Vincent , Khedher Mariem Ben , Chaudet Hervé , Million Matthieu , Tissot-Dupont Hervé , Lagier Jean-Christophe , Mboup Souleymane , Fournier Pierre-Edouard , Raoult Didier
Published: December 2020

BACKGROUND

In Marseille, France, the COVID-19 incidence evolved unusually with several successive epidemic episodes. The second outbreak started in July, was associated with North Africa, and involved travelers and an outbreak on passenger ships. This suggested the involvement of a new viral variant.

METHODS

We sequenced the genomes from 916 SARS-CoV-2 strains from COVID-19 patients in our institute. The patients’ demographic and clinical features were compared according to the infecting viral variant.

RESULTS

From June 26th to August 14th, we identified a new viral variant (Marseille-1). Based on genome sequences (n=89) or specific qPCR (n=53), 142 patients infected with this variant were detected. It is characterized by a combination of 10 mutations located in the nsp2, nsp3, nsp12, S, ORF3a, ORF8 and N/ORF14 genes. We identified Senegal and Gambia, where the virus had been transferred from China and Europe in February-April as the sources of the Marseille-1 variant, which then most likely reached Marseille through Maghreb when French borders reopened. In France, this variant apparently remained almost limited to Marseille. In addition, it was significantly associated with a milder disease compared to clade 20A ancestor strains.

CONCLUSION

Our results demonstrate that SARS-CoV-2 can genetically diversify rapidly, its variants can diffuse internationally and cause successive outbreaks.
Discrepancies in automated, electronic medical record-based CHA2DS2-VASc scores and clinician assessment for atrial fibrillation patients
Authors: Jones Aubrey E. , Abedin Zameer , Ilkun Olesya , Mukherjee Rebeka , Zhang Mingyuan , White Michael , Steinberg Benjamin A. , Shah Rashmee U.
Published: December 2020

Background

Clinical decision support tools for atrial fibrillation (AF) should include CHA2DS2- VASc scores to guide oral anticoagulant (OAC) treatment.

Objective

We compared automated, electronic medical record (EMR) generated CHA2DS2- VASc scores to clinician-documented scores, and report the resulting proportions of patients in the OAC treatment group.

Methods

Patients were included if they had both a clinician documented and EMR-generated CHA2DS2-VASc score on the same day. EMR scores were based on billing codes, left ventricular ejection fraction from echocardiograms, and demographics; documented scores were identified using natural language processing. Patients were deemed “re-classified” if the EMR score was ≥2 but the documented score was <2, and vice versa. For the overall cohort and subgroups (sex and age group), we compared mean scores using paired t-tests and re-classification rates using chi-squared tests.

Results

Among 5,767 patients, the mean scores were higher using EMR compared to documented scores (4.05 [SD 2.1] versus 3.13 [SD 1.8]; p<0.01) for the full cohort, and all subgroups (p<0.01 for all comparisons). If EMR scores were used to determine OAC treatment instead of documented scores, 8.3% (n=479, p<0.01) of patients would be re-classified, with 7.2% moving into and 1.1% moving out of the treatment group. Among 2,322 women, 4.7% (n=109, p<0.01) would be re-classified, with 4.1% into and 0.7% out of the treatment group. Among 3,445 men, 10.7% (n=370, p<0.01) would be re-classified, with 9.2% into and 1.5% out of the treatment group. Among 2,060 patients <65 years old, 18.1% (n=372, p<0.01) would be re-classified, with 15.8% into and 2.3% out of the treatment group. Among 1,877 patients 65-74 years old, 5.4% (n=101, p<0.01) would be re-classified, with 4.4% into and 1.0% out of the treatment group. Among 1,830 patients ≥75 years old, <1% would move into to the treatment group and none would move out of the treatment group.

Conclusions

EMR-based CHA2DS2-VASc scores were, on average, almost a full point higher than the clinician-documented scores. Using EMR scores in lieu of documented scores would result in a significant proportion of patients moving into the treatment group, with the highest re-classifications rates in men and patients <65 years old.
The experience of European hospital-based health care workers on following infection prevention and control procedures for COVID-19
Authors: van Hout Denise , Hutchinson Paul , Wanat Marta , Pilbeam Caitlin , Goossens Herman , Anthierens Sibyl , Tonkin-Crine Sarah , Gobat Nina
Published: December 2020

Background

Working under pandemic conditions exposes health care workers (HCWs) to infection risk and psychological strain. Protecting the physical and psychological health of HCWs is a key priority. This study assessed the perceptions of European hospital HCWs of local infection prevention and control (IPC) procedures during the COVID-19 pandemic and the impact on their emotional wellbeing.

Methods

We performed two rounds of an international cross-sectional survey, between 31 March and 17 April 2020 via existing research networks (round 1), and between 14 May and 31 August 2020 via online convenience sampling (round 2). Main outcome measures were (1) behavioural determinants of HCW adherence with IPC procedures, (2) WHO-5 Well-Being Index, a validated scale of 0-100 reflecting emotional wellbeing. The WHO-5 was interpreted as a score below or above 50 points, a cut-off score used in previous literature to screen for depression.

Results

2,289 HCWs (round 1: n=190, round 2: n=2,099) from 40 countries in Europe participated. Mean age of respondents was 42 (±11) years, 66% were female, 47% and 39% were medical doctors and nurses, respectively. 74% (n=1699) of HCWs were directly treating patients with COVID-19, of which 32% (n=527) reported they were fearful of caring for these patients. HCWs reported high levels of concern about COVID-19 infection risk to themselves (71%) and their family (82%) as a result of their job. 40% of HCWs considered that getting infected with COVID-19 was not within their control. This was more common among junior than senior HCWs (46% versus 38%, P value <.01). Sufficient COVID-19-specific IPC training, confidence in PPE use and institutional trust were positively associated with the feeling that becoming infected with COVID-19 was within their control. Female HCWs were more likely than males to report a WHO-5 score below 50 points (aOR 1.5 (95% confidence interval (CI) 1.2-1.8).

Conclusions

In Europe, the COVID-19 pandemic has had a differential impact on those providing direct COVID-19 patient care, junior staff and women. Health facilities must be aware of these differential impacts, build trust and provide tailored support for this vital workforce during the current COVID-19 pandemic.
Reducing contacts to stop SARS-CoV-2 transmission during the second pandemic wave in Brussels, Belgium
Authors: Ingelbeen Brecht , Peckeu Laurène , Laga Marie , Hendrix Ilona , Neven Inge , van der Sande Marianne A. B. , van Kleef Esther
Published: December 2020

Background

Reducing contacts is a cornerstone of containing SARS-CoV-2. We evaluated the effect of physical distancing measures and of school reopening on contacts and consequently on SARS-CoV-2 transmission in Brussels, a hotspot during the second European wave.

Methods

Using SARS-CoV-2 case reports and contact tracing data during August-November 2020, we estimated changes in the age-specific number of reported contacts. We associated these trends with changes in the instantaneous reproduction number Rt and in age-specific transmission-events during distinct intervention periods in the Brussels region. Furthermore, we analysed trends in age-specific case numbers, pre- and post-school opening.

Findings

When schools reopened and physical distancing measures relaxed, the weekly mean number of reported contacts surged from 2.01 (95%CI 1.73-2.29) to 3.04 (95%CI 2.93-3.15), increasing across all ages. The fraction of cases aged 10-19 years started increasing before school reopening, with no further increase following school reopening (risk ratio 1.23, 95%CI 0.79-1.94). During the subsequent month, 8.9% (67/755) of infections identified were from teenagers to other ages, while 17.0% (131/755) from other ages to teenagers. Rt peaked mid-September at 1.48 (95%CI 1.35-1.63). Reintroduction of physical distancing measures reduced reported contacts to 1.85 (95%CI 1.78-1.91), resulting in Rt dropping below 1 within 3 weeks.

Interpretation

The second pandemic wave in Brussels was the result of increased contacts across all ages following school reopening. Stringent physical distancing measures, including closure of bars and limiting close contacts while schools remain open, reduced social mixing, in turn controlling SARS-CoV-2 transmission.

Funding

European Commission H2020. GGC Brussel.
Plasmodiophora brassicaechitin-binding effectors guard and mask spores during infection
Authors: Muirhead Kevin , Pérez-López Edel
Published: December 2020

Plants have a sophisticated and multilayered immune system. However, plant pathogens, helped by effector proteins, have found several strategies to evade plant immunity. For instance, the clubroot pathogen,Plasmodiophora brassicae,is able to turn the roots of the susceptible hosts into nutrient-sink galls surpassing patterns-triggered immunity (PTI) and effector-triggered immunity (ETI). Chitin, the main component ofP. brassicaespores cell walls and a well-known pathogens-associated molecular pattern (PAMP), can elicit PTI but is also the target of plant chitinases and chitin deacetylases. The fact thatP. brassicaedoes not trigger PTI during the infection of the susceptible hosts motivated a genome-wide search of genes coding for secreted chitin-related proteins. We found thatP. brassicaegenome encodes a large repertoire of candidate-secreted effectors containing the chitin-binding domain carbohydrate-binding module family 18 (CBM18), along with chitinases and chitin deacetylases domains. The role of such proteins in the pathogenicity of the clubroot pathogen is unknown. Here, we characterized the function of two effectors,PbChiB2 andPbChiB4, which are transcriptionally activated during the spores transition to uninucleate primary plasmodium and during the spore formation. Through co-precipitation, we found that recombinantPbChiB2 andPbChiB4 bind to the spores and to chitin oligomersin vitro. We also showed that both proteins suppress chitin-triggered activation of the immune MPK3 and MPK6 in the hostBrassica napus. These findings suggest a dual role for theP. brassicaeCBM18 proteins as effectors for protecting zoospores and resting spores formation and for suppressing chitin-triggered immunity during the infection.
Comparative assessment of allelopathic herbicidal actions and total phenolics content of seven Indian medicinal plants
Authors: Goswami Souren , Ray Sanjib
Published: December 2020

Allelopathy is a vital ecological process that influences the dynamics of ecological succession, structure, and composition of plant communities. The present study aimed to evaluate a comparative account of allelopathic inhibitory actions in relation to total phenolic contents of aqueous extracts from seven traditionally used medicinal plants of India.Triticum aestivumandCicer arietinumseedlings were used to test seed germination inhibition, seedling growth retardation and branch root sprouting inhibition.Allium ceparoot tip cells were used for mitotic index inhibition and abnormal cell percentage analysis. The correlation between the total phenolics content and allelopathic activities was analyzed. The different extracts show the varied degree of allelopathic inhibitory activity. Out of these seven used extracts,Crinum asiaticumleaf extract (CaLAE) showed the highest allelopathic inhibitory action and it could reduce 94.3 and 79.59% root and shoot growth respectively at 96 h of treatment (1 mg/mL) and that was increased to 96.18 and 93.78% respectively with 2 mg/mL. The quantitative phytochemical analysis also revealed that CaLAE also possess relatively higher amounts of total phenolics. The growth retardation effects of the extract are in accordance with the mito-depression and increased chromosomal abnormality inA. ceparoot tip cells. In conclusion,Crinum asiaticummay be considered as a prospective source of allelochemicals for plant growth regulation and a source of commercial herbicidal products.
The hidden state-dependency of transcranial alternating current stimulation (tACS)
Authors: Kasten Florian H. , Herrmann Christoph S.
Published: December 2020

Non-invasive techniques to electrically stimulate the brain such as transcranial direct and alternating current stimulation (tDCS/tACS) are increasingly used in human neuroscience and offer potential new avenues to treat brain disorders. However, their often weak and variable effects have also raised concerns in the scientific community. A possible factor influencing the efficacy of these methods is the dependence on brain-states. Here, we utilized Hidden Markov Models (HMM) to decompose concurrent tACS-magnetoencephalography data into transient brain-states with distinct spatial, spectral and connectivity profiles. We found that out of four spontaneous brain-states only one was susceptible to tACS. No or only marginal effects were found in the remaining states. TACS did not influence the time spent in each state. Our results suggest, that tACS effects may be mediated by a hidden, spontaneous state-dependency and provide novel insights to the changes in oscillatory activity underlying aftereffects of tACS.
Evolution of a virus-like architecture and packaging mechanism in a repurposed bacterial protein
Authors: Tetter Stephan , Terasaka Naohiro , Steinauer Angela , Bingham Richard J. , Clark Sam , Scott Andrew J. P. , Patel Nikesh , Leibundgut Marc , Wroblewski Emma , Ban Nenad , Stockley Peter G. , Twarock Reidun , Hilvert Donald
Published: December 2020

Viruses are ubiquitous pathogens of global impact. Prompted by the hypothesis that their earliest progenitors recruited host proteins for virion formation, we have used stringent laboratory evolution to convert a bacterial enzyme lacking affinity for nucleic acids into an artificial nucleocapsid that efficiently packages and protects multiple copies of its own encoding mRNA. Revealing remarkable convergence on the molecular hallmarks of natural viruses, the accompanying changes reorganized the protein building blocks into an interlaced 240-subunit icosahedral capsid impermeable to nucleases, while emergence of a robust RNA stem-loop packaging cassette ensured high encapsidation yields and specificity. In addition to evincing a plausible evolutionary pathway for primordial viruses, these findings highlight practical strategies for developing non-viral carriers for diverse vaccine and delivery applications.
Genetically engineered retina for improved retinal reconstruction after transplantation
Authors: Matsuyama Take , Tu Hung-Ya , Sun Jianan , Hashiguchi Tomoyo , Akiba Ryutaro , Sho Junki , Fujii Momo , Onishi Akishi , Takahashi Masayo , Mandai Michiko
Published: December 2020

ES/iPS-retinal sheet transplantation, which supplies photoreceptors as well as other retinal cells, has been shown able to restore visual function in mice with end-stage retinal degeneration. Here, by introducing a novel type of genetically engineered ES/iPS-retinal sheet with reduced numbers of secondary retinal neurons but intact photoreceptor cell layer structure, we reinforced the evidence that ES/iPS-retinal sheet transplantation can establish synaptic connections with the host, restore light responsiveness and reduce aberrant RGC spiking. Furthermore, we show that genetically engineered grafts can substantially improve the outcome of the treatment by improving neural integration. We speculate that this leads to reduced spontaneous activity in the host which in turn contributes to a better visual recovery.
The singleMarchantia polymorpha FERONIAhomolog reveals an ancestral role in regulating cellular expansion and integrity
Authors: Mecchia Martin A. , Rövekamp Moritz , Giraldo-Fonseca Alejandro , Meier Dario , Gadient Philippe , Vogler Hannes , Limacher Daria , Bowman John L. , Grossniklaus Ueli
Published: December 2020

Plant cells are surrounded by a cell wall, a rigid structure that is not only important for cell and organ shape, but crucial for intercellular communication and interactions with the environment. In the flowering plantArabidopsis thaliana, the 17 members of theCatharanthus roseusRLK1-like (CrRLK1L) receptor kinase family are involved in a multitude of physiological and developmental processes, making it difficult to assess their primary or ancestral function. To reduce genetic complexity, we characterized the singleCrRLK1L gene ofMarchantia polymorpha, MpFERONIA(MpFER). Plants with reduced MpFERlevels show defects in vegetative development, i.e., rhizoid formation and cell expansion, and have reduced male fertility. In contrast, Mpfernull mutants and overexpression lines severely affect cell integrity and morphogenesis of the gametophyte. Thus, theCrRLK1L gene family originated from a single gene with an ancestral function in cell expansion and the maintenance of cellular integrity. During land plant evolution, this ancestral gene diversified to fulfil a multitude of specialized physiological and developmental and roles in the formation of both gametophytic and sporophytic structures essential to the life cycle of flowering plants.

Summary statement

TheCrRLK1L family arose in land plants and theMarchantia polymorpha genomecontains a single copy, MpFER,which is broadly expressed and regulates cell expansion and cell wall integrity.
Narratives: fMRI data for evaluating models of naturalistic language comprehension
Authors: Nastase Samuel A. , Liu Yun-Fei , Hillman Hanna , Zadbood Asieh , Hasenfratz Liat , Keshavarzian Neggin , Chen Janice , Honey Christopher J. , Yeshurun Yaara , Regev Mor , Nguyen Mai , Chang Claire H. C. , Baldassano Christopher , Lositsky Olga , Simony Erez , Chow Michael A. , Leong Yuan Chang , Brooks Paula P. , Micciche Emily , Choe Gina , Goldstein Ariel , Vanderwal Tamara , Halchenko Yaroslav O. , Norman Kenneth A. , Hasson Uri
Published: December 2020

The “Narratives” collection aggregates a variety of functional MRI datasets collected while human subjects listened to naturalistic spoken stories. The current release includes 345 subjects, 891 functional scans, and 27 diverse stories of varying duration totaling ~4.6 hours of unique stimuli (~43,000 words). This data collection is well-suited for naturalistic neuroimaging analysis, and is intended to serve as a benchmark for models of language and narrative comprehension. We provide standardized MRI data accompanied by rich metadata, preprocessed versions of the data ready for immediate use, and the spoken story stimuli with time-stamped phoneme- and word-level transcripts. All code and data are publicly available with full provenance in keeping with current best practices in transparent and reproducible neuroimaging.
Mechanism of cellular production and in vivo seeding effects of hexameric β-amyloid assemblies
Authors: Vrancx Céline , Vadukul Devkee M , Contino Sabrina , Suelves Nuria , D’Auria Ludovic , Perrin Florian , Van Pesch Vincent , Hanseeuw Bernard , Quinton Loïc , Kienlen-Campard Pascal
Published: December 2020

Background

The β-amyloid peptide (Aβ) plays a key role in Alzheimer’s disease. After its production by catabolism of the amyloid precursor protein (APP) through the action of presenilin 1 (PS1)- or presenilin 2 (PS2)-dependent γ-secretases, monomeric Aβ can assemble in oligomers. In a pathological context, this eventually leads to the formation of fibrils, which deposit in senile plaques. Many studies suggest that Aβ toxicity is related to its soluble oligomeric intermediates. Among these, our interest focuses on hexameric Aβ, which acts as a nucleus for Aβ self-assembly.

Methods

Biochemical analyses were used to identify hexameric Aβ in a wide range of models; cell lines, cerebrospinal fluid from cognitively impaired patients and transgenic mice exhibiting human Aβ pathology (5xFAD). We isolated this assembly and assessed both its effect on primary neuron viability in vitro, and its contribution to amyloid deposition in vivo following intracerebral injection. In both cases, we used wild-type mice (C57BL/6) to mimic an environment where hexameric Aβ is present alone and 5xFAD mice to incubate hexameric Aβ in a context where human Aβ species are pre-existing. Using CRISPR-Cas9, we produced stable knockdown human cell lines for either PS1 or PS2 to elucidate their contribution to the formation of hexameric Aβ.

Results

In WT mice, we found that neither in vitro or in vivo exposure to hexameric Aβ was sufficient to induce cytotoxic effects or amyloid deposition. In 5xFAD mice, we observed a significant increase in neuronal death in vitro following exposure to 5μM hexameric Aβ, as well as a 1.47-fold aggravation of amyloid deposition in vivo. At the cellular level, we found hexameric Aβ in extracellular vesicles and observed a strong decrease in its excretion when PS2 was knocked down by 60%.

Conclusions

Our results indicate the absence of cytotoxic effects of cell-derived hexameric Aβ by itself, but its capacity to aggravate amyloid deposition by seeding other Aβ species. We propose an important role for PS2 in the formation of this particular assembly in vesicular entities, in line with previous reports linking the restricted location of PS2 in acidic compartments to the production of more aggregation-prone Aβ.
Deciphering the mystery of influenza virus A antigenic drift and immune escape
Authors: Ma Yongping , Fang Changyin
Published: December 2020

The biggest challenge of influenza A virus vaccine development is the constant mutation of the virus, especially the antigenic drift. Therefore, we suggest establishing a research system for upgrading of current influenza A vaccines. The most fundamental but neglected thing is to determine the immune escape mutation (IEM) map (IEMM) of 20 amino acids in linear epitope to reveal the precise mechanism of the viral immune escape. Based on this assumption, we primarily divided IEM of HA-tag linear epitope into four types according to antibody affinity by ELISA. Our aim is to attract scholars to establish of IEMM library to deal with influenza A virus mutations in the future.
De novocoding variants in theAGO1gene cause a neurodevelopmental disorder with intellectual disability
Authors: Schalk Audrey , Cousin Margot A. , Challman Thomas D. , Wain Karen E. , Powis Zöe , Minks Kelly , Trimouille Aurélien , Lasseaux Eulalie , Lacombre Didier , Angelini Chloé , Michaud Vincent , Van-Gils Julien , Spataro Nino , Ruiz Anna , Gabau Elizabeth , Stolerman Elliot , Washington Camerun , Louie Raymond J. , Lanpher Brendan C , Kemppainen Jennifer L. , Innes A. Micheil , Kooy R. Frank , Meuwissen Marije , Goldenberg Alice , Lecoquierre François , Vera Gabriella , Diderich Karin E M , Sheidley Beth Rosen , El Achkar Christelle Moufawad , Park Meredith , Hamdan Fadi F. , Michaud Jacques L. , Lewis Ann J. , Zweier Christiane , Reis André , Wagner Matias , Weigand Heike , Journel Hubert , Keren Boris , Passemard Sandrine , Mignot Cyril , van Gassen Koen L.I. , Brilstra Eva H. , Itzikowitz Gina , O’Heir Emily , Allen Jake , Donald Kirsten A. , Korf Bruce R. , Skelton Tammi , Thompson Michelle L , Robin Nathaniel H. , Rudy Natasha , Dobyns William B. , Foss Kimberly , Zarate Yuri A , Bosanko Katherine A. , Alembik Yves , Durand Benjamin , Mau-Them Frédéric Tran , Ranza Emmanuelle , Blanc Xavier , Antonarakis Stylianos E. , McWalter Kirsty , Torti Erin , Millan Francisca , Dameron Amy , Tokita Mari J. , Zimmermann Michael T. , Dsouza Nikita R. , Klee Eric W. , Piton Amélie , Gerard Bénédicte
Published: December 2020

High-impact pathogenic variants in more than 1,000 protein-coding genes cause Mendelian forms of neurodevelopmental disorders (NDD), including the newly reportedAGO2gene. This study describes the molecular and clinical characterization of 28 probands with NDD harboring heterozygousAGO1coding variants.De novostatus was always confirmed when parents were available (26/28). A total of 15 unique variants leading to amino acid changes or deletions were identified: 12 missense variants, two in-frame deletions of one codon, and one canonical splice variant leading to a deletion of two amino acid residues. Some variants were recurrently identified in several unrelated individuals: p.(Phe180del), p.(Leu190Pro), p.(Leu190Arg), p.(Gly199Ser), p.(Val254Ile) and p.(Glu376del).AGO1encodes the Argonaute 1 protein, which functions in gene-silencing pathways mediated by small non-coding RNAs. Three-dimensional protein structure predictions suggest that these variants might alter the flexibility of the AGO1 linkers domains, which likely would impair its function in mRNA processing. Affected individuals present with intellectual disability of varying severity, as well as speech and motor delay, autistic behavior and additional behavioral manifestations. Our study establishes thatde novocoding variants inAGO1are involved in a novel monogenic form of NDD, highly similar toAGO2phenotype.
RNA polymerase II assembly and mRNA decay regulation are mediated and interconnectedviaCTD Ser5P phosphatase Rtr1 inSaccharomyces cerevisiae
Authors: Garrido-Godino A.I. , Cuevas-Bermúdez A. , Gutiérrez-Santiago F. , Mota-Trujillo M.C. , Navarro F.
Published: December 2020

Rtr1 is an RNA pol II CTD-phosphatase that influences gene expression by acting during the transition from transcription initiation to elongation, and during transcription termination. Rtr1 has been proposed as an RNA pol II import factor in RNA pol II biogenesis, and participating in mRNA decay by autoregulating the turnover of its own mRNA. In addition, the interaction of Rtr1 with RNA pol II depends on the phosphorylation state of CTD, which also influences Rpb4/7 dissociation during transcription. In this work, we demonstrate that Rtr1 acts in RNA pol II assembly, likely in a final cytoplasmic RNA pol II biogenesis step, and mediates the Rpb4 association with the rest of the enzyme, However, we do not rule out discard a role in the Rpb4 association with RNA pol II in the nucleus. This role of Rtr1 interplays RNA pol II biogenesis and mRNA decay regulation. In fact,RTR1deletion alters RNA pol II assembly and leads to the chromatin association of RNA pol II lacking Rpb4, in addition to whole RNA pol II, decreasing mRNA-Rpb4 imprinting and, consequently, increasing mRNA stability. Notably, theRPB5overexpression that overcomes RNA pol II assembly and the defect in Rpb4 binding to chromatin-associated RNA pol II partially suppresses the mRNA stability defect ofrtr1Δcells. Our data also indicate that Rtr1 mediates mRNA decay regulation more broadly than previously proposed in cooperation with Rpb4 and Dhh1. Interestingly, these data include new layers in the crosstalk between mRNA synthesis and decay.