bluuebunny/crossref_metadata_2025 huggingface dataset:
CLOT STIFFNESS MEASURED BY SEER SONORHEOMETRY AS A MARKER OF POOR PROGNOSIS IN HOSPITALIZED COVID-19 PATIENTS
Authors: López-Jaime Francisco José , Martín-Téllez Sandra , Doblas-Márquez Alberto , Márquez-Gómez Ignacio , Reguera-Iglesias José María , Muñoz-Pérez Manuel Isidro , Fernández-Bello Ihosvany , Montaño Adrián
Published: July 2021

Background

High incidence of life-threatening thrombotic complications is observed in severely ill COVID-19 patients. D-dimer may help evaluate disease severity and predict outcomes at hospital admission. However, its non-specificity and long analysis times strongly constrain its clinical value. Viscoelastic tests (VET) are widely available rapid point-of-care devices that have been shown to detect a hypercoagulable state (increased clot stiffness and fibrinolysis shutdown) as major contributors of the thrombotic complication in COVID-19. Nevertheless, based on the data obtained so far, definitive conclusions have not been drawn.

Objectives

We aim to evaluate the association between VET parameters, standard coagulation tests and inflammation markers assessed in COVID-19 patients at hospital admission with disease severity and outcomes.

Patients/Methods

A total of 69 COVID-19 patients requiring hospitalization were included in the study. The pro-inflammatory and pro-thrombotic state was analyzed by a panel of inflammation markers (IL-6, CRP, LDH, ferritin), routine coagulation tests (PT, aPTT, platelet count, fibrinogen, D-dimer) and a SEER sonorheometry VET profile (Quantra® System).

Results

Inflammatory markers IL-6, CRP, LDH and ferritin were elevated in a high percentage of patients (73.6%, 89.2%, 57.1% and 52.4%), as were coagulation-related parameters such as fibrinogen (81.4%) and D-dimer levels (66.2%). Quantra® analysis revealed increased clot stiffness (CS) in 34.8%, particularly due to increased fibrinogen contribution (FCS) in 63.7%. Increased clot stability to lysis (CSL) was observed in 32.4%. Age > 65 years, elevated values of fibrinogen, D-dimer, LDH, increased clot stiffness and resistance to clot lysis were significantly associated with worsening disease. The Quantra® FCS parameter showed a particularly high prognostic value in distinguishing patients with severe symptomatology.

Conclusion

The global study of hemostasis by the whole blood point-of-care Quantra® VET system may be a powerful tool for identifying poor prognosis in COVID-19 patients at hospital admission. In particular, FCS measured by Quantra® could be established as a plausible prognostic marker to aid the clinical management of COVID-19 patients.
Pre-existing antibodies targeting a linear epitope on SARS-CoV-2 S2 cross-reacted with commensal gut bacteria and shaped vaccine induced immunity
Authors: Jia Liqiu , Weng Shufeng , Wu Jing , Tian Xiangxiang , Zhang Yifan , Wang Xuyang , Wang Jing , Yan Dongmei , Wang Wanhai , Fang Fang , Zhu Zhaoqin , Qiu Chao , Zhang Wenhong , Xu Ying , Wan Yanmin
Published: July 2021

The origins of pre-existing SARS-CoV-2 cross-reactive antibodies and their potential impacts on vaccine efficacy have not been fully clarified. In this study, we demonstrated that S2 was the prevailing target of the pre-existing S protein cross-reactive antibodies in both healthy human and SPF mice. A dominant antibody epitope was identified on the connector domain of S2 (1147-SFKEELDKYFKNHT-1160, P144), which could be recognized by pre-existing antibodies in both human and mouse. Through metagenomic sequencing and fecal bacteria transplant, we proved that the generation of S2 cross-reactive antibodies was associated with commensal gut bacteria. Furthermore, six P144 specific monoclonal antibodies were isolated from naïve SPF mice and proved to cross-react with commensal gut bacteria collected from both human and mouse. Mice with high levels of pre-existing S2 cross-reactive antibodies mounted higher S protein specific binding antibodies, especially against S2, after being immunized with a SARS-CoV-2 S DNA vaccine. Similarly, we found that levels of pre-existing S2 and P144 reactive antibodies correlated positively with RBD specific binding antibody titers after two doses of inactivated SARS-CoV-2 vaccination in human. Finally, we provided data demonstrating that immunization of a SARS-CoV-2 S DNA vaccine could alter the gut microbiota compositions of mice.
Adding a reaction-restoration type transmission rate dynamic law to the basic SEIR COVID-19 model
Authors: Córdova-Lepe F. , Vogt-Geisse K.
Published: July 2021

The classical SEIR model, being an autonomous system of differential equations, has important limitations when representing a pandemic situation. Particularly, the geometric unimodal shape of the epidemic curve is not what is generally observed. This work introduces theβSEIR model, which adds to the classical SEIR model a differential law to model the variation in the transmission rate. It considers two opposite thrives generally found in a population: first, reaction to disease presence that may be linked to mitigation strategies, which tends to decrease transmission, and second, the urge to return to normal conditions that pulls to restore the initial value of the transmission rate. Our results open a wide spectrum of dynamic variabilities in the curve of new infected, which are justified by reaction and restoration thrives that affect disease transmission over time. Some of these dynamics have been observed in the existing COVID-19 disease data. In particular and to further exemplify the potential the model proposed in this article, we show its capability of capturing the evolution of the number of new confirmed cases of Chile and Italy for several months after epidemic onset, while incorporating a reaction to disease presence with decreasing adherence to mitigation strategies, as well as a seasonal effect on the restoration of the initial transmissibility conditions.
Persistence of neutralizing antibodies a year after SARS-CoV-2 infection
Authors: Haveri Anu , Ekström Nina , Solastie Anna , Virta Camilla , Österlund Pamela , Isosaari Elina , Nohynek Hanna , Palmu Arto A. , Melin Merit
Published: July 2021

Understanding for how long antibodies persist following Severe acute respiratory coronavirus 2 (SARS-CoV-2) infection provides important insight into estimating the duration of immunity induced by infection.

We assessed the persistence of serum antibodies following wild-type SARS-CoV-2 infection six and twelve months after diagnosis in 367 individuals of whom 13% had severe disease requiring hospitalization. We determined the SARS-CoV-2 spike (S-IgG) and nucleoprotein IgG concentrations and the proportion of subjects with neutralizing antibodies (NAb). We also measured the NAb titers among a smaller subset of participants (n=78) against a wild-type virus (B.1) and three variants of concern (VOCs): Alpha (B.1.1.7), Beta (B.1.351) and Delta (B.1.617.2).

We found that NAb against the wild-type virus and S-IgG persisted in 89% and 97% of subjects for at least twelve months after infection, respectively. IgG and NAb levels were higher after severe infection. NAb titers were significantly lower against variants compared to the wild-type virus.
Rapid and Quantitative Detection of Human Antibodies Against the 2019 Novel Coronavirus SARS CoV2 and its Variants as a Result of Vaccination and Infection
Authors: Taubner Benjamin , Peredo-Wende Ruben , Ramani Ananthakrishnan , Singh Gurpreet , Strle Klemen , Cady Nathaniel C.
Published: July 2021

Measuring the antibody response to 2019 SARS CoV2 is critical for diagnostic purposes, monitoring the prevalence of infection, and for gauging the efficacy of the worldwide vaccination effort COVID-19. In this study, a microchip-based grating coupled fluorescent plasmonic (GC-FP) assay was used to measure antibody levels that resulted from COVID-19 infection and vaccination. In addition, we measured the relative antibody binding towards antigens from variants CoV2 virus variants, strains B.1.1.7 (UK) and B.1.351 (S. African). Antibody levels against multiple antigens within the SARS CoV2 spike protein were significantly elevated for both vaccinated and infected individuals, while those against the nucleocapsid (N) protein were only elevated for infected individuals. GC-FP was effective for monitoring the IgG-based serological response to vaccination throughout the vaccination sequence, and could also resolve acute (within hours) increases in antibody levels. A significant decrease in antibody binding to antigens from the B.1.351 variant, but not B.1.1.7, was observed for all vaccinated subjects when measured by GC-FP as compared to the 2019 SARS CoV2 antigens. These results were corroborated by competitive ELISA assay. Collectively, the findings suggest that GC-FP is a viable, rapid, and accurate method for measuring both overall antibody levels to CoV2 and relative antibody binding to viral variants during infection or vaccination.
The I-KID Study Protocol: Evaluation of Efficacy, Outcomes and Safety of a New Infant Haemodialysis and Ultrafiltration Machine in Clinical Use: a Randomised Clinical Investigation using a Cluster Stepped-wedge Design
Authors: Lambert Heather J , Sharma Shriya , Matthews John NS
Published: July 2021

Introduction

The I-KID study aims to determine the clinical efficacy, outcomes and safety of a novel non-CE-marked infant haemodialysis machine, the Newcastle Infant Dialysis Ultrafiltration System (NIDUS), compared to currently available therapy in the UK. NIDUS is specifically designed for renal replacement therapy in small babies between 0.8 and 8 kilograms.

Methods and analysis

The clinical investigation is taking place in six UK centres. This is a randomised clinical investigation using a cluster stepped-wedge design. The study aims to recruit 95 babies requiring renal replacement therapy in paediatric intensive care units over 20 months.

Registration

IRAS ID number: 170481

MHRA Reference: CI/2017/0066

ISRCT Number: 13787486

CPMS ID number: 36558

NHS REC reference: 16/NE/0008

Eudamed number: CIV-GB-18-02-023105

Link to full protocol v6.0: https://fundingawards.nihr.ac.uk/award/14/23/26

What is known about this subject

Babies in paediatric intensive care unit (PICU) may develop acute renal failure and require therapeutic support.

Renal replacement options for babies are limited because of their small size and limitations of technology.

Current haemodialysis and filtration systems in use in UK are not recommended or licensed for children under 8kg.

What this study hopes to add

Renal replacement methods for infants under 8kg in PICU will be compared.

The efficacy, outcomes and safety of a new infant haemodialysis device will be assessed.

Usability of the new device in normal clinical settings outside of the development centre will be examined.
Characterization of long-term patient-reported symptoms of COVID-19: an analysis of social media data
Authors: Banda Juan M. , Adderley Nicola , Ahmed Waheed-Ul-Rahman , AlGhoul Heba , Alser Osaid , Alser Muath , Areia Carlos , Cogenur Mikail , Fišter Krisitina , Gombar Saurabh , Huser Vojtech , Jonnagaddala Jitendra , Lai Lana YH , Leis Angela , Mateu Lourdes , Mayer Miguel Angel , Minty Evan , Morales Daniel , Natarajan Karthik , Paredes Roger , Periyakoil Vyjeyanthi S. , Prats-Uribe Albert , Ross Elsie G. , Singh Gurdas , Subbian Vignesh , Vivekanantham Arani , Prieto-Alhambra Daniel
Published: July 2021

As the SARS-CoV-2 virus (COVID-19) continues to affect people across the globe, there is limited understanding of the long term implications for infected patients1–3. While some of these patients have documented follow-ups on clinical records, or participate in longitudinal surveys, these datasets are usually designed by clinicians, and not granular enough to understand the natural history or patient experiences of ‘long COVID’. In order to get a complete picture, there is a need to use patient generated data to track the long-term impact of COVID-19 on recovered patients in real time. There is a growing need to meticulously characterize these patients’ experiences, from infection to months post-infection, and with highly granular patient generated data rather than clinician narratives. In this work, we present a longitudinal characterization of post-COVID-19 symptoms using social media data from Twitter. Using a combination of machine learning, natural language processing techniques, and clinician reviews, we mined 296,154 tweets to characterize the post-acute infection course of the disease, creating detailed timelines of symptoms and conditions, and analyzing their symptomatology during a period of over 150 days.
THE COMPARISON OF THREE REAL-TIME PCR KITS FOR SARS-COV-2 DIAGNOSIS REVEALS DISCREPANCIES ON THE IDENTIFICATION OF POSITIVE COVID-19 CASES AND DISPERSION ON THE VALUES OBTAINED FOR THE DETECTION OF SARS-COV-2 VARIANTS
Authors: Santibáñez Álvaro , Luraschi Roberto , Barrera-Avalos Carlos , Vallejos-Vidal Eva , Alarcón Javiera , Cayunao Javiera , Mella Andrea , Figueroa Maximiliano , Hernández Felipe , Plaza Bárbara , Inostroza-Molina Ailen , Valdés Daniel , Imarai Mónica , Acuña-Castillo Claudio , Reyes-López Felipe E. , Sandino Ana María
Published: July 2021

The COVID-19 pandemic has generated a huge challenge and threat to public health throughout the world population. Reverse transcription associated with real-time Polymerase Chain Reaction (RT-qPCR) has been the gold-standard molecular tool for diagnosis and detection of the SARS-CoV-2. Currently, it is used as the main strategy for testing, traceability, and control of positive cases For this reason, the on-top high demand for reagents has produced stock-out on several occasions and the only alternative to keep population diagnosis has been the use of different RT-qPCR kits. Therefore, we evaluate the performance of three of the commercial RT-qPCR kits currently in use for SARS-CoV-2 diagnosis in Chile, consisting in: TaqMan 2019-nCoV Assay Kit v1 (Thermo). Real-Time Fluorescent RT-PCR Kit for Detecting SARS-CoV-2 (BGI), and LightCycler® Multiplex RNA Virus Master (Roche). Results of quantification cycle (Cq) and relative fluorescence units (RFU) obtained from their RT-qPCR reactions revealed important discrepancies on the total RNA required for the identification of SARS-CoV-2 genes and diagnosis. Marked differences between kits in samples with 30>Cq value< 34 was observed. Samples with positive diagnoses for Covid-19 using the Thermo Fisher kit had different results when the same samples were evaluated with Roche and BGI kits. The displacement on the Cq value for SARS-CoV-2 identification between the three different RT-qPCR kits was also evident when the presence of single nucleotide variants was evaluated in the context of genomic surveillance. Taken together, this study emphasizes the special care adjusting RT-qPCR reaction conditions of the different kits must be taken by all the laboratories before carrying out the detection of SARS-CoV-2 genes from total RNA nasopharyngeal swab (NPS) samples.
The Reliability and Validity of the Hebrew Patient Health Questionnaire (PHQ-9) in the General Population
Authors: Yona Tomer , Weisman Asaf , Gottlieb Uri , Lin Eshed , Masharawi Youssef
Published: July 2021

Objective

To assess the psychometric properties of the Hebrew version of the Patient Health Questionnaire (PHQ-9) in the general population.

Methods

Using an online survey, we assessed test-retest reliability with a two-week time interval. A total of 118 participants enrolled in the study, of whom 103 completed the survey twice. Each participant filled out the PHQ-9 and the 12-Item Short Form Survey (SF-12). Our statistical analysis includes Cronbach’s alpha, Intraclass Correlation Coefficient (ICC2,1), Spearman’s rank correlation coefficient, Standard Error of Measurement (SEM), and Minimal Detectable Change (MDC).

Results

Internal consistency of the Hebrew version of the PHQ-9 ranged from α=0.79-0.83. The test-retest reliability of the questionnaire is good (ICC2,1= 0.81), and it is moderately and negatively correlated to the mental component of the SF-12 (Spearman ρ= -0.57, p< .05). The SEM of the PHQ-9 is 1.83 points, and the MDC was found to be 5 points.

Conclusion

The Hebrew version of the PHQ-9 is valid and reliable for screening self-reported depressive symptoms online in the general Hebrew-speaking population.
PRISMA2020: an R package and Shiny app for producing PRISMA 2020-compliant flow diagrams, with interactivity for optimised digital transparency and Open Synthesis
Authors: Haddaway Neal R. , Page Matthew J. , Pritchard Chris C. , McGuinness Luke A.
Published: July 2021

Background

Reporting standards, such as PRISMA aim to ensure that the methods and results of systematic reviews are described in sufficient detail to allow full transparency. Flow diagrams in evidence syntheses allow the reader to rapidly understand the core procedures used in a review and examine the attrition of irrelevant records throughout the review process. Recent research suggests that use of flow diagrams in systematic reviews is poor and of low quality and called for standardised templates to facilitate better reporting in flow diagrams. The increasing options for interactivity provided by the Internet gives us an opportunity to support easy-to-use evidence synthesis tools, and here we report on the development of tools for the production of PRISMA 2020-compliant systematic review flow diagrams.

Methods and Findings

We developed a free-to-use, Open Source R package and web-based Shiny app to allow users to design PRISMA flow diagrams for their own systematic reviews. Our tools allow users to produce standardised visualisations that transparently document the methods and results of a systematic review process in a variety of formats. In addition, we provide the opportunity to produce interactive, web-based flow diagrams (exported as HTML files), that allow readers to click on boxes of the diagram and navigate to further details on methods, results or data files. We provide an interactive example here;https://driscoll.ntu.ac.uk/prisma/.

Conclusions

We have developed a user-friendly suite of tools for producing PRISMA 2020-compliant flow diagrams for users with coding experience and, importantly, for users without prior experience in coding by making use of Shiny. These free-to-use tools will make it easier to produce clear and PRISMA 2020-compliant systematic review flow diagrams. Significantly, users can also produce interactive flow diagrams for the first time, allowing readers of their reviews to smoothly and swiftly explore and navigate to further details of the methods and results of a review. We believe these tools will increase use of PRISMA flow diagrams, improve the compliance and quality of flow diagrams, and facilitate strong science communication of the methods and results of systematic reviews by making use of interactivity. We encourage the systematic review community to make use of these tools, and provide feedback to streamline and improve their usability and efficiency.
Variation in COVID-19 excess mortality by age, sex, and province within Italy
Authors: Henry Nathaniel , Elagali Ahmed , Nguyen Michele , Chipeta Michael , Moore Catrin
Published: July 2021

1

Although previous evidence suggests that the infection fatality rate from COVID-19 varies by age and sex, and that transmission intensity varies geographically within countries, no study has yet explored the age-sex-space distribution of excess mortality associated with the COVID pandemic. By applying the principles of small-area estimation to existing models formulations for excess mortality, this study develops a method for assessing excess mortality across small populations and assesses the pattern of COVID excess mortality by province, year, week, age group, and sex in Italy from March through May 2020. We estimate that 53,200 excess deaths occurred across Italy during this time period, compared to just 35,500 deaths where COVID-19 was registered as the underlying cause of death. Out of the total excess mortality burden, 97% of excess deaths occurred among adults over age 60, and 68% of excess deaths were concentrated among adults over age 80. The burden of excess mortality was unevenly distributed across the country, with just three of Italy’s 107 provinces accounting for 32% of all excess mortality. This method for estimating excess mortality can be adapted to other countries where COVID-19 diagnostic capacity is still insufficient, and could be incorporated into public health rapid response systems.
Cloud-based DIA data analysis module for signal refinement improves accuracy and throughput of large datasets
Authors: Christianson Karen E. , Jaffe Jacob. D. , Carr Steven A. , Jacome Alvaro Sebastian Vaca
Published: July 2021

Data-independent acquisition (DIA) is a powerful mass spectrometry method that promises higher coverage, reproducibility, and throughput than traditional quantitative proteomics approaches. However, the complexity of DIA data caused by fragmentation of co-isolating peptides presents significant challenges for confident assignment of identity and quantity, information that is essential for deriving meaningful biological insight from the data. To overcome this problem, we previously developed Avant-garde, a tool for automated signal refinement of DIA and other targeted mass spectrometry data. AvG is designed to work alongside existing tools for peptide detection to address the reliability and quantitative suitability of signals extracted for the identified peptides. While its use is straightforward and offers efficient refinement for small datasets, the execution of AvG for large DIA datasets is time-consuming, especially if run with limited computational resources. To overcome these limitations, we present here an improved, cloud-based implementation of the AvG algorithm deployed on Terra, a user-friendly cloud-based platform for large-scale data analysis and sharing, as an accessible and standardized resource to the wider community.
Gut microbiome dysbiosis during COVID-19 is associated with increased risk for bacteremia and microbial translocation
Authors: Venzon Mericien , Bernard-Raichon Lucie , Klein Jon , Axelrad Jordan E. , Zhang Chenzhen , Hussey Grant A. , Sullivan Alexis P. , Casanovas-Massana Arnau , Noval Maria G. , Valero-Jimenez Ana M. , Gago Juan , Putzel Gregory , Pironti Alejandro , Wilder Evan ,   Yale IMPACT Research Team, Thorpe Lorna E. , Littman Dan R. , Dittmann Meike , Stapleford Kenneth A. , Shopsin Bo , Torres Victor J. , Ko Albert I. , Iwasaki Akiko , Cadwell Ken , Schluter Jonas
Published: July 2021

The microbial populations in the gut microbiome have recently been associated with COVID-19 disease severity. However, a causal impact of the gut microbiome on COVID-19 patient health has not been established. Here we provide evidence that gut microbiome dysbiosis is associated with translocation of bacteria into the blood during COVID-19, causing life-threatening secondary infections. Antibiotics and other treatments during COVID-19 can potentially confound microbiome associations. We therefore first demonstrate in a mouse model that SARS-CoV-2 infection can induce gut microbiome dysbiosis, which correlated with alterations to Paneth cells and goblet cells, and markers of barrier permeability. Comparison with stool samples collected from 96 COVID-19 patients at two different clinical sites also revealed substantial gut microbiome dysbiosis, paralleling our observations in the animal model. Specifically, we observed blooms of opportunistic pathogenic bacterial genera known to include antimicrobial-resistant species in hospitalized COVID-19 patients. Analysis of blood culture results testing for secondary microbial bloodstream infections with paired microbiome data obtained from these patients indicates that bacteria may translocate from the gut into the systemic circulation of COVID-19 patients. These results are consistent with a direct role for gut microbiome dysbiosis in enabling dangerous secondary infections during COVID-19.
Functional and Structural Segregation of Overlapping Helices in HIV-1
Authors: Safari Maliheh , Jayaraman Bhargavi , Yang Shumin , Smith Cynthia , Fernandes Jason D. , Frankel Alan D.
Published: July 2021

Overlapping coding regions balance selective forces between multiple genes. One possible division of nucleotide sequence is that the predominant selective force on a particular nucleotide can be attributed to just one gene. While this arrangement has been observed in regions in which one gene is structured and the other is disordered, we sought to explore how overlapping genes balance constraints when both protein products are structured over the same sequence. We use a combination of sequence analysis, functional assays and selection experiments to examine an overlapped region in HIV-1 that encodes helical regions in both Env and Rev. We find that functional segregation occurs even in this overlap, with each protein spacing its functional residues in a manner that allows a mutable non-binding face of one helix to encode important functional residues on a charged face in the other helix. Additionally, our experiments reveal novel and critical functional residues in Env and have implications for the therapeutic targeting of HIV-1.
Model-based identification of conditionally-essential genes from transposon-insertion sequencing data
Authors: Sarsani Vishal , Aldikacti Berent , He Shai , Zeinert Rilee , Chien Peter , Flaherty Patrick
Published: July 2021

The understanding of bacterial gene function has been greatly enhanced by recent advancements in the deep sequencing of microbial genomes. Transposon insertion sequencing methods combines next-generation sequencing techniques with transposon mutagenesis for the exploration of the essentiality of genes under different environmental conditions. We propose a model-based method that uses regularized negative binomial regression to estimate the change in transposon insertions attributable to gene-environment changes without transformations or uniform normalization. An empirical Bayes model for estimating the local false discovery rate combines unique and total count information to test for genes that show a statistically significant change in transposon counts. When applied to RB-TnSeq (randomized barcode transposon sequencing) and Tn-seq (transposon sequencing) libraries made in strains of Caulobacter crescentus using both total and unique count data the model was able to identify a set of conditionally essential genes for each target condition that shed light on their functions and roles during various stress conditions.

Author summary

Transposon insertion sequencing allows the study of bacterial gene function by combining next-generation sequencing techniques with transposon mutagenesis under different genetic and environmental perturbations. Our proposed regularized negative binomial regression method improves the quality of analysis of this data.
Limitations of lymphoblastoid cell lines for establishing genetic reference datasets in the immunoglobulin loci
Authors: Rodriguez Oscar L. , Sharp Andrew J. , Watson Corey T.
Published: July 2021

Lymphoblastoid cell lines (LCLs) have been critical to establishing genetic resources for biomedical science. They have been used extensively to study human genetic diversity, genome function, and inform the development of tools and methodologies for augmenting disease genetics research. While the validity of variant callsets from LCLs has been demonstrated for most of the genome, previous work has shown that DNA extracted from LCLs is modified by V(D)J recombination within the immunoglobulin (IG) loci, regions that harbor antibody genes critical to immune system function. However, the impacts of V(D)J on data generated from LCLs has not been extensively investigated. In this study, we used LCL-derived short read sequencing data from the 1000 Genomes Project (n=2,504) to identify signatures of V(D)J recombination. Our analyses revealed sample-level impacts of V(D)J recombination that varied depending on the degree of inferred monoclonality. We showed that V(D)J associated somatic deletions impacted genotyping accuracy, leading to adulterated population-level estimates of allele frequency and linkage disequilibrium. These findings illuminate limitations of using LCLs for building genetic resources in the IG loci, with implications for interpreting previous disease association studies in these regions.

Author summary

Lymphoblastoid cell lines (LCLs) are cells that have been manipulated to proliferate indefinitely in order to provide a replenishable source of DNA. However, because these cell lines are derived from B cells which have undergone V(D)J recombination they contain somatic deletions within regions of the genome that encode antibody genes. Although several large collaborative projects have utilized DNA from LCLs to generate invaluable genomic resources for the scientific community, the negative impacts of cell line artifacts in these regions of the genome have not been fully appreciated. In this study, we used newly released sequencing data from a large collection of LCLs to determine that the non-inherited artificial deletions within the antibody gene loci can have detrimental effects on downstream genetic analyses.
Inactivation effects of plasma-activated water on Fusarium graminearum
Authors: Guo Jian , Wang Jiaoyu , Xie Hui , Jiang Junlong , Li Chunyuan , Li Wanting , Li Ling , Liu Xingquan , Lin Fucheng
Published: July 2021

The continuous usage of fungicides poses a potential threat to the environment, ranging from mere irritation to being very toxic to human beings and organisms. Plasma-activated water (PAW) has recently gained much interest as a promising candidate to inactivate fungi. However, the inactivation mechanisms of PAW are still not well understood. In this study, the effect of PAW on the viability and the cellular responses of Fusarium graminearum in PAW inactivation were investigated. The results showed that microbial activity of spores was significantly inhibited by PAW treatment (P < 0.05). The symptoms caused by F. graminearum were significantly reduced on the spikelets. Our data indicated that PAW could induce cell wall sculpturing, membrane permeability changes, and mitochondrial dysfunction. Differential gene expression analysis also confirmed that the cell membrane, the cell wall and the mitochondria were the organelles most affected by PAW. The results from this study facilitate the understanding of the mechanisms underlying the responses of F. graminearum to PAW and the development of PAW as a potential fungicidal agent or an effective supplement to fungicides.

Highlights

The viability of F. graminearum is notably inhibited by PAW

The symptoms caused by F. graminearum were significantly reduced on the spikelets

Oxidative stress induce cell wall sculpturing, membrane permeability change

PAW can cause the mitochondrial dysfunction

Cell wall, membrane and mitochondria are the most affected organelles by PAW
Comparative Genome Analysis Reveals Human Pathogenic Potential of ESBL-Escherichia coli Isolated from Swine Microbiomes
Authors: Founou Luria Leslie , Founou Raspail Carrel , Allam Mushal , Ismail Arshad , Essack Sabiha Yusuf
Published: July 2021

Background

Extended-spectrum β-lactamase-producing E. coli (ESBL-Ec) harbouring virulence genes in the microbiome of food animals could likely threaten human health but is poorly understood in Cameroon and South Africa. Here, we assessed the resistome, virulome and mobilome of ESBL-Ec isolated from swine microbiomes in these countries, using whole genome sequencing (WGS).

Materials/methods

Eleven clonally-related phenotypic ESBL-Ec isolates were subjected to WGS. The isolates were de novo assembled using the CLC Genomics Workbench and SPAdes while RAST and PROKKA were used for annotation of the assembled contigs. Prediction of antibiotic resistance genes, virulence factors and plasmids was performed using ResFinder, VirulenceFinder and PlasmidFinder, respectively.

Results

Diverse STs were detected with sequence types ST2144 and ST88 predominating and blaCTX-M-15 (55%) as principal ESBL genes. Although the isolates belonged mainly to commensal phylogroups A/B1 (45/28.3%) and C (18.18%), all harboured at least three extraintestinal pathogenic E. coli (ExPEC) VFs with one isolate harbouring up to 18 ExPEC VFs.

Conclusion

The resistance and pathogenic potential of ESBL-Ec colonizing the gut microbiota of swine in both countries demonstrate the urgent need to implement effective strategies to contain the dissemination of virulent ESBL-Ec through the food chain in Cameroon and South Africa.
The role of the first transmembrane helix in bacterial YidC: Insights from the crystal structure and molecular dynamics simulations
Authors: Nass Karol J. , Ilie Ioana M. , Saller Manfred J. , Driessen Arnold J.M. , Caflisch Amedeo , Kammerer Richard A. , Li Xiaodan
Published: July 2021

The evolutionary conserved YidC is a unique dual-function protein that adopts insertase and chaperone conformations. The TM1 helix of Escherichia coli YidC mediates the interaction between the YidC chaperone and the Sec translocon. Here, we report the first crystal structure of Thermotoga maritima YidC (TmYidC) including the TM1 helix (PDB ID: 6Y86). The TM1 helix lies on the periplasmic side of the bilayer forming an angle of about 15 degrees with the membrane surface. Our functional studies suggest a role of TM1 for the species-specific interaction with the Sec translocon. The reconstitution data and the superimposition of TmYidC with known YidC structures suggest an active insertase conformation for YidC. Molecular dynamics (MD) simulations of TmYidC provide evidence that the TM1 helix acts as a membrane anchor for the YidC insertase and highlight the flexibility of the C1 region underlining its ability to switch between insertase and chaperone conformations. A structure-based model is proposed to rationalize how YidC performs the insertase and chaperone functions by re-positioning of the TM1 helix and the other structural elements.
Ammonium regulates the development of pine roots through hormonal crosstalk and differential expression of transcription factors in the apex
Authors: Ortigosa Francisco , Lobato-Fernández César , Shikano Hitomi , Ávila Concepción , Taira Shu , Cánovas Francisco M. , Cañas Rafael A.
Published: July 2021

Ammonium is a prominent source of inorganic nitrogen for plant nutrition, but excessive amounts can be toxic for many species. However, most conifers are tolerant to ammonium, a relevant physiological feature of this ancient evolutionary lineage. For a better understanding of the molecular basis of this trait, ammonium-induced changes in the transcriptome of maritime pine (Pinus pinasterAit.) root apex have been determined by laser capture microdissection and RNA sequencing. Ammonium promoted changes in the transcriptional profiles of multiple transcription factors, such asSHORT-ROOT, and phytohormone-related transcripts, such asACO, involved in the development of the root meristem. Nano-PALDI-MSI and transcriptomic analyses showed that the distributions of IAA and CKs were altered in the root apex in response to ammonium nutrition. Taken together, the data suggest that this early response is involved in the increased lateral root branching and principal root growth, which characterize the long-term response to ammonium supply in pine. All these results suggest that ammonium induces changes in the root system architecture through the IAA-CK-ET phytohormone crosstalk and transcriptional regulation.
SMC complexes can traverse physical roadblocks bigger than their ring size
Authors: Pradhan Biswajit , Barth Roman , Kim Eugene , Davidson Iain F. , Bauer Benedikt , van Laar Theo , Yang Wayne , Ryu Je-Kyung , van der Torre Jaco , Peters Jan-Michael , Dekker Cees
Published: July 2021

The ring-shaped structural-maintenance-of-chromosomes (SMC) complexes condensin and cohesin extrude loops of DNA as a key motif in chromosome organization. It remains, how ever, unclear how these SMC motor proteins can extrude DNA loops in chromatin that is bound with proteins. Here, using in vitro single-molecule visualization, we show that nucleosomes, RNA polymerase, and dCas9 pose virtually no barrier to DNA loop extrusion by yeast condensin. Strikingly, we find that even DNA-bound nanoparticles as large as 200 nm, much bigger than the SMC ring size, can be translocated into DNA loops during condensin-driven extrusion. Similarly, human cohesin can pass 200 nm particles during loop extrusion, which even occurs for a single-chain version of cohesin in which the ring-forming subunits are covalently linked and cannot open up to entrap DNA. These findings disqualify all common loop-extrusion models where DNA passes through the SMC rings (pseudo)topologically, and instead point to a nontopological mechanism for DNA loop extrusion.

One-sentence summary

Huge DNA-bound roadblocks can be incorporated into SMC-extruded DNA loops, pointing to a nontopological mechanism for loop extrusion.
Experience-Driven Rate Modulation is Reinstated During Hippocampal Replay
Authors: Tirole M. , Huelin Gorriz M. , Takigawa M. , Kukovska L. , Bendor D.
Published: July 2021

Replay, the sequential reactivation within a neuronal ensemble, is a central hippocampal mechanism postulated to drive memory processing. While both rate and place representations are used by hippocampal place cells to encode behavioral episodes, replay has been largely defined by only the latter – based on the fidelity of sequential activity across neighboring place fields. Here we show that dorsal CA1 place cells in rats can modulate their firing rate between replay events of two different contexts. This experience-dependent phenomenon mirrors the same pattern of rate modulation observed during behavior and can be used independently from place information within replay sequences to discriminate between contexts. Our results reveal the existence of two complementary neural representations available for memory processes.
Minimizing the ex vivo confounds of cell-isolation techniques on transcriptomic -profiles of purified microglia
Authors: Ocañas Sarah R. , Pham Kevin D. , Blankenship Harris E. , Machalinski Adeline H. , Chucair-Elliott Ana J. , Freeman Willard M.
Published: July 2021

Modern molecular neuroscience studies require analysis of specific cellular populations derived from brain tissue samples to disambiguate cell-type specific events. This is particularly true in the analysis of minority glial populations in the brain, such as microglia, which may be obscured in whole tissue analyses. Microglia have central functions in development, aging, and neurodegeneration and are a current focus of neuroscience research. A long-standing concern for glial biologists using in vivo models is whether cell isolation from CNS tissue could introduce ex vivo artifacts in microglia, which respond quickly to changes in the environment. Mouse microglia were purified by magnetic-activated cell sorting (MACS), as well as cytometer- and cartridge-based fluorescence-activated cell sorting (FACS) approaches to compare and contrast performance. The Cx3cr1-NuTRAP mouse model was used here to provide an endogenous fluorescent microglial marker and a microglial-specific translatome profile as a baseline comparison lacking cell isolation artifacts. All methods performed similarly for microglial purity with main differences being in cell yield and time of isolation. Ex vivo activation signatures occurred principally during the initial tissue dissociation and cell preparation and not the microglial cell sorting. Utilizing transcriptional and translational inhibitors during the cell preparation prevented the activational phenotype. These data demonstrate that a variety of microglial isolation approaches can be used, depending on experimental needs, and that inhibitor cocktails are effective at reducing cell preparation artifacts.

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Main Points

MACS, cytometer-FACS, and cartridge-FACS give equivalent and sufficient yield/purity for microglial analyses. Ex vivo microglial activation is prevented by supplementation with transcription/translation inhibitors during cell preparation.
Gambling environment exposure increases temporal discounting but improves model-based control in regular slot-machine gamblers
Authors: Wagner Ben , Mathar David , Peters Jan
Published: July 2021

Gambling disorder is a behavioral addiction that negatively impacts personal finances, work, relationships and mental health. In this pre-registered study (https://osf.io/5ptz9/?view_only=62956a2afcd1495984db4be18c54b50a) we investigated the impact of real-life gambling environments on two computational markers of addiction, temporal discounting and model-based reinforcement learning. Gambling disorder is associated with increased temporal discounting and reduced model-based learning. Regular gamblers (n = 30, DSM-5 score range 3-9) performed both tasks in a neutral (café) and a gambling-related environment (slot-machine venue) in counterbalanced order. Data were modeled using drift diffusion models for temporal discounting and reinforcement learning via hierarchical Bayesian estimation. Replicating previous findings, gamblers discounted rewards more steeply in the gambling-related context. This effect was positively correlated with gambling related cognitive distortions (pre-registered analysis). In contrast to our pre-registered hypothesis, model-based reinforcement learning was improved in the gambling context. Here we show that temporal discounting and model-based reinforcement learning are modulated in opposite ways by real-life gambling cue exposure. Results challenge aspects of habit theories of addiction, and reveal that laboratory-based computational markers of psychopathology are under substantial contextual control.
Antagonists targeting eEF2 kinase rescue multiple aspects of pathophysiology in Alzheimer’s disease model mice
Authors: Kasica Nicole P , Zhou Xueyan , Wang Xin , Yang Wenzhong , Zimmermann Helena R , Holland Caroline E , Koscielniak Elizabeth , Wu Hanzhi , Cox Anderson O , Lee Jingyun , Ryazanov Alexey G , Furdui Cristina M. , Ma Tao
Published: July 2021

It is imperative to develop novel therapeutic strategies for Alzheimer’s disease (AD) and related dementia syndromes based on solid mechanistic studies. Maintenance of memory and synaptic plasticity relies on de novo protein synthesis, which is partially regulated by phosphorylation of eukaryotic elongation factor 2 (eEF2) via its kinase eEF2K. Abnormally increased eEF2 phosphorylation and impaired mRNA translation have been linked to AD. We recently reported that prenatal genetic suppression of eEF2K is able to prevent aging-related cognitive deficits in AD model mice, suggesting the therapeutic potential of targeting eEF2K/eEF2 signaling in AD. Here, we tested two structurally distinct small-molecule eEF2K inhibitors in two different lines of AD model mice after onset of cognitive impairments. Our data revealed that treatment with eEF2K inhibitors improved AD-associated synaptic plasticity impairments and cognitive dysfunction, without altering brain amyloid β (Aβ) and tau pathology. Furthermore, eEF2K inhibition alleviated AD-associated defects in dendritic spine morphology, postsynaptic density formation, protein synthesis, and dendritic polyribosome assembly. Our results may offer critical therapeutic implications for AD, and the proof-of-principle study indicates translational implication of inhibiting eEF2K for AD and related dementia syndromes.

One Sentence Summary

Treatment with eEF2K inhibitors and genetic eEF2K knockout improved cognitive deficits in Alzheimer’s disease model mice.
Feedbacks between size and density determine rapid eco-phenotypic dynamics
Authors: Gibert Jean Philippe , Han Ze-Yi , Wieczynski Daniel J , Votzke Samantha , Yammine Andrea
Published: July 2021

Body size is a fundamental trait linked to many ecological processes—from individuals to ecosystems. Although the effects of body size on metabolism are well-known, the potential reciprocal effects of body size and density are less clear. Specifically, 1) whether changes in body size or density more strongly influence the other and 2) whether coupled rapid changes in body size and density are due to plasticity, rapid evolutionary change, or a combination of both.

Here, we address these two issues by experimentally tracking population density and mean body size in the protistTetrahymena pyriformisas it grows from low density to carrying capacity. We then useConvergent Cross Mappingtime series analyses to infer the direction, magnitude, and causality of the link between body size and ecological dynamics. We confirm the results of our analysis by experimentally manipulating body size and density while keeping the other constant. Last, we fit mathematical models to our experimental time series that account for purely plastic change in body size, rapid evolution in size, or a combination of both, to gain insight into the processes that most likely explain the observed dynamics.

Our results indicate that changes in body size more strongly influence changes in density than the other way around, but also show that there is reciprocity in this effect (i.e., afeedback). We show that a model that only accounts for purely plastic change in size most parsimoniously explains observed, coupled phenotypic and ecological dynamics.

Together, these results suggest 1) that body size can shift dramatically through plasticity, well within ecological timescales, 2) that rapid changes in body size may have a larger effect on ecological dynamics than the reverse, but 3) phenotypic and ecological dynamics influence each as populations grow. Overall, we show that rapid plastic changes in functional traits like body size may play a fundamental –but currently unrecognized– role in familiar ecological processes such as logistic population growth.
Segmenting and Predicting Musical Phrase Structure Exploits Neural Gain Modulation and Phase Precession
Authors: Teng Xiangbin , Larrouy-Maestri Pauline , Poeppel David
Published: July 2021

Music, like language, is characterized by hierarchically organized structure that unfolds over time. Music listening therefore requires not only the tracking of notes and beats but also internally constructing high-level musical structures or phrases and anticipating incoming contents. Unlike for language, mechanistic evidence for online musical segmentation and prediction at a structural level is sparse. We recorded neurophysiological data from participants listening to music in its original forms as well as in manipulated versions with locally or globally reversed harmonic structures. We discovered a low-frequency neural component that modulated the neural rhythms of beat tracking and reliably parsed musical phrases. We next identified phrasal phase precession, suggesting that listeners established structural predictions from ongoing listening experience to track phrasal boundaries. The data point to brain mechanisms that listeners use to segment continuous music at the phrasal level and to predict abstract structural features of music.