bluuebunny/crossref_metadata_2025 huggingface dataset:
A single cell atlas of the cycling murine ovary
Authors: Morris ME , Meinsohn MC , Chauvin M , Saatcioglu HD , Kashiwagi A. , Sicher NA. , Nguyen NMP , Yuan S , Stavely Rhian , Hyun M , Donahoe PK , Sabatini B , Pépin D
Published: February 2022

The estrous cycle is regulated by rhythmic endocrine interactions of the nervous and reproductive systems, which coordinate the hormonal and ovulatory functions of the ovary. Folliculogenesis and follicle progression require the orchestrated response of a variety of cell types to allow the maturation of the follicle and its sequela, ovulation, corpus luteum (CL) formation, and ovulatory wound repair. Little is known about the cell state dynamics of the ovary during the estrous cycle, and the paracrine factors that help coordinate this process. Herein we used single-cell RNA sequencing to evaluate the transcriptome of > 34,000 cells of the adult mouse ovary and describe the transcriptional changes that occur across the normal estrous cycle and other reproductive states to build a comprehensive dynamic atlas of murine ovarian cell types and states.
Orchestration of Chlorophyll and Carotenoid Biosynthesis by ORANGE Family Proteins in Plant
Authors: Sun Tianhu , Wang Peng , Lu Shan , Yuan Hui , Yang Yong , Fish Tara , Thannhauser Theodore , Liu Jiping , Mazourek Michael , Grimm Bernhard , Li Li
Published: February 2022

Chlorophyll and carotenoid are essential photosynthetic pigments. Plants must spatiotemporally coordinate the needs of chlorophyll and carotenoid for optimal photosynthesis and plant fitness in response to diverse environmental and developmental cues. However, how these two biosynthesis pathways are orchestrated remains largely unknown. Here, we report that the highly conserved ORANGE (OR) family proteins are the common regulators of both pathways via posttranslationally regulating the first committed enzyme in each pathway. We demonstrate that OR family proteins physically interact with magnesium chelatase subunit I (CHLI) in addition to phytoene synthase (PSY) and concurrently regulate CHLI and PSY protein stability and activity. We show that loss of OR genes hinders both chlorophyll and carotenoid biosynthesis, limits light-harvesting complex assembly, and impairs thylakoid grana stacking in chloroplast. OR overexpression safeguards photosynthetic pigment biosynthesis and enhances thermotolerance in both Arabidopsis and tomato plants. Our findings establish a conserved mechanism of green plant to coordinate chlorophyll and carotenoid biosynthesis and provide a potential genetic target to generate climate-resilient crops.
Somatic mutations reveal hypermutable brains and are associated with neuropsychiatric disorders
Authors: Bae Taejeong , Fasching Liana , Wang Yifan , Shin Joo Heon , Suvakov Milovan , Jang Yeongjun , Norton Scott , Dias Caroline , Mariani Jessica , Jourdon Alexandre , Wu Feinan , Panda Arijit , Roberts Rosalinda C. , Huttner Anita , Kleinman Joel E. , Hyde Thomas M. , Straub Richard E. , Walsh Christopher A. ,   Brain Somatic Mosaicism Network, Urban Alexander , Leckman James F. , Weinberger Daniel R. , Vaccarino Flora M. , Abyzov Alexej
Published: February 2022

Somatic mutations have causative roles in many diseases and contribute to neuropsychiatric disorders. Here, we analyzed 131 human brains (44 neurotypical, 19 with Tourette syndrome, 9 with schizophrenia, and 59 with autism) for somatic single nucleotide and structural mutations after whole genome sequencing to a depth of over 200X. Typically, brains had 20 to 60 detectable single nucleotide mutations that likely arose in early development; however, about 5% of brains harbored hundreds and up to 2000 somatic mutations. Hypermutability was associated with age and putative damaging mutations in genes previously implicated in cancer and likely reflectsin vivoclonal expansions. Somatic duplications of likely early developmental origin were present in 1 out of 20 normal and diseased brains, reflecting background mutagenesis. Brains of individuals with autism were enriched in somatic deletions and in point mutations that create putative transcription factor binding motifs in enhancers that are active in the developing brain. The most affected motifs corresponded to MEIS transcription factors, suggesting a potential link between their involvement in gene regulation and autism.
Machine Learning Generalizability Across Healthcare Settings: Insights from multi-site COVID-19 screening
Authors: Yang Jenny , Soltan Andrew A. S. , Clifton David A.
Published: February 2022

As patient health information is highly regulated due to privacy concerns, the majority of machine learning (ML)-based healthcare studies are unable to test on external patient cohorts, resulting in a gap between locally reported model performance and cross-site generalizability. Different approaches have been introduced for developing models across multiple clinical sites, however no studies have compared methods for translating ready-made models for adoption in new settings. We introduce three methods to do this – (1) applying a ready-made model “as-is”; (2) readjusting the decision threshold on the output of a ready-made model using site-specific data; and (3) finetuning a ready-made model using site-specific data via transfer learning. Using a case study of COVID-19 diagnosis across four NHS Hospital Trusts, we show that all methods achieve clinically-effective performances (NPV >0.959), with transfer learning achieving the best results (mean AUROCs between 0.870-0.925). Our models demonstrate that site-specific customization improves predictive performance when compared to other ready-made approaches.
Cov2MS: an automated matrix-independent assay for mass spectrometric detection and measurement of SARS-CoV-2 nucleocapsid protein in infectious patients
Authors: Van Puyvelde Bart , Van Uytfanghe Katleen , Van Oudenhove Laurence , Gabriels Ralf , Van Royen Tessa , Matthys Arne , Razavi Morteza , Yip Richard , Pearson Terry , van Hulle Marijn , Claereboudt Jan , Wyndham Kevin , Jones Don , Saelens Xavier , Martens Geert A. , Stove Christophe , Deforce Dieter , Martens Lennart , Vissers Johannes P.C. , Anderson N. Leigh , Dhaenens Maarten
Published: February 2022

INTRODUCTION

The pandemic readiness toolbox needs to be extended, providing diagnostic tools that target different biomolecules, using orthogonal experimental setups and fit-for-purpose specification of detection. Here we build on a previous Cov-MS effort that used liquid chromatography-mass spectrometry (LC-MS) and describe a method that allows accurate, high throughput measurement of SARS-CoV-2 nucleocapsid (N) protein.

MATERIALS and METHODS

We used Stable Isotope Standards and Capture by Anti-Peptide Antibodies (SISCAPA) technology to enrich and quantify proteotypic peptides of the N protein from trypsin-digested samples from COVID-19 patients.

RESULTS

The Cov2MS assay was shown to be compatible with a variety of sample matrices including nasopharyngeal swabs, saliva and blood plasma and increased the sensitivity into the attomole range, up to a 1000-fold increase compared to direct detection in matrix. In addition, a strong positive correlation was observed between the SISCAPA antigen assay and qPCR detection beyond a quantification cycle (Cq) of 30-31, the level where no live virus can be cultured from patients. The automatable “addition only” sample preparation, digestion protocol, peptide enrichment and subsequent reduced dependency upon LC allow analysis of up to 500 samples per day per MS instrument. Importantly, peptide enrichment allowed detection of N protein in a pooled sample containing a single PCR positive sample mixed with 31 PCR negative samples, without loss in sensitivity. MS can easily be multiplexed and we also propose target peptides for Influenza A and B virus detection.

CONCLUSIONS

The Cov2MS assay described is agnostic with respect to the sample matrix or pooling strategy used for increasing throughput and can be easily multiplexed. Additionally, the assay eliminates interferences due to protein-protein interactions including those caused by anti-virus antibodies. The assay can be adapted to test for many different pathogens and could provide a tool enabling longitudinal epidemiological monitoring of large numbers of pathogens within a population, applied as an early warning system.
COVID Testing in the Workplace: Return to Work Testing in an Occupational Cohort
Authors: Sikka Robby , Wyllie Anne L. , Premsrirut Prem , Berke Ethan M.
Published: February 2022

Background

The Omicron SARS-CoV-2 variant resulted in significant community-based transmission. Numerous occupational settings have employed surveillance testing strategies to minimize occupational exposure and return workers safely to work following isolation.

Methods

From an occupational COVID-19 testing program, we obtained longitudinal (February 2021-January 2022) saliva-based RT-qPCR results and starting December 27th, 2021, daily on-site molecular over-the-counter (OTC) nasal swab-based isothermal nucleic acid amplification test (molecular OTC; Cue Health COVID-19 test) results. We quantified the fraction of tests with PCR cycle threshold (Ct) values <30 on each day post detection from suspected and confirmed Omicron infections (n=37), compared results to molecular OTC testing, and measured workplace and household transmission. We evaluated return-to-work timing using a post-isolation, two-test threshold of Ct >30, or two negative molecular OTC tests over a 24 hour period, or a single PCR test >30 plus negative molecular OTC test.

Results

From the paired testing cohort, 37 (48%) individuals tested positive; all 37 were vaccinated. All individuals tested positive ≤1 day after a previous negative test, and 19 (51.3%) remained PCR-positive with Ct values <30 at day 5. While 3 (8.1%) remained PCR-positive with a Ct value <30 on day 10, no individuals remained PCR-positive on day 12. The average time to PCR clearance/return-to-work was 7.94 days (median=9.5 days). Time to clearance for those boosted (n=8; 7.75 days) and those not yet boosted (8.04 days) did not differ (p=0.49). Peak viral load measured by PCR was 1.97 days from the initial positive test. There were no cases of transmission after returning to work.

Conclusions

A large percentage of individuals remain contagious at day 5 post first positive test based on serial PCR testing and can continue until day 12. Early discontinuation of isolation can utilize a two test framework separated by 24 hours. Rapid onsite tests may be useful.
Viruses previously identified in Brazil as belonging to HIV-1 circulating recombinant form (CRF) 72_BF1 represent two closely related CRFs, one of which, designated CRF122_BF1, is also circulating in Spain
Authors: Cañada-García Javier E. , Delgado Elena , Gil Horacio , Benito Sonia , Sánchez Mónica , Ocampo Antonio , Cabrera Jorge Julio , Miralles Celia , García-Bodas Elena , Mariño Ana , Ordóñez Patricia , Gude María José , Ezpeleta Carmen , Thomson Michael M
Published: February 2022

Circulating recombinant forms (CRFs) are important components of the HIV-1 pandemic. Those derived from recombination between subtype B and subsubtype F1, with 18 reported, most of them of South American origin, are among the most diverse. Here we identify a HIV-1 BF1 recombinant cluster that is expanding in Spain, transmitted mainly via heterosexual contact, which, analyzed in near full-length genomes in 4 viruses, exhibited a coincident BF1 mosaic structure, with 12 breakpoints, that fully coincided with that of two viruses from Brazil (10BR_MG003 and 10BR_MG005), previously classified as CRF72_BF1. The three remaining Brazilian viruses previously identified as CRF72_BF1 (10BR_MG002, 10BR_MG004, and 10BR_MG008), exhibited mosaic structures highly similar, but not identical, to that of the Spanish viruses and to 10BR_MG003 and 10BR_MG005, with discrepant subtypes in two short genome segments, located in pol and gp120env. Based on these results, we propose that the 5 viruses from Brazil previously identified as CRF72_BF1 actually belong to two closely related CRFs, one comprising 10BR_MG002, 10BR_MG004, and 10BR_MG008, which keep their CRF72_BF1 designation, and the other, designated CRF122_BF1, comprising 10BR_MG003, 10BR_MG005 and the viruses of the identified Spanish cluster. Three other BF1 recombinant genomes, 2 from Brazil and 1 from Italy, previously identified as unique recombinant forms, were classified as CRF72_BF1. CRF122_BF1, but not CRF72_BF1, was associated with protease L89M substitution, reported to contribute to antiretroviral drug resistance. Phylodynamic analyses estimate the emergence of CRF122_BF1 in Brazil around 1987. Given their close phylogenetic relationship and similar structures, the grouping of CRF72_BF1 and CRF122_BF1 in a CRF family is proposed.
Enhancing the Discriminatory Power of ADHD and Autism Spectrum Disorder Polygenic Scores in Clinical and Non-Clinical Samples
Authors: Li James J. , He Quanfa , Wang Zihang , Lu Qiongshi
Published: February 2022

Objective

Polygenic scores (PGS) are widely used in psychiatric genetic associations studies due to their impressive power to predict focal outcomes. However, they lack in discriminatory power, in part due to the high degree of genetic overlap between psychiatric disorders. The lack of prediction specificity limits the clinical utility of psychiatric PGS, particularly for diagnostic applications. The goal of the study was to enhance the discriminatory power of psychiatric PGS for two highly comorbid and genetically correlated neurodevelopmental disorders in ADHD and autism spectrum disorder (ASD).

Methods

Genomic structural equation modeling (GenomicSEM) was used to generate novel PGS for ADHD and ASD by accounting for the genetic overlap between these disorders (and eight others) to achieve greater discriminatory power in non-focal outcome predictions. PGS associations were tested in two large independent samples – the Philadelphia Neurodevelopmental Cohort (N=4,789) and the Simons Foundation Powering Autism Research for Knowledge (SPARK) ASD and sibling controls (N=5,045) cohort.

Results

PGS from GenomicSEM achieved superior discriminatory power in terms of showing significantly attenuated associations with non-focal outcomes relative to traditionally computed PGS for these disorders. Additionally, genetic correlations between GenomicSEM PGS for ASD and ADHD were significantly attenuated in cross-trait associations with other psychiatric disorders and outcomes.

Conclusions

Psychiatric PGS associations are likely inflated by the high degree of genetic overlap between the psychiatric disorders. Methods such as GenomicSEM can be used to refine PGS signals to be more disorder-specific, thereby enhancing their discriminatory power for future diagnostic applications.
Sun exposure behavior and knowledge on photoprotection of children and adolescents living in tropical regions
Authors: de Paula Corrêa Marcelo , Martins Fabrina Bolzan , Campos Yamamoto Ana Letícia , Paiva Natana Batista , Silva Luiz Felipe , Sant’Anna Silva Reynaldo José , Melo Mayara Motta , de Carvalho Ribeiro Clarissa Santos
Published: February 2022

Background

Excessive and continuous exposure to ultraviolet radiation (UVR) can cause skin cancer (SC), photoaging, and cataracts. Photoprotection (PhP) is the most important tool in preventing against these harmful effects. Elementary and high school students should be targeted in PhP campaigns because the solar radiation that youngers receive increases the risk of SC in adulthood. However, PhP policies are scarce in developing countries.

Objectives

To evaluate the use and knowledge of PhP with youngsters living in tropical regions.

Methods

2,844 students aged from 4 to 20 years-old were interviewed about their knowledge on sun exposure and PhP habits. Age, sex, family income and skin phototype were statistically related to the proposed questions.

Results

Brazilian youngsters do not have the habit of wearing long-sleeved clothing (<15% in summer), nor sunglasses (0.0%), and hats (2.1%). More than 40% had no knowledge about UVI while another 30% misinterpret what it is. Less than half of all students wear sunscreen when out in the sun. Despite this low PhP use-rate, more than 90% know that UVR causes SC. Income was the factor that showed the greatest number of significant relationships respect to PhP.

Conclusions

Children and adolescents showed little knowledge about the sun exposure effects and lack PhP use. The lack of educational programs predisposes these youngsters to an increased chance of SC in the future. These results suggest that PhP campaigns should be part of school curricula from elementary school onwards.
Glycomic Analysis Identifies Pre-Vaccination Markers of Response to Influenza Vaccine, Implicating the Complement Pathway
Authors: Qin Rui , Meng Guanmin , Pushalkar Smruti , Carlock Michael A. , Ross Ted M. , Vogel Christine , Mahal Lara K.
Published: February 2022

Response to vaccination can vary significantly from person to person. A key to improving vaccine design and vaccination strategy is to understand the mechanism behind this variation. The role of glycosylation, a critical modulator of immunity, is unknown in determining vaccine responses. To gain insight into the association between glycosylation and vaccine-induced antibody levels we profiled the pre- and post-vaccination serum protein glycomes of 160 Caucasian adults receiving the FLUZONE™ influenza vaccine during the 2019-2020 influenza season. Using lectin microarrays, we observed that pre-vaccination levels of Lewis A antigen (Lea) are significantly higher in people who did not mount significant antibody responses, when compared to responders. Glycoproteomic analysis showed that Lea-bearing proteins are enriched in complement activation pathways, suggesting a potential role of glycosylation in tuning the activities of complement proteins, which may be implicated in mounting vaccine responses. We also observed post-vaccination increases in sialyl Lewis X antigen (sLex) and decreases in high mannose glycans among high responders, which were not observed in non-responders. This data suggests that the immune system may actively modulate glycosylation as part of its effort to establish effective protection post-vaccination.
Spliceosomic dysregulation unveilsNOVA1as an actionable therapeutic target in pancreatic neuroendocrine tumors
Authors: Pedraza-Arevalo Sergio , Alors-Pérez Emilia , Blázquez-Encinas Ricardo , Herrera-Martínez Aura D. , Jiménez-Vacas Juan M. , Fuentes-Fayos Antonio C. , Reyes Óscar , Ventura Sebastián , Sánchez-Sánchez Rafael , Ortega-Salas Rosa , Serrano-Blanch Raquel , Gálvez-Moreno María A. , Gahete Manuel D. , Ibáñez-Costa Alejandro , Luque Raúl M. , Castaño Justo P.
Published: February 2022

Dysregulation of the splicing machinery is emerging as a hallmark in cancer due to its association with multiple dysfunctions in tumor cells. Inappropriate function of this machinery can generate tumor-driving splicing variants and trigger oncogenic actions. However, its role in pancreatic neuroendocrine tumors (PanNETs) is poorly defined. In this study we aimed to characterize the expression pattern of a set of splicing machinery components in PanNETs, and their relationship with aggressiveness features. A qPCR-based array was first deployed to determine the expression levels of components of the major (n=13) and minor spliceosome (n=4) and associated splicing factors (n=27), using a microfluidic technology in 20 PanNETs and non-tumoral adjacent samples. Subsequently,in vivoandin vitromodels were applied to explore the pathophysiological role ofNOVA1. Expression analysis revealed that a substantial proportion of splicing machinery components was altered in tumors. Notably, key splicing factors were overexpressed in PanNETs samples, wherein their levels correlated with clinical and malignancy features. Usingin vivoandin vitroassays, we demonstrate that one of those altered factors,NOVA1, is tightly related to cell proliferation, alters pivotal signaling pathways and interferes with responsiveness to drug treatment in PanNETs, suggesting a role for this factor in the aggressiveness of these tumors and its suitability as therapeutic target. Altogether, our results unveil a severe alteration of the splicing machinery in PanNETs and identify the putative relevance ofNOVA1in tumor development/progression, which could provide novel avenues to develop diagnostic biomarkers and therapeutic tools for this pathology.
Cell delivery peptides for small interfering RNAs targeting SARS-CoV-2 new variants through a bioinformatics and deep learning design
Authors: González Ricardo D. , Figueiredo Pedro R. , Carvalho Alexandra T. P.
Published: February 2022

Nucleic acid technologies with designed delivery systems have surged as one the most promising therapies of the future, due to their contribution in combating SARS-CoV-2 severe disease. Nevertheless, the emergence of new variants of concern still represents a real threat in the years to come. It is here that the use of small interfering RNA sequences to inhibit gene expression and, thus, protein synthesis, may complement the already developed vaccines, with faster design and production. Here, we have designed new sequences targeting COVID-19 variants and other related viral diseases through bioinformatics, while also addressing the limited number of delivery peptides by a deep learning approach. Two sequences databases were produced, from which 62 were able to target the virus mRNA, and ten displayed properties present in delivery peptides, which we compared to the broad use TAT delivery peptide.
Predicting Epitope Candidates for SARS-CoV-2
Authors: Agarwal Akshay , Beck Kristen L. , Capponi Sara , Kunitomi Mark , Nayar Gowri , Seabolt Edward , Mahadeshwar Gandhar , Bianco Simone , Mukherjee Vandana , Kaufman James H.
Published: February 2022

Epitopes are short amino acid sequences that define the antigen signature to which an antibody binds. In light of the current pandemic, epitope analysis and prediction is paramount to improving serological testing and developing vaccines. In this paper, we leverage known epitope sequences from SARS-CoV, SARS-CoV-2 and other Coronaviridae and use those known epitopes to identify additional antigen regions in 62k SARS-CoV-2 genomes. Additionally, we present epitope distribution across SARS-CoV-2 genomes, locate the most commonly found epitopes, discuss where epitopes are located on proteins, and how epitopes can be grouped into classes. We also discuss the mutation density of different regions on proteins using a big data approach. We find that there are many conserved epitopes between SARS-CoV-2 and SARS-CoV, with more diverse sequences found in Nucleoprotein and Spike Glycoprotein.
A pair of isoleucyl-tRNA synthetases in Bacilli fulfill complementary roles to keep fast translation and provide antibiotic resistance
Authors: Zanki Vladimir , Bozic Bartol , Mocibob Marko , Ban Nenad , Gruic-Sovulj Ita
Published: February 2022

Isoleucyl-tRNA synthetase (IleRS) is an essential enzyme that covalently couples isoleucine to the corresponding tRNA. Bacterial IleRSs group in two clades, ileS1 and ileS2, the latter bringing resistance to the natural antibiotic mupirocin. Generally, bacteria rely on either ileS1 or ileS2 as a standalone housekeeping gene. However, we have found an exception by noticing that Bacillus species with genomic ileS2 consistently also keep ileS1, which appears mandatory in the family Bacillaceae. Taking Priestia (Bacillus) megaterium as a model organism, we showed that PmIleRS1 is constitutively expressed, while PmIleRS2 is stress-induced. Both enzymes share the same level of the aminoacylation accuracy. Yet, PmIleRS1 exhibited a twofold faster aminoacylation turnover (kcat) than PmIleRS2 and permitted a notably faster cell-free translation. At the same time, PmIleRS2 displayed a 104-fold increase in its Ki for mupirocin, arguing that the aminoacylation turnover in IleRS2 could have been traded-off for antibiotic resistance. As expected, a P. megaterium strain deleted for ileS2 was mupirocin-sensitive. Interestingly, an attempt to construct a mupirocin-resistant strain lacking ileS1, a solution not found among species of the family Bacillaceae in nature, led to a viable but compromised strain. Our data suggests that PmIleRS1 is kept to promote fast translation, whereas PmIleRS2 is maintained to provide antibiotic resistance when needed. This is consistent with an emerging picture in which fast-growing organisms predominantly use IleRS1 for competitive survival.
Dual Inhibition of Cathepsin L and 3CL-Pro by GC-376 Constrains SARS Cov2 Infection Including Omicron Variant
Authors: Kumar Prabhakaran , Ratia Kiira M , Richner Justin M , Thatcher Gregory R J , Kadam Rashmi , Smieszek Sandra P , Przychodzen Bartlomiej P , Koprivica Vuk , Birznieks Gunther , Polymeropoulos Mihael H , Prabhakar Bellur S
Published: February 2022

Recurrent waves of SARS CoV2 infections remain a major global health concern. Emergence of highly infectious variants with reduced sensitivity to neutralization by vaccines and monoclonal antibodies (mAb) necessitates a deeper understanding of factors involved in SARS CoV2 infections and identification of drug candidates to halt infection. Here, we determined the primacy of endosomal protease cathepsin-L in mediating SARS CoV2 entry and screened a library of well-annotated bioactive compounds for potent cathepsin-L inhibitory activity. Whilst the potent cathepsin-L inhibitors were capable of inhibiting SARS CoV2 entry and cytopathic effect (CPE) in less susceptible cell lines such as human ACE2 expressing 293T cells, these drugs failed to inhibit SARS CoV2 in highly susceptible cell lines such as human TMPRSS2 or human-ACE2-TMPRSS2 overexpressing Vero E6 cells. Only drugs with dual inhibitory effect on both host cathepsin-L and virus 3CL-Protease enzymes such as Z-FA-FMK and GC-376 were capable of inhibiting prototypic (USA-WA1/2020, Lineage A) SARS CoV2 induced CPE in highly susceptible cell lines. Moreover, these drugs inhibited delta (Lineage-B.1.617.2) and omicron (Lineage-B.1.1.529) infection with equal potency showing that the newer mutations harbored in these variants did not affect the mechanism of action of these drugs such as cathepsin-L or 3CL-Pro inhibition. Moreover, our early evidence that 3CL-Pro inhibition can effectively inhibit omicron-induced CPE in highly susceptible cell lines suggests that the recently FDA-approved oral drug, a 3CL-Pro inhibitor which is a combination of nirmatrelvir/ritonavir (Paxlovid) could be effective against omicron variant which shows reduced sensitivity to vaccines and mAb.

Importance

We report that cathepsin-L and 3CL-Pro as major targets for designing antivirals against SARS CoV2. Dual inhibition of cathepsin-L and 3CL-Pro by GC-376 renders it effective in inhibiting SARS CoV2-induced cytopathic effect in highly susceptible cell lines. Moreover, this candidate drug is equally effective against prototypic SARS CoV2 lineage A and emerging variants such as delta and omicron which show reduced sensitivity to vaccines and monoclonal antibodies. Given the recent wave of SARS CoV2 omicron variant infection around the world, and 3CL-Pro inhibitor nirmatrelvir is one of the components of the FDA-approved Paxlovid, our findings are timely, important and should be of broad interest.
The rise and fall of SARS-CoV-2 variants and the emergence of competing Omicron lineages
Authors: Wiegand Tanner , McVey Aidan , Nemudraia Anna , Nemudryi Artem , Wiedenheft Blake
Published: February 2022

In late December of 2019, high throughput sequencing technologies enabled rapid identification of SARS-CoV-2 as the etiological agent of COVID-19, and global sequencing efforts are now a critical tool for monitoring the ongoing spread and evolution of this virus. Here, we analyze a subset (n=83,204) of all publicly available SARS-CoV-2 genomes (n=~5.6 million) that were randomly selected, but equally distributed over the course of the pandemic. We plot the emergence and extinction of new variants of concern (VOCs) over time and show how this corresponds to the ongoing accumulation of mutations in SARS-CoV-2 genomes and individual proteins. While the accumulation of mutations generally follows a linear regression, non-synonymous mutations are significantly greater in Omicron viruses than in previous variants–especially in the spike and nucleoproteins–and these differences are more pronounced in a recently identified sub-lineage (BA.2) of Omicron.

Importance

Omicron is the fifth SARS-CoV-2 variant to be designated a Variant of Concern (VOC) by the World Health Organization (WHO). Here we provide a retrospective analysis of SARS-CoV-2 variants and explain how the Omicron variant is distinct. Our work shows that the spike and nucleoproteins have accumulated the most mutations in Omicron variants, but that the accessory proteins of SARS-CoV-2 sequences are changing most rapidly relative to their size. Collectively, this “Observation” provides a concise overview of SARS-CoV-2 evolution, reveals mutational differences between two Omicron lineages, and highlights changes in the SARS-CoV-2 proteome that have been under reported.
The REinfection in COVID-19 Estimation of Risk (RECOVER) study: Reinfection and serology dynamics in a cohort of Canadian healthcare workers
Authors: Racine Étienne , Boivin Guy , Longtin Yves , McCormack Deirde , Decaluwe Hélène , Savard Patrice , Cheng Matthew P. , Hamelin Marie-Ève , Tadount Fazia , Adams Kelsey , Bourdin Benoîte , Nantel Sabryna , Gilca Vladimir , Corbeil Jacques , De Serres Gaston , Quach Caroline
Published: February 2022

Background

Understanding the immune response to natural infection by SARS-CoV-2 is key to pandemic management, especially in the current context of emerging variants. Uncertainty remains regarding the efficacy and duration of natural immunity against reinfection.

Method

We conducted an observational prospective cohort study in Canadian healthcare workers (HCWs) with a history of PCR-confirmed SARS-CoV-2 infection to : (i) measure the average incidence rate of reinfection and (ii), describe the serological immune response to the primary infection.

Results

We detected 5 cases of reinfection over 14 months of follow-up, for a reinfection incidence rate of 3.3 per 100 person-years. Median duration of seropositivity was 420 days in symptomatics at primary infection compared to 213 days in asymptomatics (p<0.0001). Other variables associated with prolonged seropositivity for IgG against the spike protein included age 55 and above, obesity, and non-Caucasian ethnicity.

Among healthcare workers, the incidence of reinfection with SARS-CoV-2 following a primary infection remained rare, although our analysis predates the circulation of the Omicron variant.
A scoping review protocol onin vivohuman plastic exposure and health impacts
Authors: Goodes Louise M. , Wong Enoch V.S. , Alex Jennifer , Mofflin Louise , Toshniwal Priyanka , Brunner Manuel , Solomons Terena , White Emily , Choudhury Omrik , Seewoo Bhedita J. , Mulders Yannick R. , Dale Tristan , Newman Hamish J. , Naveed Alina , Lowe Andrew B. , Hendrie Delia V. , Symeonides Christos , Dunlop Sarah A.
Published: February 2022

Background

Global plastic production has increased exponentially since the 1960s, with more than 6300 million metric tons of plastic waste generated to date. Studies have found a range of human health impacts associated with exposure to plastic chemicals. However, only a fraction of plastic chemicals used have been studiedin vivo, and then often in animals, for acute toxicological effects. With many questions still unanswered about how long-term exposure to plastic impacts human health, there is an urgent need to map humanin vivoresearch conducted to date, casting a broad net by searching terms for a comprehensive suite of plastic chemical exposures and the widest range of health domains.

Methods

This protocol describes a scoping review that will follow the recommended framework outlined in2017 Guidance for the Conduct of Joanna Briggs Institute (JBI) Scoping Reviews, to be reported in accordance withPreferred Reporting Items for Systematic ReviewsandMeta-Analyses extension for Scoping Reviews (PRISMA-ScR) Checklist. A literature search of primary clinical studies in English from 1960 onwards will be conducted in MEDLINE (Ovid) and EMBASE (Ovid) databases. References eligible for inclusion will be identified through a quality-controlled, multi-level screening process. Extracted data will be presented in diagrammatic and tabular form, with a narrative summary addressing the review questions.

Discussion

This scoping review will comprehensively map the primary research undertaken to date on plastic exposure and human health. Secondary outputs will include extensive databases on plastic chemicals and human health outcomes/impacts.

Registration

Open Science Framework (OSF)-Standard Pre-Data Collection Registration,https://osf.io/gbxpsDOI: 10.17605/OSF.IO/GBXPS
The effect of competition between health opinions on epidemic dynamics
Authors: Teslya Alexandra , Nunner Hendrik , Buskens Vincent , Kretzschmar Mirjam E
Published: February 2022

Past major epidemic events showed that when an infectious disease is perceived to cause severe health outcomes, individuals modify health behavior affecting epidemic dynamics. To investigate the effect of this feedback relationship on epidemic dynamics, we developed a compartmental model that couples a disease spread framework with competition of two mutually exclusive health opinions (health-positive and health-neutral) associated with different health behaviors. The model is based on the assumption that individuals switch health opinions as a result of exposure to opinions of others through interpersonal communications. To model opinion switch rates, we considered a family of functions and identified the ones that allow health opinions to co-exist. In the disease-free population, either the opinions cannot co-exist and one of them is always dominating (monobelief equilibrium) or there is at least one stable co-existence of opinions equilibrium. In the latter case, there is multistability between the co-existence equilibrium and the two monobelief equilibria. When two opinions co-exist, it depends on their distribution whether the infection can invade. If presence of the infection leads to increased switching to a health-positive opinion, the epidemic burden becomes smaller than indicated by the basic reproduction number. Additionally, a feedback between epidemic dynamics and health opinion dynamics may result in (sustained) oscillatory dynamics and a switch to a different stable opinion distribution. Our model captures feedback between spread of awareness through social networks and infection dynamics and can serve as a basis for more elaborate individual-based models.

Significance Statement

Disease epidemics often co-evolve with opinions on health-related behavior. Most existing models have difficulties understanding co-existence of different opinions in a population when the disease is not present, while we do observe this. We modeled opinion switching process by using an innovative way to capture the dependence of opinion switching rate on the population state. We combined this with network interaction patterns and were able to derive conditions under which a stable co-existence of opinions can occur. We used this insight to explain appearance of epidemic cycles and the population switching between different distributions of opinions. Our work demonstrates that for information interventions accurate understanding of opinion propagation processes is crucial.
Elevated brain-derived cell-free DNA among patients with first psychotic episode - a proof-of-concept study
Authors: Lubotzky Asael , pelov Ilana , Teplitz Ronen , Neiman Daniel , Smadja Adama , Zemmour Hai , Piyanzin Sheina , Ochana Bracha-Lea , Spalding Kirsty L. , Glaser Benjamin , Shemer Ruth , Dor Yuval , Kohn Yoav
Published: February 2022

Background

Schizophrenia is a common, severe and debilitating psychiatric disorder. Despite extensive research there is as yet no biological marker that can aid in its diagnosis and course prediction. This precludes early detection and intervention. Imaging studies suggest brain volume loss around the onset and over the first few years of schizophrenia, and apoptosis has been proposed as the underlying mechanism. Cell free DNA fragments (cfDNA) are released into the bloodstream following cell death. Tissue-specific methylation patterns allow the identification of the tissue origins of cfDNA.

Methods

We developed a cocktail of brain specific DNA methylation markers, and used it to assess the presence of brain-derived cfDNA in the plasma of patients with a first psychotic episode.

Results

We detected significantly elevated neuron- (p=0.0013), astrocyte- (p=0.0016), oligodendrocyte- (p=0.0129) and whole brain-derived (p=0.0012) cfDNA in the plasma of patients during their first psychotic episode (n=29), compared with healthy controls (n=31). Increased cfDNA levels were not correlated with psychotropic medications use. Area Under the Curve (AUC) was 0.77, with 65% sensitivity at 90% specificity in patients with a psychotic episode.

Conclusions

Potential interpretations of these findings include increased brain cell death, disruption of the blood brain barrier or a defect in clearance of material from dying brain cells. Brain-specific cfDNA methylation markers can potentially assist early detection and monitoring of schizophrenia and thus allow early intervention and adequate therapy.
Impact of COVID-19 pandemic and anti-pandemic measures on tuberculosis, viral hepatitis, HIV/AIDS and malaria – a systematic review
Authors: Kessel Barbora , Heinsohn Torben , Ott Jördis J , Wolff Jutta , Hassenstein Max J , Lange Berit
Published: February 2022

COVID-19 pandemic puts an enormous strain on health care systems worldwide and may have a detrimental effect on prevention, treatment and outcomes of tuberculosis (TB), viral hepatitis, HIV/AIDS and malaria, whose ending is part of the United Nations 2030 Agenda for Sustainable Development. We conducted a systematic review of scientific and grey literature in order to collect wide-ranging evidence with emphasis on quantification of the projected and actual indirect impacts of COVID-19 on the four infectious diseases with a global focus. We followed PRISMA guidelines and the protocol registered for malaria (CRD42021234974). We searched PubMed, Scopus, preView (last search: January 13, 2021) and websites of main (medical) societies and leading NGOs related to each of the four considered infectious diseases. The identified modelling studies warned about under-diagnosis (TB), anti-retroviral therapy interruption/decrease in viral load suppression (HIV), disruptions of insecticide-treated nets (ITN) distribution and access to effective treatment (malaria), and treatment delays and vaccination interruptions (viral hepatitis). The reported disruptions were very heterogeneous both between and within countries. If observed at several points in time, the initial drops (partly dramatic, e.g. TB notifications/cases, or HIV testing volumes decreased up to -80%) were followed by a gradual recovery. However, the often-missing assessment of the changes against the usual pre-pandemic fluctuations hampered the interpretation of less severe ones. Given the recurring waves of the pandemic and the unknown mid- to long-term effects of adaptation and normalisation, the real consequences for the fight against leading infectious diseases will only manifest over the coming years.
Implementation and economic effects of local non-pharmaceutical interventions
Authors: Godøy Anna , Grøtting Maja Weemes
Published: February 2022

In this paper, we analyze economic costs and consequences of local non-pharmaceutical interventions (NPIs) aimed at containing the COVID-19 pandemic. Using comprehensive data on municipal and regional policies in Norway, we implement a difference-in-differences framework identifying impacts of local NPIs from discontinuous differential shifts in outcomes following the implementation of new policies. In treated municipalities, local NPIs lead to persistent reductions in mobility, persistent increases in unemployment, and transient reductions in consumer spending. Analyses of spatial spillovers show that the implementation of local NPIs increases retail mobility in non-treated neighboring municipalities. Overall, our findings suggest that local NPIs have economic consequences for local economies and induce residents to shift their consumption of goods and services to neighboring municipalities.
Lem2 is essential for cardiac development by maintaining nuclear integrity
Authors: Ross Jacob A. , Arcos-Villacis Nathaly , Battey Edmund , Boogerd Cornelis , Marhuenda Emilie , Hodzic Didier , Prin Fabrice , Mohun Tim , Catibog Norman , Tapia Olga , Gerace Larry , Iskratsch Thomas , Shah Ajay M. , Stroud Matthew J.
Published: February 2022

Nuclear envelope integrity is essential for compartmentalisation of nucleus and cytoplasm. Importantly, mutations in nuclear envelope-encoding genes are the second-highest cause of familial dilated cardiomyopathy. One such nuclear envelope protein that causes cardiomyopathy in humans and affects mouse heart development is Lem2. However, its role in mechanically active tissue such as heart remains poorly understood.

We generated mice in which Lem2 was specifically ablated in cardiomyocytes and carried out detailed physiological, tissue and cellular analyses. Importantly, our data showed that Lem2 was essential for cardiac development, and hearts from Lem2 cKO mice were morphologically and transcriptionally underdeveloped. Lem2 cKO hearts displayed high levels of DNA damage, nuclear rupture, and apoptosis. Crucially, we found that these defects were driven by muscle contraction as they were ameliorated by inhibiting myosin contraction and conversely were exacerbated upon myosin activation.

Our data suggest that Lem2 is critical for integrity at the nascent nuclear envelope in fetal hearts, and protects the nucleus from the mechanical forces of muscle contraction. Taken together, these data provide novel insight into mechanisms underlying striated muscle diseases caused by altered nuclear envelope integrity.
High diversity of type I polyketide genes in Bacidia rubella as revealed by the comparative analysis of 23 lichen fungal genomes
Authors: Gerasimova Julia , Beck Andreas , Werth Silke , Resl Philipp
Published: February 2022

Fungi involved in lichen symbioses produce a large array of different secondary metabolites. The high diversity of those substances has been known for decades and are often considered characteristic for taxonomical delimitation in lichen-forming fungi. Polyketides, the most common secondary metabolites, are synthesized by the Type I Polyketide synthases (TI-PKS) comprised of different enzymatic domains. We present a phylogenetic overview of Type I PKS genes recovered from the de-novo sequenced genome of Bacidia rubella in the context of additional twenty-one fungal genomes from the largest radiation of lichen-forming Ascomycetes (Lecanoromycetes) as well as the lichen-forming Eurotiomycete, Endocarpon pusillum. Using de-novo gene prediction and functional annotation combined with a phylogenetic analysis, we provide insights into the biosynthetic potential and PKS gene diversity of lichen-forming fungi. We discuss genes predicted in the lichen-forming fungal genomes in relation to previously characterized PKS genes from other fungi and bacteria. Our results reveal a high number of biosynthetic gene clusters and their gene domain composition. PKS gene content outnumbers known secondary substances produced by the lichen-forming fungi. We were able to assign putative functions to several of those PKS genes in silico, based on similarity to already characterized genes. In particular, we identified a putative PKS23 gene of Bacidia rubella, producing the common lichen substance atranorin. However, we also found that several lichen-forming fungi still possess homologs of different biosynthetic genes without producing the corresponding substances in detectable amounts. Although many PKSs remain without functional assignments in our analysis, our findings highlight that genes from lichen-forming fungi represent an untapped source of novel polyketide compounds. However, additional experimental approaches are necessary to link biosynthetic genes and secondary metabolites with confidence.
Gi/o protein–coupled receptor inhibition of beta-cell electrical excitability and insulin secretion depends on Na+/K+ ATPase activation
Authors: Dickerson Matthew T. , Dadi Prasanna K. , Zaborska Karolina E. , Nakhe Arya Y. , Schaub Charles M. , Dobson Jordyn R. , Wright Nicole M. , Lynch Joshua C. , Scott Claire F. , Jacobson David A.
Published: February 2022

Gi/o protein-coupled receptors (Gi/o-GPCRs) limit pancreatic islet insulin secretion by decreasing β-cell Ca2+ entry, which is essential for maintenance of glucose homeostasis. However, the Gi/o-GPCR signaling mechanism that mediates inhibition of human islet hormone secretion has not been identified. Here we demonstrate that Gi/o-GPCRs cause hyperpolarization of the β-cell membrane potential through activation of Na+/K+ ATPases (NKAs) in mouse and human islets. Stimulation of Gi/o-coupled somatostatin or α2-adrenergic receptors induced oscillations in β-cell NKA activity, which resulted in islet Ca2+ fluctuations. Selective induction of β-cell Gi/o signaling with a chemogenetic Gi/o-GPCR also activated NKAs and initiated islet Ca2+ oscillations, suggesting that β-cell Gi/o-GPCRs tune pulsatile insulin secretion. Furthermore, intra-islet paracrine activation of β-cell Gi/o-GPCR signaling and NKAs by δ-cell somatostatin secretion slowed Ca2+ oscillations, which decreased insulin secretion. Gi/o-GPCR-mediated oscillations in β-cell membrane potential and Ca2+ were dependent on NKA phosphorylation by Src tyrosine kinases; an effect that was mimicked by stimulating islet insulin receptor tyrosine kinases. Whereas β-cell NKA function was completely inhibited by cAMP-dependent PKA activation. Taken together, these data reveal that NKA-mediated hyperpolarization of β-cell membrane potential serves as the primary and conserved mechanism for Gi/o-GPCR control of electrical excitability, Ca2+ handling, and insulin secretion.
Lyophilized mRNA-lipid nanoparticle vaccines with long-term stability and high antigenicity against SARS-CoV-2
Authors: Ai Liangxia , Li Yafei , Zhou Li , Yao Wenrong , Zhang Hao , Hu Zhaoyu , Han Jinyu , Wu Junmiao , Wang Weijie , Xu Pan , Wang Ruiyue , Li Zhangyi , Li Zhouwang , Wei Chengliang , Chen Haobo , Liang Jianqun , Guo Ming , Huang Zhixiang , Wang Xin , Zhang Zhen , Xiang Wenjie , Xu Lianqiang , Lv Bin , Peng Peiqi , Zhang Shangfeng , Ji Xuhao , Luo Huiyi , Chen Nanping , Chen Jianping , Lan Ke , Hu Yong
Published: February 2022

Advanced mRNA vaccines play vital roles against SARS-CoV-2. However, due to their poor stability, most current mRNA delivery platforms need to be stored at -20°C or -70°C, which severely limits their distribution. Herein, we present lyophilized SARS-CoV-2 mRNA-lipid nanoparticle vaccines, which can be stored at room temperature with long-term thermostability. In the invivoDelta virus challenge experiment, lyophilized Delta variant mRNA vaccine successfully protected mice from infection and cleared the virus. Lyophilized omicron mRNA vaccine enabled to elicit both potent humoral and cellular immunity. In booster immunization experiments in mice and old monkeys, lyophilized omicron mRNA vaccine could effectively increase the titers of neutralizing antibodies against wild-type coronavirus and omicron variants. In humans, lyophilized omicron mRNA vaccine as a booster shot could also engender excellent immunity and had less severe adverse events. This lyophilization platform overcomes the instability of mRNA vaccines without affecting their bioactivity, and significantly improved their accessibility, particularly in remote regions.