bluuebunny/crossref_metadata_2025 huggingface dataset:
Interferon Resistance of Emerging SARS-CoV-2 Variants
Authors: Guo Kejun , Barrett Bradley S. , Mickens Kaylee L. , Vladar Ezster K. , Morrison James H. , Hasenkrug Kim J. , Poeschla Eric M. , Santiago Mario L.
Published: March 2021

The emergence of SARS-CoV-2 variants with enhanced transmissibility, pathogenesis and resistance to vaccines presents urgent challenges for curbing the COVID-19 pandemic. While Spike mutations that enhance virus infectivity or neutralizing antibody evasion may drive the emergence of these novel variants, studies documenting a critical role for interferon responses in the early control of SARS-CoV-2 infection, combined with the presence of viral genes that limit these responses, suggest that interferons may also influence SARS-CoV-2 evolution. Here, we compared the potency of 17 different human interferons against multiple viral lineages sampled during the course of the global outbreak, including ancestral and four major variants of concern. Our data reveal increased interferon resistance in emerging SARS-CoV-2 variants, suggesting that evasion of innate immunity may be a significant, ongoing driving force for SARS-CoV-2 evolution. These findings have implications for the increased lethality of emerging variants and highlight the interferon subtypes that may be most successful in the treatment of early infections.

Author Summary

In less than 2 years since its spillover into humans, SARS-CoV-2 has infected over 220 million people, causing over 4.5 million COVID-19 deaths. High infection rates provided substantial opportunities for the virus to evolve, as variants with enhanced transmissibility, pathogenesis, and resistance to vaccine-elicited neutralizing antibodies have emerged. While much focus has centered on the Spike protein which the virus uses to infect target cells, mutations were also found in other viral proteins that might inhibit innate immune responses. Specifically, viruses encounter a potent innate immune response mediated by the interferons, two of which, IFNα2 and IFNβ, are being repurposed for COVID-19 treatment. Here, we compared the potency of human interferons against ancestral and emerging variants of SARS-CoV-2. Our data revealed increased interferon resistance in emerging SARS-CoV-2 strains that included the alpha, beta, gamma and delta variants of concern, suggesting a significant, but underappreciated role for innate immunity in driving the next phase of the COVID-19 pandemic.
Structural and energetic profiling of SARS-CoV-2 antibody recognition and the impact of circulating variants
Authors: Yin Rui , Guest Johnathan D. , Taherzadeh Ghazaleh , Gowthaman Ragul , Mittra Ipsa , Quackenbush Jane , Pierce Brian G.
Published: March 2021

The SARS-CoV-2 pandemic highlights the need for a detailed molecular understanding of protective antibody responses. This is underscored by the emergence and spread of SARS-CoV-2 variants, including B.1.1.7, P1, and B.1.351, some of which appear to be less effectively targeted by current monoclonal antibodies and vaccines. Here we report a high resolution and comprehensive map of antibody recognition of the SARS-CoV-2 spike receptor binding domain (RBD), which is the target of most neutralizing antibodies, using computational structural analysis. With a dataset of nonredundant experimentally determined antibody-RBD structures, we classified antibodies by RBD residue binding determinants using unsupervised clustering. We also identified the energetic and conservation features of epitope residues and assessed the capacity of viral variant mutations to disrupt antibody recognition, revealing sets of antibodies predicted to effectively target recently described viral variants. This detailed structure-based reference of antibody RBD recognition signatures can inform therapeutic and vaccine design strategies.
Participation after childhood stroke: Is there a relationship with lesion size, motor function and manual ability?
Authors: Simon-Martinez Cristina , Kamal Sandeep , Frickmann Fabienne , Steiner Leonie , Slavova Nedelina , Everts Regula , Steinlin Maja , Grunt Sebastian
Published: March 2021

Background

Childhood arterial ischemic stroke (AIS) is associated with significant morbidity with up to 50% of affected children developing hemiparesis. Hemiparesis is assumed to influence participation within the peer group, but it is unclear to what extent its severity affects participation in different areas of social life.

Methods

Thirteen children (mean age 9y6m) with AIS (6 without hemiparesis, 7 with hemiparesis) and 21 controls (mean age 9y8m) participated. We scored hemiparesis severity with hand strength asymmetry (pinch and grip strength), measured with a dynamometer. We assessed manual ability (ABILHAND-Kids), socioeconomic status (Family Affluence Scale) and participation (Participation and Environment Measure – Children and Youth). From structural MRI, we measured lesion size. We investigated differences in participation and its relationship with hemiparesis severity using non-parametric partial correlations (controlling for lesion size, manual ability, and socioeconomic status), interpreted as absent (r<0.25), weak (r=0.25-0.50), moderate (r=0.50-0.75) or strong (r>0.75). Analyses were performed in jamovi 1.6.3.

Results

Children with AIS (with or without hemiparesis) showed reduced participation frequency at school (p<0.001), whilst participation at home and in the community resembled that of their peers. Severity of hemiparesis was moderately related to frequency and involvement at home and to involvement and desire for change in the community, although unrelated to school participation.

Conclusion

Reduced participation in school life requires close attention in the follow-up of children with AIS - regardless of the severity of hemiparesis. Participation at home and in the community is related to hemiparesis severity and may be improved with participation-focused motor intervention strategies.

Highlights

Children with stroke participate less frequently at school but are equally involved.

Decreased participation at school is not related to hemiparesis severity.

Participation at home and in the community are related to hemiparesis severity.
Multiplex Antibody Analysis of IgM, IgA and IgG to SARS-CoV-2 in Saliva and Serum from Infected Children and their Close Contacts
Authors: Dobaño Carlota , Alonso Selena , Vidal Marta , Jiménez Alfons , Rubio Rocío , Santano Rebeca , Barrios Diana , Tomas Gemma Pons , Melé Casas María , Hernández García María , Girona-Alarcón Mònica , Puyol Laura , Melero Natalia Rodrigo , Carolis Carlo , Garcia-Miquel Aleix , Bonet-Carne Elisenda , Claverol Joana , Cubells Marta , Fortuny Claudia , Fumadó Victoria , Codina Anna , Bassat Quique , Muñoz-Almagro Carmen , Fernández de Sevilla Mariona , Gratacós Eduard , Izquierdo Luis , García-García Juan José , Aguilar Ruth , Jordan Iolanda , Moncunill Gemma
Published: March 2021

COVID-19 affects children to a lesser extent than adults but they can still get infected and transmit SARS-CoV-2 to their contacts. Field deployable non-invasive sensitive diagnostic techniques are needed to evaluate the infectivity dynamics of the coronavirus in pediatric populations and guide public health interventions.

We evaluated the utility of high-throughput Luminex-based assays applied to saliva samples to quantify IgM, IgA and IgG antibodies against five SARS-CoV-2 spike (S) and nucleocapsid (N) antigens in the context of a contacts and infectivity longitudinal study. We compared the antibody levels obtained in saliva versus serum/plasma samples from a group of children and adults tested weekly by RT-PCR over 35 days and diagnosed as positive (n=58), and a group of children and adults who consistently tested negative over the follow up period (n=61), in the Summer of 2020 in Barcelona, Spain.

Antibody levels in saliva samples from individuals with confirmed RT-PCR diagnosis of SARS-CoV-2 infection were significantly higher than in negative individuals and correlated with those measured in sera/plasmas. Higher levels of anti-S IgG were found in asymptomatic individuals that could indicate protection against disease in infected individuals. Higher anti-S IgG and IgM levels in serum/plasma and saliva, respectively, in infected children compared to infected adults could also be related to stronger clinical immunity in them. Among infected children, males had higher levels of saliva IgG to N and RBD than females. Despite overall correlation, individual clustering analysis suggested that responses that may not be detected in blood could be patent in saliva, and vice versa, and therefore that both measurements are complementary.

In addition to serum/plasma, measurement of SARS-CoV-2-specific saliva antibodies should be considered as a complementary non-invasive assay to better estimate the percentage of individuals who have experienced coronavirus infection. Saliva antibody detection could allow determining COVID-19 prevalence in pediatric populations, alternative to bleeding or nasal swab, and serological diagnosis following vaccination.
Risk of reactivation of hepatitis B virus (HBV) and tuberculosis (TB) and complications of hepatitis C virus (HCV) following Tocilizumab therapy: A systematic review to inform risk assessment in the COVID era
Authors: Campbell Cori , Andersson Monique , Ansari M Azim , Moswela Olivia , Misbah Siraj A , Klenerman Paul , Matthews Philippa C
Published: March 2021

Tocilizumab (TCZ), an IL-6 receptor antagonist, is used in the treatment of COVID. However, this agent carries a ‘black box’ warning for infection complications, which may include reactivation of tuberculosis (TB) or hepatitis B virus (HBV), or worsening of hepatitis C virus (HCV). Due to the pace of clinical research during the COVID pandemic, prospective evaluation of these risks has not been possible. We undertook a systematic review, generating mean cumulative incidence estimates for reactivation of HBV and TB at 3.3% and 4.3%. We could not generate estimates for HCV. These data derive from heterogeneous studies pre-dating the COVID outbreak, with differing epidemiology and varied approaches to screening and prophylaxis. We underline the need for careful individual risk assessment prior to TCZ prescription, and present an algorithm for clinical stratification. There is an urgent need for ongoing collation of safety data as TCZ therapy is used in COVID.

KEY POINTS

Use of tocilizumab treatment in COVID-19 may risk infective complications. We have undertaken a systematic literature review to assess the risks of reactivation of HBV and TB, generating mean estimates of 3.3% and 4.3% incidence, respectively.
Disease and Social Media in Post-Natural Disaster Recovery Philippines
Authors: Charles Lauren E. , Corley Courtney D.
Published: March 2021

Introduction

The Philippines is plagued with natural disasters and resulting precipitating factors for disease outbreaks. The developing country has a strong disease surveillance program during and post-disaster phases; however, latent disease contracted during these emergency situations emerges once the Filipinos return to their homes. Coined the social media capital of the world, the Philippines provides an opportunity to evaluate the potential of social media use in disease surveillance during the post-recovery period. By developing and defining a non-traditional method for enhancing detection of infectious diseases post-natural disaster recovery in the Philippines, this research aims to increase the resilience of affected developing countries through advanced passive disease surveillance with minimal cost and high impact.

Methods

We collected 50 million geo-tagged tweets, weekly case counts for six diseases, and all natural disasters from the Philippines between 2012 and 2013. We compared the predictive capability of various disease lexicon-based time series models (e.g., Twitter’s BreakoutDetection, Autoregressive Integrated Moving Average with Explanatory Variable [ARIMAX], Multilinear regression, and Logistic regression) and document embeddings (Gensim’s Doc2Vec).

Results

The analyses show that the use of only tweets to predict disease outbreaks in the Philippines has varying results depending on which technique is applied, the disease type, and location. Overall, the most consistent predictive results were from the ARIMAX model which showed the significance in tweet value for prediction and a role of disaster in specific instances.

Discussion

Overall, the use of disease/sick lexicon-filtered tweets as a predictor of disease in the Philippines appears promising. Due to the consistent and large increase use of Twitter within the country, it would be informative to repeat analysis on more recent years to confirm the top method for prediction. In addition, we suggest that a combination disease-specific model would produce the best results. The model would be one where the case counts of a disease are updated periodically along with the continuous monitoring of lexicon-based tweets plus or minus the time from disaster.
Tocilizumab in hospitalized patients with COVID-19: A meta analysis of randomized controlled trials
Authors: Selvaraj Vijairam , Khan Mohammad Saud , Dapaah-Afriyie Kwame , Finn Arkadiy , Bavishi Chirag , Lal Amos , Mylonakis Eleftarios
Published: March 2021

Background

To date, only dexamethasone has been shown to reduce mortality in COVID-19 patients. Tocilizumab has been recently added to the treatment guidelines for hospitalized COVID-19 patients, but data remains conflicting.

Methods

Electronic databases such as MEDLINE, EMBASE and Cochrane central were searched from March 1, 2020, until February 28th, 2021, for randomized controlled trials evaluating the efficacy of tocilizumab in hospitalized COVID-19 patients. The outcomes assessed were all-cause mortality at 28 days, mechanical ventilation, and time to discharge.

Results

Eight studies (with 6,311 patients) were included in the analysis. In total, 3,267 patients received tocilizumab, and 3,044 received standard care/placebo. Pooled analysis showed a significantly decreased risk of all-cause mortality at 28 days (RR 0.90, 95% CI 0.83-0.97, p=0.009) and progression to mechanical ventilation (RR 0.79, 95% CI 0.70-0.90, p=0.0002) in the tocilizumab arm compared to standard therapy or placebo. In addition, there was a trend towards improved median time to hospital discharge (RR 1.18, 95% CI 1.05-1.34, p=0.007).

Conclusions

Tocilizumab therapy improves outcomes of mortality and need for mechanical ventilation, in hospitalized patients with COVID-19 infection compared with standard therapy or placebo. Our findings suggest the efficacy of tocilizumab therapy in hospitalized COVID-19 patients and strengthen the concept that tocilizumab is a promising therapeutic intervention to improve mortality and morbidity in COVID-19 patients.
Covid-19 High Attack Rate Can Lead to High Case Fatality Rate
Authors: Raham Tareef Fdahil
Published: March 2021

Background

During the current Covid-19 pandemic case fatality rate (CFR) estimates were subjected to a lot of debates regarding the accuracy of its estimations, predictions, and the reason of across countries variances. In this context, we conduct this study to see the relationship between attack rate (AR) and CFR.

The study hypothesis is based on two: 1-evidence suggests that the mortality rate (MR) has a positive influence on case fatality ratio (CFR), 2- and increase number of Covid-19 cases leads to increased mortality rate (MR).

Material and methods

Thirty countries and territories were chosen. Inclusion criterion was > 500 Covid-19 reported cases per 10,000 population inhabitants. Data on covid-19 cases and deaths was selected as it was on March 10, 2021. Statistical methods used are descriptive and one-sample Kolmogorov-Smirnov (K-S), the one-way ANOVA, Levene, least significant different (LSD), and matched paired-samples T-tests.

Results

ANOVA test showed a significant difference at P<0.01 among all studied groups concerning AR and CFR mean values. Group of countries with MR ≥ 15 death / 104 inhabitants recorded the highest level of crude mean CFR and AR values, and recorded the highest gap with leftover groups, especially with countries reported MR of <10 death/ 104 inhabitants. There were independence 95% confidence intervals of mean CFR and AR values between countries with ≥ 15 death / 104 MR and countries with MR of <10 death /104. There was a significant difference between countries with MR ≥ 15 death / 104 inhabitants and countries with MR of <10 death / 10 4 inhabitants groups through least significant difference (LSD) test for CFR%(0.042 p-value) and Games Howell (GH) test for AR/104 (p-value 0.000).

Conclusions

Total and mean AR and CFR are higher in high MR countries compared to low MR countries.
The impact of customized head molds on motion and motion-related artifacts from structural and functional MRI scans in children
Authors: Weng Timothy B. , Vela Ruben D. , Weber Wade , Dodla Manwitha , Heinsfeld Anibal S. , Parker Samuel D. , Simon Blake , Demeter Damion V. , Nugiel Tehila , Whitmore Lucy , Mills Kathryn L. , Church Jessica A. , Haberman Michael R. , Craddock R. Cameron
Published: March 2021

Although neuroimaging provides powerful tools for assessing brain structure and function, their utility for elucidating mechanisms underlying neuropsychiatric disorders is limited by their sensitivity to head motion. Several publications have shown that standard retrospective motion correction and arduous quality assessment are insufficient to fully remove the deleterious impacts of motion on functional (fMRI) and structural (sMRI) neuroimaging data. These residual errors tend to be correlated with age and clinical diagnosis, resulting in artifactual findings in studies of clinical, developmental, and aging populations. As such there is a continued need to explore and evaluate novel methods for reducing head motion, and their applicability in these populations. Recently, a custom-fitted styrofoam head mold was reported to reduce motion across a range of ages, mostly adolescents, during a resting state fMRI scan.

In the present study, we tested the efficacy of these head molds in a sample exclusively of young children (N = 19; mean age = 7.9 years) including those with ADHD (N = 6). We evaluated the head mold’s impact on head motion, data quality, and analysis results derived from the data. Importantly, we also evaluated whether the head molds were tolerated by our population. We also assessed the extent to which the head mold’s efficacy was related to anxiety levels and ADHD symptoms. In addition to fMRI, we examined the head mold’s impact on sMRI by using a specialized sequence with embedded volumetric navigators (vNAV) to determine head motion during sMRI. We evaluated the head mold’s impact on head motion, data quality, and analysis results derived from the data. Additionally, we conducted acoustic measurements and analyses to determine the extent to which the head mold reduced the noise dosage from the scanner. We found that some individuals benefited while others did not improve significantly. One individual’s sMRI motion was made worse by the head mold. We were unable to identify predictors of the head mold response due to the smaller sample size. The head molds were tolerated well by young children, including those with ADHD, and they provided ample hearing protection. Although the head mold was not a universal solution for reducing head motion and improving data quality, we believe the time and cost required for using the head mold may outweigh the potential loss of data from excessive head motion for developmental studies.
Understanding the Paradox of Primary Health Care Use: Empirical Evidence from India
Authors: Sur Pramod Kumar
Published: March 2021

I study households’ primary health care usage in India, which presents a paradox. I examine why most households use fee-charging private health care services even though (1) most providers have no formal medical qualifications and (2) in markets where qualified doctors offer free care through public hospitals. I present evidence that this puzzling practice has deep historical routes. I examine India’s coercive forced sterilization policy implemented between 1976 and 1977. Utilizing the unexpected timing of the policy, multiple measures of forced sterilization, including at a granular level, and an instrumental variable approach, I document that places heavily affected by the policy have lower public health care usage today. I also show that the instrument I use is unrelated to a battery of demographic, economic, or political aspects before the forced sterilization period. Finally, I explore the mechanism and document that supply-side factors do not explain these differences. Instead, I demonstrate that places with greater exposure to forced sterilization have higher confidence in private hospitals and doctors to provide good treatment.
Fast, scalable, and statistically robust cell extraction from large-scale neural calcium imaging datasets
Authors: Dinc Fatih , Inan Hakan , Hernandez Oscar , Schmuckermair Claudia , Hazon Omer , Tasci Tugce , Ahanonu Biafra O. , Zhang Yanping , Lecoq Jerome , Haziza Simon , Wagner Mark J. , Erdogdu Murat A. , Schnitzer Mark J.
Published: March 2021

State-of-the-art calcium imaging studies that monitor large-scale neural dynamics can produce video datasets that tally up to ~100 TB in size (~10 days transfer over 1 Gbit/s ethernet). Processing such data volumes requires automated, general-purpose and fast computational methods for cell identification that are robust to a wide variety of noise sources. We present EXTRACT, an algorithm that is based on robust estimation theory and uses graphical processing units (GPUs) to extract neural dynamics from a typical calcium video in computing times up to ~10-times faster than imaging durations. We extensively validated EXTRACT on simulated and experimental data and processed 199 public datasets (~12 TB) from the Allen Institute in a day. Showcasing its superiority over past cell extraction methods at removing noise contaminants, neural activity traces from EXTRACT allow more accurate decoding of animal behavior. Overall, EXTRACT is a powerful computational tool matched to the present challenges of neural calcium imaging studies in behaving animals.
Sysrev: A FAIR platform for Data Curation and Systematic Evidence Review
Authors: Bozada Thomas , Borden James , Workman Jeffrey , Del Cid Mardo , Malinowski Jennifer , Luechtefeld Thomas
Published: March 2021

Well-curated datasets are essential to evidence based decision making and to the integration of artificial intelligence with human reasoning across disciplines. However, many sources of data remain siloed, unstructured, and/or unavailable for complementary and secondary research. Sysrev was developed to address these issues. First, Sysrev was built to aid in systematic evidence reviews (SER), where digital documents are evaluated according to a well defined process, and where Sysrev provides an easy to access, publicly available and free platform for collaborating in SER projects. Secondly, Sysrev addresses the issue of unstructured, siloed, and inaccessible data in the context of generalized data extraction, where human and machine learning algorithms are combined to extract insights and evidence for better decision making across disciplines. Sysrev uses FAIR - Findability, Accessibility, Interoperability, and Reuse of digital assets - as primary principles in design. Sysrev was developed primarily because of an observed need to reduce redundancy, reduce inefficient use of human time and increase the impact of evidence based decision making. This publication is an introduction to Sysrev as a novel technology, with an overview of the features, motivations and use cases of the tool.

Methods

Sysrev.comis a FAIR motivated web platform for data curation and SER. Sysrev allows users to create data curation projects called “sysrevs” wherein users upload documents, define review tasks, recruit reviewers, perform review tasks, and automate review tasks.

Conclusion

Sysrev is a web application designed to facilitate data curation and SERs. Thousands of publicly accessible Sysrev projects have been created, accommodating research in a wide variety of disciplines. Described use cases include data curation, managed reviews, and SERs.
Lack of sex differences in gonadotropin-releasing hormone (GnRH) neuron potassium currents and excitability
Authors: DeFazio R. Anthony , Moenter Suzanne M.
Published: March 2021

Gonadotropin-releasing hormone (GnRH) drives pituitary secretion of luteinizing hormone (LH) and follicle-stimulating hormone, which in turn regulate gonadal functions including steroidogenesis. The pattern of GnRH release and thus fertility depend on gonadal steroid feedback. Under homeostatic (negative) feedback conditions, removal of the gonads from either females or males increases the amplitude and frequency of GnRH release and alters the long-term firing pattern of these neurons in brain slices. The neurobiological mechanisms intrinsic to GnRH neurons that are altered by homeostatic feedback are not well studied and have not been compared between sexes. During estradiol positive feedback, which is unique to females, there are correlated changes in voltage-gated potassium currents and neuronal excitability. We thus hypothesized these same mechanisms would be engaged in homeostatic negative feedback. Voltage-gated potassium channels play a direct role in setting excitability and action potential properties. Whole-cell patch-clamp recordings of GFP-identified GnRH neurons in brain slices from sham-operated and castrated adult female and male mice were made to assess fast (IA) and slow (IK) inactivating potassium currents as well as action potential properties. Surprisingly, no changes were observed in most potassium current properties, input resistance or capacitance and this was reflected in a lack of differences in excitability and specific action potential properties. These results support the concept that, in contrast to positive feedback, steroid negative feedback regulation of GnRH neurons in both sexes is likely conveyed to GnRH neurons via mechanisms that do not induce major changes in the biophysical properties of these cells.

Significance Statement

The pattern of activity of gonadotropin-releasing hormone (GnRH) neurons is crucial to reproductive success in both males and females. Direct comparison of GnRH neurons from mice of both sexes during negative feedback and after gonadectomy revealed few differences in potassium currents, excitability, and action potential properties. These results support the hypothesis that neurons presynaptic to GnRH neurons communicate negative feedback to these cells in a manner that does not alter their intrinsic biophysical properties.
Acis-RNA-mediated expression regulation of thetet(M) resistance gene inEnterococcus faecium
Authors: Le Neindre Killian , Dejoies Loren , Reissier Sophie , Felden Brice , Cattoir Vincent
Published: March 2021

A set of putative novel small RNAs was recently identified as expressed inEnterococcus faecium, a major opportunistic pathogen involved in numerous healthcare-associated infections and hospital outbreaks. The aim of this study was to characterize the first functional analysis of one of them,srn0030, by phenotypic, genomic and transcriptomic approaches. By genomic analysis and RACE mapping, we revealed the presence of this RNA (previously designated as Ptet) within the 5’-untrasnlated region (UTR) oftet(M), a gene conferring tetracycline resistance through ribosomal protection. The regulatory mechanism has previously been described as transcriptional attenuation, but has actually been poorly characterized. Hence, we provide original additional data, especially the presence of three upstream transcripts of ~100, ~150 and ~230 nt within the 5’-UTR oftet(M), suggesting an alternative regulatory mechanism. The total deletion of these three transcripts causes an unexpected decreasing of tetracycline resistance inE. faecium. The attenuation mechanism was investigated, and we confirmed that the transcriptional read-through andtet(M) overexpression induced by tetracycline addition but the function of putative peptide leader on attenuation mechanism was not supported by our data. We report here new phenotypic and transcriptomic observations inE. faeciumdemonstrating an alternative regulatory mechanism oftet(M) gene expression.
From classic to rap: Airborne transmission of different singing styles, with respect to risk assessment of a SARS-CoV-2 infection
Authors: Richter Bernhard , Hipp Anna , Schubert Bernd , Axt Marcus Rudolf , Stratmann Markus , Schmölder Christian , Spahn Claudia
Published: March 2021

1.

Since the Covid-19 virus spreads through airborne transmission, questions concerning the risk of spreading infectious droplets during singing and music making has arisen.

To contribute to this question and to help clarify the possible risks, we analyzed 15 singing scenarios (1) qualitatively – by making airflows visible, while singing – and (2) quantitatively – by measuring air velocities at three distances (1m, 1.5m and 2m). Air movements were considered positive when lying above 0.1 m/s, which is the usual room air velocity in venue, such as the concert hall of the Bamberg Symphony, where our measurements with three professional singers (female classical style, male classic style, female popular music style) took place.

Our findings highlight that high measurements for respiratory air velocity while singing are comparable to measurements of speaking and – by far – less than coughing. All measurements for singing stayed within a reach of 1.5m, while only direct voiceless blowing achieved measurements at the 2m sensor. Singing styles that use plosive sounds, i.e. using consonants more often as in rap, produced the highest air velocities of 0.17 m/s at the 1m sensor. Also, singing while wearing a facemask produces no air movements over 0.1 m/s.

On the basis of our recent studies on measurements of airflows and air velocities of professional singers and wind instrument players, as well as further studies on CO□ measurements in room settings of music activities, we publish our results – in consideration of further up-to-date research – in our frequently updated risk assessment (first published in April 2020). On this behalf, we suggest 2m radial distances for singers, especially in choirs.
Emergence of N antigen SARS-CoV-2 genetic variants escaping detection of antigenic tests
Authors: Del Vecchio Claudia , Brancaccio Giuseppina , Brazzale Alessandra Rosalba , Lavezzo Enrico , Onelia Francesco , Franchin Elisa , Manuto Laura , Bianca Federico , Cianci Vito , Cattelan Annamaria , Toppo Stefano , Crisanti Andrea
Published: March 2021

SARS-CoV-2 genetic variants are emerging as a major threat to vaccination efforts worldwide as they may increase virus transmission rate and/or confer the ability to escape vaccine induced immunity with knock on effects on the level of herd immunity and vaccine efficacy respectively. These variants concern the Spike protein, which is encoded by the S gene, involved in virus entry into host cells and the major target of vaccine development. We report here that genetic variants of the N gene can impair our ability to utilize antigenic tests for both diagnosis and mass testing efforts aimed at controlling virus transmission. While conducting a large validation study on the Abbott Panbio™ COVID-19 Ag test, we noticed that some swab samples failed to generate a positive result in spite of a high viral load in Rt-PCR assays. Sequencing analysis of viruses showing discordant results in the RT-PCR and antigen assays revealed the presence of multiple disruptive amino-acid substitutions in the N antigen (the viral protein detected in the antigen test) clustered from position 229 to 374 a region known to contain an immunodominant epitope. A relevant fraction of the variants, undetected by the antigen test, contained the mutations A376T coupled to M241I. Intriguingly we found that virus sequences with this mutation were over-represented in the antigen-test-negative and PCR-positive samples and progressively increased in frequency over time in Veneto, a region of Italy that has aggressively scaled up the utilization of antigen tests, which reached nearly 68% of all the SARS-CoV-2 swab assays performed there. We speculate that mass utilization of antigen assays could create a selection pressure on the target that may favor the spread of undetectable virus variants.
From loss to recovery: how to effectively assess chemosensory impairments during COVID-19 pandemic
Authors: Cecchetto Cinzia , Pizio Antonella Di , Genovese Federica , Calcinoni Orietta , Macchi Alberto , Dunkel Andreas , Ohla Kathrin , Spinelli Sara , Farruggia Michael C. , Joseph Paule V. , Menini Anna , Cantone Elena , Dinnella Caterina , Cecchini Maria Paola , D’Errico Anna , Mucignat-Caretta Carla , Parma Valentina , Dibattista Michele
Published: March 2021

Chemosensory impairments have been established as a specific indicator of COVID-19. They affect most patients and may persist long past the resolution of respiratory symptoms, representing an unprecedented medical challenge. Since the SARS-CoV-2 pandemic started, we now know much more about smell, taste, and chemesthesis loss associated with COVID-19. However, the temporal dynamics and characteristics of recovery are still unknown. Here, capitalizing on data from the Global Consortium for Chemosensory Research (GCCR) crowdsourced survey, we assessed chemosensory abilities after the resolution of respiratory symptoms in participants diagnosed with COVID-19 during the first wave of the pandemic in Italy. This analysis led to the identification of two patterns of chemosensory recovery, limited (partial) and substantial, which were found to be associated with differential age, degrees of chemosensory loss, and regional patterns. Uncovering the self-reported phenomenology of recovery from smell, taste, and chemesthetic disorders is the first, yet essential step, to provide healthcare professionals with the tools to take purposeful and targeted action to address chemosensory disorders and its severe discomfort.
Wastewater monitoring outperforms case numbers as a tool to track COVID-19 incidence dynamics when test positivity rates are high
Authors: Fernandez-Cassi Xavier , Scheidegger Andreas , Bänziger Carola , Cariti Federica , Corzon Alex Tuñas , Ganesanandamoorthy Pravin , Lemaitre Joseph C. , Ort Christoph , Julian Timothy R. , Kohn Tamar
Published: March 2021

Wastewater-based epidemiology (WBE) has been shown to coincide with, or anticipate, confirmed COVID-19 case numbers. During periods with high test positivity rates, however, case numbers may be underreported, whereas wastewater does not suffer from this limitation. Here we investigated how the dynamics of new COVID-19 infections estimated based on wastewater monitoring or confirmed cases compare to true COVID-19 incidence dynamics. We focused on the first pandemic wave in Switzerland (February to April, 2020), when test positivity ranged up to 26%. SARS-CoV-2 RNA loads were determined 2-4 times per week in three Swiss wastewater treatment plants (Lugano, Lausanne and Zurich). Wastewater and case data were combined with a shedding load distribution and an infection-to-case confirmation delay distribution, respectively, to estimate incidence dynamics. Finally, the estimates were compared to reference incidence dynamics determined by a validated compartmental model. Incidence dynamics estimated based on wastewater data were found to better track the timing and shape of the reference infection peak compared to estimates based on confirmed cases. In contrast, case confirmations provided a better estimate of the subsequent decline in infections. Under a regime of high-test positivity rates, WBE thus provides critical information that is complementary to clinical data to monitor the pandemic trajectory.
Neural dynamics of parametrically modulated human mechanical pain determined using whole-brain quantitative perfusion imaging
Authors: Segerdahl A.R. , Kong Y. , Ho I. , Tracey I
Published: March 2021

Arterial spin labelling (ASL) FMRI is a powerful tool to noninvasively image tonic and ongoing pain states in both healthy participants and patients. We used ASL to image the neural correlates of extended, parametrically modulated mechanical pain in healthy human participants. The aims of this study were to: i) assess if force-calibrated pin-prick probes could safely and robustly evoke tonic mechanical pain; ii) determine the neural correlates of the parametric changes in both the “force” of the stimulus and the “intensity” of the perception that this elicits using ASL; and iii) provide an initial assessment of the capacity for ALFF to differentiate painful versus non-painful tonic stimuli based on changes in the dynamics of the evoked signal. Our data confirm that it is possible to employ a stimulus force-locked design to induce robust, well maintained ongoing mechanical pain and to observe significant changes in rCBF relative to underlying component processes such as monitoring graded changes in the force applied to the skin (dACC, aMCC, pMCC, PCC, SI, SII, putamen, thalamus and the insula (anterior and posterior subsections); ipsilateral amygdala and hypothalamus; and the contralateral DLPFC) and tracking changes in the perceived intensity of the experience (: bilateral dACC, aMCC, pMCC, PCC, thalamus, SII and the cerebellum; and contralateral SI, insula (including the dpIns). Further exploration of the data using analyses targeting the spectral frequency aspects of the rCBF signal observed reveals that a collection of regions (e.g. the contralateral VLPFC, inferior frontal gyrus, insula (anterior, mid and posterior subsections), SII, putamen, OFC, amygdala, and the hippocampus) exhibit unique perfusion dynamics during extended painful stimulation compared to non-painful ‘touch’. Results from this study provide further validation for the application of ASL to image experimental pain in healthy human subjects while interrogation of the data offers unique insight into the dynamic signal changes underlying the perception of a tonic mechanical pain experience.
Abated immune responses against recombinant hepatitis-b vaccine by chitin in mice
Authors: Joshua Parker Elijah , Ayogu Nnaemeka Emmanuel , Ezeorba Timothy Prince Chidike , Odimegwu Damian Chukwu , Asomadu Rita Onyekachukwu , Ukachukwu Uzochukwu Gospel
Published: March 2021

Abated immune responses against recombinant hepatitis-b protein vaccine by chitin in mice

Majority of recombinant protein vaccines employ alum-based adjuvants to boost their immunogenicity in subjects. However, the safe-profiled alum-based adjuvants demonstrate relative ineffectiveness with these recombinant vaccines. This work investigated the adjuvant potential of chitin with recombinant Hepatitis-B protein vaccine (HBsAg) and its possible toxicological effects. Six to eight weeks old female albino mice, which were randomly and equally distributed into five groups were used for this study. Blood collection was done before each vaccination schedule and the samples were used for analysis. Results revealed that IgG and IgG1titres of mice administered 2 doses of HBsAg-Chitin formulation was significantly (p < 0.05) lower than those administered 3 doses of HBsAg and was not significantly (p > 0.05) higher than those administered 2 doses of HBsAg. However, a progressive increase in the anti-HBsAg titres in mice that received the HBsAg-Chitin formulation was observed as days came by. Activities of alanine and aspartate aminotransferases of all experimental groups, including their liver weights, inferred that the HBsAg-Chitin formulation exert no toxic effect on the liver. The findings of this research revealed that chitin demonstrated a relatively unimpressive adjuvant activity with the recombinant hepatitis-B protein vaccine.

GRAPHICAL ABSTRACT
Brain virtual histology with X-ray phase-contrast tomography Part II: 3D morphologies of amyloid-β plaques in Alzheimer’s disease models
Authors: Chourrout Matthieu , Roux Margaux , Boisvert Carlie , Gislard Coralie , Legland David , Arganda-Carreras Ignacio , Olivier Cécile , Peyrin Françoise , Boutin Hervé , Rama Nicolas , Baron Thierry , Meyronet David , Brun Emmanuel , Rositi Hugo , Wiart Marlène , Chauveau Fabien
Published: March 2021

While numerous transgenic mouse strains have been produced to model the formation of amyloid-β (Aβ) plaques in the brain, efficient methods for whole-brain 3D analysis of Aβ deposits are lacking. Moreover, standard immunohistochemistry performed on brain slices precludes any shape analysis of Aβ plaques. The present study shows how in-line (propagation-based) X-ray phase-contrast tomography (XPCT) combined with ethanol-induced brain sample dehydration enables hippocampus-wide detection and morphometric analysis of Aβ plaques. Performed in three distinct Alzheimer mouse strains, the proposed workflow identified differences in signal intensity and 3D shape parameters: 3xTg displayed a different type of Aβ plaques, with a larger volume and area, greater elongation, flatness and mean breadth, and more intense average signal than J20 and APP/PS1. As a label-free non-destructive technique, XPCT can be combined with standard immunohistochemistry. XPCT virtual histology could thus become instrumental in quantifying the 3D spreading and the morphological impact of seeding when studying prion-like properties of Aβ aggregates in animal models of Alzheimer’s disease. This is Part II of a series of two articles reporting the value of in-line XPCT for virtual histology of the brain; Part I shows how in-line XPCT enables 3D myelin mapping in the whole rodent brain and in human autopsy brain tissue.

Highlights

X-ray phase-contrast tomography (XPCT) enables whole brain detection of Aβ plaques

Morphometric parameters of Aβ plaques may be readily retrieved from XPCT data

New shape parameters were successfully extracted from three Alzheimer’s disease models

A Fiji-based “biologist-friendly” analysis workflow is proposed and shared

XPCT is a powerful virtual histology tool that requires minimal sample preparation

Graphical abstract
Brain image-derived phenotypes yield insights into causal risk of psychiatric disorders using a Mendelian randomization study
Authors: Guo Jing , Yu Ke , Guo Yan , Yao Shi , Wu Hao , Zhang Kun , Rong Yu , Guo Ming-Rui , Dong Shan-Shan , Yang Tie-Lin
Published: March 2021

Brain imaging-derived phenotypes (IDPs) serve as underlying functional intermediates in psychiatric disorders, both of which are highly polygenic and heritable. Observational studies have elucidated the correlation between IDPs and psychiatric disorders, yet no systematic screening of IDPs to confer the causal liability in such disorders. We conducted a bidirectional two-sample Mendelian randomization framework to explore the causality of 1,901 IDPs on 10 psychiatric disorders and established the BrainMR database (http://brainmr.online/idp2psy/Index.php). We identified 17 causalities in forward MR analyses and 14 causalities in reverse MR analyses, which all rigorously examined them through various sensitivity analyses. The top significant relationship in forward was a unit lower volume of right central lateral of the thalamic nuclei, which was causally associated with an increased anorexia nervosa risk with an estimated OR of 0.52 (95% CI 0.41-0.64,P= 3.32 × 10−9). In reverse, the top significant IDP to be affected was the area of superior segment of the circular sulcus of the insula in the right hemisphere, which was increased by the reason of SCZ risk with an estimated association effect size of 0.068 (95% CI 0.046-0.090,P= 1.12 × 10−6). Overall, our study provides unique insights into causal pathways of psychiatric disorders at the imaging levels.
Transcription factor RFX7 governs a tumor suppressor network in response to p53 and stress
Authors: Coronel Luis , Riege Konstantin , Schwab Katjana , Förste Silke , Häckes David , Semerau Lena , Bernhart Stephan H. , Siebert Reiner , Hoffmann Steve , Fischer Martin
Published: March 2021

Despite its prominence, the mechanisms through which the tumor suppressor p53 regulates most genes remain unclear. Recently, the regulatory factor X 7 (RFX7) emerged as a suppressor of lymphoid neoplasms, but its regulation and target genes mediating tumor suppression remain unknown. Here, we identify a novel p53-RFX7 signaling axis. Integrative analysis of the RFX7 DNA binding landscape and the RFX7-regulated transcriptome in three distinct cell systems reveals that RFX7 directly controls multiple established tumor suppressors, including PDCD4, PIK3IP1, MXD4, and PNRC1, across cell types and is the missing link for their activation in response to p53 and stress. RFX7 target gene expression correlates with cell differentiation and better prognosis in numerous cancer types. Interestingly, we find that RFX7 sensitizes cells to Doxorubicin by promoting apoptosis. Together, our work establishes RFX7’s role as a ubiquitous regulator of cell growth and fate determination and a key node in the p53 transcriptional program.
Endocytic recycling is central to circadian collagen fibrillogenesis and disrupted in fibrosis
Authors: Chang Joan , Pickard Adam , Herrera Jeremy A. , O’Keefe Sarah , Garva Richa , Knox John , Jowitt Thomas A. , Hartshorn Matthew , Hoyle Anna , Dingle Lewis , Coy Madeleine , Zeltz Cédric , Wong Jason , Reid Adam , Venkateswaran Rajamiyer V. , Lu Yinhui , Caswell Patrick , High Stephen , Gullberg Donald , Kadler Karl E.
Published: March 2021

Collagen-I fibrillogenesis is crucial to health and development, where dysregulation is a hallmark of fibroproliferative diseases. Here, we show that collagen-I fibril assembly required a functional endocytic system that recycles collagen-I to assemble new fibrils. Endogenous collagen production was not required for fibrillogenesis if exogenous collagen was available, but the circadian-regulated vacuolar protein sorting (VPS) 33b and collagen-binding integrin α11 subunit were crucial to fibrillogenesis. Cells lacking VPS33B secrete soluble collagen-I protomers but were deficient in fibril formation, thus secretion and assembly are separately controlled. Overexpression of VPS33B led to loss of fibril rhythmicity and over-abundance of fibrils, which was mediated through integrin α11β1. Endocytic recycling of collagen-I was enhanced in human fibroblasts isolated from idiopathic pulmonary fibrosis, where VPS33B and integrin α11 subunit were overexpressed at the fibrogenic front; this correlation between VPS33B, integrin α11 subunit, and abnormal collagen deposition was also observed in samples from patients with chronic skin wounds. In conclusion, our study showed that circadian-regulated endocytic recycling is central to homeostatic assembly of collagen fibrils and is disrupted in diseases.