bluuebunny/crossref_metadata_2025 huggingface dataset:
Trajectories of Nicotine Use Leading to Dual and Cyclical Tobacco Product Use in Young Adults
Authors: Kechter Afton , Simpson Kelsey A , Ceasar Rachel Carmen , Schiff Sara J , Yamaguchi Naosuke , Bluthenthal Ricky N , Smiley Sabrina L , Barrington-Trimis Jessica L
Published: November 2021

Introduction

Young adult never-smokers who vape are at elevated risk of initiating cigarettes, while young adults who smoke often begin vaping to substitute or reduce cigarette use. Reasons underlying different use patterns of tobacco products are not well-understood.

Aims and Methods

We conducted 1-on-1 qualitative interviews with young adults (N = 62) who vape in Los Angeles, California from June 2018 to June 2019. Participants were 18–25 years old (79% male; racially/ethnically diverse) and self-reported vaping ≥1x/week. We used a semi-structured interview guide and applied thematic analysis method to analyze data.

Results

Young adults initiated vaping due to peer socialization and e-liquid flavor novelty. They often reported vaping (after first smoking) due to a belief that e-cigarettes are healthier, social pressure to quit smoking, and convenience of use. Participants reported smoking (after first vaping) when traveling outside of the United States where vaping products were less accessible, and cigarettes were normative. Many of the personal narratives described patterns of dual and cyclical use, which was often attributed to nicotine dependence and cost, or described as dependent upon the current environment (eg, at a party).

Conclusions

The current study characterizes nicotine use trajectories and reasons why young adults vape, and smoke cigarettes. Dual and cyclical use of both e-cigarettes and cigarettes was common; this pattern of use should be considered in policy and prevention work to address nicotine dependence among young people.

Implications

We display findings from the current study in a model depicting common trajectories of nicotine use, along with reasons for initiation, transitions between products, and dual/cyclical e-cigarette and combustible cigarette use.
A systematic review on the efficacy of vitamin B supplementation on diabetic peripheral neuropathy
Authors: Farah Stephanie , Yammine Kaissar
Published: November 2021

Context

Diabetic peripheral neuropathy (DPN) is a common complication.

Objective

To re-evaluate the role of vitamin B supplementation on reducing the signs and symptoms of DPN.

Data Sources

Electronic databases such as PubMed, Cochrane Library, and Medline.

Data Extraction

An Excel spreadsheet was used to report the extracted relevant data.

Data Analysis

Fourteen randomized controlled trials were selected, comprising a pooled sample of 997 study subjects. The pooled odds ratio values were 3.1 (95%CI, 1.197–8.089) and 3.04 (95%CI, 1.556–5.937) for pain and dysesthesia outcomes, respectively. For the amplitude change in electromyography of the sensory sural nerve, the weighted difference from 2 studies was 0.37 (95%CI, 0.034–0.709) in favor of intervention. Peak latency changes were in favor of the intervention group. Two studies yielded a weighted difference of 0.571 (95%CI, 0.310–0.831) for the velocity outcome in favor of intervention. Unlike the fibular nerve, the electromyographic motor outcomes of the tibial nerve were in favor of vitamin B supplementation.

Conclusion

Vitamin B supplementation could improve many symptoms and signs of DPN.
Auxin biosynthesis maintains embryo identity and growth during BABY BOOM-induced somatic embryogenesis
Authors: Li Mengfan , Wrobel-Marek Justyna , Heidmann Iris , Horstman Anneke , Chen Baojian , Reis Ricardo , Angenent Gerco C , Boutilier Kim
Published: November 2021

Somatic embryogenesis is a type of plant cell totipotency where embryos develop from nonreproductive (vegetative) cells without fertilization. Somatic embryogenesis can be induced in vitro by auxins, and by ectopic expression of embryo-expressed transcription factors like the BABY BOOM (BBM) AINTEGUMENTA-LIKE APETALA2/ETHYLENE RESPONSE FACTOR domain protein. These different pathways are thought to converge to promote auxin response and biosynthesis, but the specific roles of the endogenous auxin pathway in somatic embryogenesis induction have not been well-characterized. Here we show that BBM transcriptionally regulates the YUCCA3 (YUC3) and YUC8 auxin biosynthesis genes during BBM-mediated somatic embryogenesis in Arabidopsis (Arabidopsis thaliana) seedlings. BBM induced local and ectopic YUC3 and YUC8 expression in seedlings, which coincided with increased DR5 auxin response and indole-3-acetic acid (IAA) biosynthesis and with ectopic expression of the WOX2 embryo reporter. YUC-driven auxin biosynthesis was required for BBM-mediated somatic embryogenesis, as the number of embryogenic explants was reduced by ca. 50% in yuc3 yuc8 mutants and abolished after chemical inhibition of YUC enzyme activity. However, a detailed YUC inhibitor time-course study revealed that YUC-dependent IAA biosynthesis is not required for the re-initiation of totipotent cell identity in seedlings. Rather, YUC enzymes are required later in somatic embryo development for the maintenance of embryo identity and growth. This study resolves a long-standing question about the role of endogenous auxin biosynthesis in transcription factor-mediated somatic embryogenesis and also provides an experimental framework for understanding the role of endogenous auxin biosynthesis in other in planta and in vitro embryogenesis systems.
Antinuclear antibodies in neurology and their clinical application
Authors: Sudheer Pachipala , Agarwal Ayush , Vishnu Venugopalan Y
Published: November 2021

Antinuclear antibodies (ANA) are a diverse group of autoantibodies found in various systemic autoimmune disorders. They represent a key diagnostic marker in the diagnosis of connective tissue disorders (CTD). Although many techniques exist, ANA by indirect immunofluorescence remains the gold standard for diagnosing CTDs. Neurologists should be aware of the type of assay used for detection and the advantages and disadvantages of using each method. Through this article, we aimed to review the methodological aspects of the detection of ANA and its subtypes and their clinical relevance in various neurologic disorders.
Dynamic computation of value signals via a common neural network in multi-attribute decision-making
Authors: Magrabi Amadeus , Ludwig Vera U , Stoppel Christian M , Paschke Lena M , Wisniewski David , Heekeren Hauke R , Walter Henrik
Published: November 2021

Studies in decision neuroscience have identified robust neural representations for the value of choice options. However, overall values often depend on multiple attributes, and it is not well understood how the brain evaluates different attributes and integrates them to combined values. In particular, it is not clear whether attribute values are computed in distinct attribute-specific regions or within the general valuation network known to process overall values. Here, we used a functional magnetic resonance imaging choice task in which abstract stimuli had to be evaluated based on variations of the attributes color and motion. The behavioral data showed that participants responded faster when overall values were high and attribute value differences were low. On the neural level, we did not find that attribute values were systematically represented in areas V4 and V5, even though these regions are associated with attribute-specific processing of color and motion, respectively. Instead, attribute values were associated with activity in the posterior cingulate cortex, ventral striatum and posterior inferior temporal gyrus. Furthermore, overall values were represented in dorsolateral and ventromedial prefrontal cortex, and attribute value differences in dorsomedial prefrontal cortex, which suggests that these regions play a key role for the neural integration of attribute values.
Phylogeny and Identification ofPantoeaSpecies Associated with Bulb Rot and Bacterial Leaf Blight of Onion Crops in Uruguay
Authors: De Armas Stefanie , Galván Guillermo A. , Lapaz María I. , González-Barrios Pablo , Vicente Esteban , Pianzzola María J. , Siri María I.
Published: November 2021

Onion is among the most consumed vegetables in Uruguay, grown in the northwestern and southern regions of the country. The onion supply presents interannual variations associated with significant postharvest losses, mainly caused by bacterial rots. Besides bulb rotting, onion leaf lesions as well as infections on seed-stalks during seed production may be devastating for some varieties under conducive conditions. This research aimed to identify the causal agents of bulb rots and leaf blight of onion crops in Uruguay. Symptomatic bulbs, seeds-stalks, and leaves were collected from commercial fields from 2015 to 2020. Bacterial colonies were isolated and identified at genera level using physiological tests and 16S rRNA gene sequence analysis. A collection of 59 Pantoea spp. isolates was obtained (11 from bulbs and 48 from leaves and seeds-stalks). Multilocus sequence analysis using four housekeeping genes (rpoB, gyrB, leuS, and fusA) allowed the assignment of the isolates to five Pantoea species: P. ananatis, P. agglomerans, P. allii, P. eucalypti, and P. vagans. The last two species were not previously reported as onion pathogens elsewhere. The ability to cause disease symptoms was tested by leaf inoculation and red onion scale assays. P. ananatis isolates showed the highest aggressiveness in both assays. Specific isolates from P. allii (MAI 6022), P. eucalypti (MAI 6036), P. vagans (MAI 6050), and Pantoea sp. (MAI 6049) ranked second in aggressiveness on onion leaves, whereas only three isolates belonging to P. eucalypti (MAI 6036 and MAI 6058) and P. agglomerans (MAI 6045) exhibited the same scale-clearing phenotype as P. ananatis. Leaf inoculation assays were also performed on a set of eight onion cultivars and breeding lines. Overall, P. ananatis MAI 6032 showed the highest aggressiveness in all tested cultivars, followed by P. eucalypti MAI 6036. The presence of new reported bacterial species leads to complex disease management and highlights the need for further studies on virulence factors and the epidemiology of these pathogens.
Exome Sequencing from Bulked Segregant Analysis Identifies a Gene for All-Stage Resistance to Stripe Rust on Chromosome 1AL in Chinese Wheat Landrace ‘Xiaohemai’
Authors: Jiang Yunfeng , Duan Luyao , Guan Fangnian , Yao Fangjie , Long Li , Wang Yuqi , Zhao Xuyang , Li Hao , Li Wei , Xu Qiang , Jiang Qiantao , Wang Jirui , Wei Yuming , Ma Jian , Kang Houyang , Qi Pengfei , Deng Mei , Zheng Youliang , Chen Guoyue
Published: November 2021

Stripe rust caused by Puccinia striiformis f. sp. tritici is one of the most destructive diseases of wheat. Identifying novel resistance genes applicable for developing disease-resistant cultivars is important for the sustainable control of wheat stripe rust. Chinese wheat landrace ‘Xiaohemai’ (‘XHM’) is an elite germplasm line with all-stage resistance (ASR) effective against predominant Chinese P. striiformis f. sp. tritici races. In this study, we performed a bulked segregant analysis coupled with exome capture sequencing (BSE-seq) to identify a candidate genomic region strongly associated with stripe rust resistance on chromosome 1AL in 173 F2:3 lines derived from the cross ‘XHM’ × ‘Avocet S’. The gene, designated as YrXH-1AL, was validated by a conventional quantitative trait locus analysis using newly developed Kompetitive allele-specific PCR (KASP) markers, explaining up to 48.50% of the phenotypic variance. By testing a secondary mapping population comprising 144 lines from the same cross at the seedling stage with prevalent P. striiformis f. sp. tritici race CYR34, YrXH-1AL was identified as a single Mendelian factor in a 1.5-cM interval flanked by KASP markers KP1A_484.33 and KP1A_490.09. This region corresponded to a 5.76-Mb genomic interval on ‘Chinese Spring’ chromosome 1AL. Furthermore, two cosegregating KASP markers showed high polymorphisms among 130 Chinese wheat cultivars and could be used for marker-assisted selection. Because no other Yr genes for ASR that originated from common wheat have been detected on chromosome 1AL, YrXH-1AL is likely a novel gene that can be incorporated into modern breeding materials to develop wheat cultivars with enhanced stripe rust resistance.
Fungicide Physical Mode of Action: Impacts on Suppression of Hop Powdery Mildew
Authors: Claassen Briana J. , Wolfenbarger Sierra N. , Gent David H.
Published: November 2021

Understanding of the physical mode of action of fungicides allows more efficient and effective application and can increase disease control. Greenhouse and field studies were conducted to explore the preinfection and postinfection duration and translocative properties of fungicides commonly used to control hop powdery mildew, caused by Podosphaera macularis. In greenhouse studies, applications made 24 h before inoculation were almost 100% effective at suppressing powdery mildew, regardless of the fungicide evaluated. However, percentage control of powdery mildew based on the number of pathogen colonies per leaf varied significantly between fungicides with increasing time from inoculation to application, ranging from 50 to 100% disease control depending on the fungicide. Fluopyram or fluopyram + trifloxystrobin was particularly efficacious, suppressing nearly all powdery mildew development independent of application timing. In translocation studies, fluopyram and flutriafol were the most effective treatments in each of two separate experiments, resulting in zones of inhibition of 1,036 and 246.3 mm2, respectively, on adaxial leaf surfaces when a single droplet of each fungicide was applied to the abaxial surface of leaves. In field experiments, all fungicide treatments provided nearly complete control of powdery mildew infection when applied before inoculation. Levels of disease control decreased with time depending on treatment, showing trends similar to those observed in greenhouse studies. In the 2017 field experiments, high levels of disease control (>75%) were observed at postinoculation time points for all treatments tested, whereas the same fungicides were more sensitive to application timing in a different year. Findings from this research indicate that differences in efficacy between fungicides are small when applications are made preventively, but postinfection activity and translaminar movement of certain fungicides may render some more effective depending on application coverage and preexisting infection.
Probing the Application of OmpA-Derived Peptides to Disrupt the Acquisition of ‘Candidatus Liberibacter asiaticus’ by Diaphorina citri
Authors: Merfa Marcus Vinícius , Fischer Eduarda Regina , de Souza e Silva Mariana , Francisco Carolina Sardinha , Della Coletta-Filho Helvécio , de Souza Alessandra Alves
Published: November 2021

Huanglongbing (HLB) is currently the most devastating disease of citrus worldwide. Both bacteria ‘Candidatus Liberibacter asiaticus’ (CLas) and ‘Candidatus Liberibacter americanus’ (CLam) are associated with HLB in Brazil but with a strong prevalence of CLas over CLam. Conventionally, HLB management focuses on controlling the insect vector population (Diaphorina citri; also known as Asian citrus psyllid [ACP]) by spraying insecticides, an approach demonstrated to be mostly ineffective. Thus, development of novel, more efficient HLB control strategies is required. The multifunctional bacterial outer membrane protein OmpA is involved in several molecular processes between bacteria and their hosts and has been suggested as a target for bacterial control. Curiously, OmpA is absent in CLam in comparison with CLas, suggesting a possible role in host interaction. Therefore, in the current study, we have treated ACPs with different OmpA-derived peptides, aiming to evaluate acquisition of CLas by the insect vector. Treatment of psyllids with 5 µM of Pep1, Pep3, Pep5, and Pep6 in artificial diet significantly reduced the acquisition of CLas, whereas increasing the concentration of Pep5 and Pep6 to 50 µM abolished this process. In addition, in planta treatment with 50 µM of Pep6 also significantly decreased the acquisition of CLas, and sweet orange plants stably absorbed and maintained this peptide for as long as 3 months post the final application. Together, our results demonstrate the promising use of OmpA-derived peptides as a novel biotechnological tool to control CLas.
An Integrated Approach for Synonymization ofRotylenchus rhomboideswithR.goodeyi(Nematoda: Hoplolaimidae) Reveals High Intraspecific Mitogenomic Variation
Authors: Singh Phougeishangbam Rolish , van de Vossenberg Bart T. L. H. , Rybarczyk-Mydłowska Katarzyna , Kowalewska-Groszkowska Magdalena , Bert Wim , Karssen Gerrit
Published: November 2021

Rotylenchus is a widely distributed, economically important plant-parasitic nematode group whose species-level identification relies largely on limited morphological characters, including character-based tabular keys and molecular data of ribosomal and mitochondrial genes. In this study, a combined morphological and molecular analysis of three populations of Rotylenchus goodeyi from Belgium, Poland, and the Netherlands revealed important character variations of this species, leading to synonymization of R. rhomboides with R. goodeyi and a high nucleotide variation within cox1 gene sequences in these populations. Additional Illumina sequencing of DNA from individuals of the Dutch population revealed two variants of mitogenomes, each approximately 23 Kb in size, differing by approximately 9% and containing 11 protein-coding genes, 2 ribosomal RNA genes, and as many as 29 transfer RNA genes. In addition to the first representative whole-genome shotgun sequence datasets of the genus Rotylenchus, this study also provides the full-length mitogenome and the ribosomal DNA sequences of R. goodeyi.
The Seven Surprises: What I've Learned About Nursing Through Yoga
Authors: McGinnis Medora
Published: November 2021

Updated several times a week with posts by a wide variety of authors, AJN's blog Off the Charts allows us to provide more timely—and often more personal—perspectives on professional, policy, and clinical issues. Best of the Blog is a regular column to draw the attention of AJN readers to posts we think deserve a wider audience. To read more, please visit: www.ajnoffthecharts.com.
2020: What a Time to Become a Nurse
Authors: Sgroi Alicia
Published: November 2021

A new nurse learns focus and grace under pressure.
Durability of SARS-CoV-2 Antibodies from Natural Infection in Children and Adolescents
Authors: Messiah Sarah E. , Brito Frances , Kohl Harold W. , DeSantis Stacia , Valerio-Shewmaker Melissa , Ross Jessica , Swartz Michael D. , Yaseen Ashraf , Kelder Steven H. , Zhang Shiming , Omega-Njemnobi Onyinye S , Gonzalez Michael O. , Wu Leqing , Boerwinkle Eric , Lakey David , Shuford Jennifer A. , Pont Stephen J.
Published: November 2021

The authors have withdrawn this manuscript for the following reasons:

Our latest analysis (mid-February, 2022) that includes the addition of 59 children with 3 completed timepoints shows a decrease in N antibodies at T2, versus this preprint that showed an increase in N antibodies from T1 to T2.

This preprint did not include those infected with the Omicron variant, which has had a substantial impact on the increase in pediatric infections and has important implications for antibody durability moving forward as such.

Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Stabilization of the SARS-CoV-2 Receptor Binding Domain by Protein Core Redesign and Deep Mutational Scanning
Authors: Leonard Alison C. , Weinstein Jonathan J. , Steiner Paul J. , Erbse Annette H. , Fleishman Sarel J. , Whitehead Timothy A.
Published: November 2021

Stabilizing antigenic proteins as vaccine immunogens or diagnostic reagents is a stringent case of protein engineering and design as the exterior surface must maintain recognition by receptor(s) and antigen—specific antibodies at multiple distinct epitopes. This is a challenge, as stability-enhancing mutations must be focused on the protein core, whereas successful computational stabilization algorithms typically select mutations at solvent-facing positions. In this study we report the stabilization of SARS-CoV-2 Wuhan Hu-1 Spike receptor binding domain (S RBD) using a combination of deep mutational scanning and computational design, including the FuncLib algorithm. Our most successful design encodes I358F, Y365W, T430I, and I513L RBD mutations, maintains recognition by the receptor ACE2 and a panel of different anti-RBD monoclonal antibodies, is between 1-2°C more thermally stable than the original RBD using a thermal shift assay, and is less proteolytically sensitive to chymotrypsin and thermolysin than the original RBD. Our approach could be applied to the computational stabilization of a wide range of proteins without requiring detailed knowledge of active sites or binding epitopes, particularly powerful for cases when there are multiple or unknown binding sites.
Non-Invasive Skin Sampling Detects Systemically Administered Drugs in Humans
Authors: Panitchpakdi Morgan , Weldon Kelly C. , Jarmusch Alan K. , Gentry Emily C. , Choi Arianna , Sepulveda Yadira , Aguirre Shaden , Sun Kunyang , Momper Jeremiah D. , Dorrestein Pieter C. , Tsunoda Shirley M.
Published: November 2021

Clinical testing typically relies on invasive blood draws and biopsies. Alternative methods of sample collection are continually being developed to improve patient experience; swabbing the skin is one of the least invasive sampling methods possible. To show that skin swabs in combination with untargeted mass spectrometry (metabolomics) can be used for non-invasive monitoring of an oral drug, we report the kinetics and metabolism of diphenhydramine in healthy volunteers (n=10) over the course of 24 hours in blood and three regions of the skin. Diphenhydramine and its metabolites were observed on the skin after peak plasma levels, varying by compound and skin location, and is an illustrative example of how systemically administered molecules can be detected on the skin surface. The observation of diphenhydramine directly from the skin supports the hypothesis that both parent drug and metabolites can be qualitatively measured from a simple non-invasive swab of the skin surface. The mechanism of the drug and metabolites pathway to the skin’s surface remains unknown.
In vivo myelin imaging and tissue microstructure in white matter hyperintensities and perilesional white matter
Authors: Ferris Jennifer K. , Greeley Brian , Vavasour Irene M. , Kraeutner Sarah N. , Rinat Shie , Ramirez Joel , Black Sandra E. , Boyd Lara A.
Published: November 2021

Introduction

White Matter hyperintensities (WMHs) relate to cognitive decline in aging, due to their deleterious effect on white matter structure. Diffusion tensor imaging (DTI) detects changes to white matter microstructure, both within the WMH and extending in a penumbra-like pattern in surrounding (perilesional) normal appearing white matter (NAWM). However, DTI markers are not specific to tissue components, complicating interpretation of previous DTI findings. Myelin water imaging is a novel imaging technique that provides specific markers of myelin content (myelin water fraction: MWF) and interstitial fluid (geometric mean T2: GMT2). Here we combined DTI and myelin water imaging to examine tissue characteristics in WMHs and perilesional NAWM. Our goal was to establish a multimodal neuroimaging approach to track WMH progression.

Methods

80 individuals (47 older adults and 33 individuals with chronic stroke) underwent neuroimaging and tissue segmentation. To measure perilesional NAWM, WMH masks were dilated in 2mm segments up to 10mm in distance from the WMH to measure perilesional NAWM. Fractional anisotropy (FA), mean diffusivity (MD), MWF, and GMT2 were extracted from WMHs and perilesional NAWM. We examined whether white matter metrics showed a spatial gradient of effects in perilesional NAWM, as a function of Distance from the WMH, and Group. We tested whether white matter metrics in the WMH lesion related to severity of cerebrovascular disease across the whole sample, indexed by whole brain WMH volume.

Results

We observed a spatial gradient of higher MD and GMT2, and lower FA, in perilesional NAWM and the WMH. In the chronic stroke group, MWF was reduced in the WMH lesion but did not show a spatial gradient in perilesional NAWM. Across the whole sample, white matter metrics within the WMH lesion related to whole-brain WMH volume; MD and GMT2 increased, and MWF decreased, with increasing WMH volume.

Conclusions

NAWM adjacent to WMHs exhibits characteristics of a transitional stage between healthy NAWM tissue and WMH lesions. This was observed in markers sensitive to interstitial fluid, but not in the specific marker of myelin concentration (MWF). Within the WMH, interstitial fluid was higher and myelin concentration was lower in individuals with more severe cerebrovascular disease. Our data suggests that fluid-sensitive imaging metrics (such as DTI) can identify NAWM at high risk of conversion to a WMH. In contrast, specific markers of myelin concentration (e.g., MWF) can be used to measure levels of demyelination in the WMH itself, which may be a useful marker for disease staging of advanced WMHs.
Economics of Implementing Preemptive School Closures to Mitigate Pandemic Influenza Outbreaks of Differing Severity in the United States
Authors: Dauelsberg Lori R , Maskery Brian , Joo Heesoo , Germann Timothy C , Del Valle Sara Y , Uzicanin Amra
Published: November 2021

The use of nonpharmaceutical interventions (NPIs) to slow disease spread, is a part of national pandemic preparedness as the first line of defense against influenza pandemics. Preemptive school closures (PSCs), an NPI reserved for use in severe pandemics, are highly effective in slowing influenza spread but have unintended consequences. We simulated PSC impacts during a 1957-like pandemic to estimate population impacts and quantify costs of closing schools at the national level. We also simulated 1957-like, 1968-like, and 2009-like pandemics at the Chicago regional level. We estimated economic impacts resulting from loss of income due to illness, providing childcare during closures, and other PSC costs while taking into consideration the number of cases averted with each mitigation strategy. The estimated net PSC costs ranged from $15 billion to $192 billion (2016 USD) (1957-like, national-level) where between 2.3 and 47 million US cases may be averted depending on strategy. We found that 2-week school-by-school PSCs (as opposed to county-wide or school district–wide ones) had the lowest cost per discounted life-year gained for both national and Chicago regional-level analyses of all pandemics. While feasibility of such spatiotemporally precise triggering is presently questionable for most locales, this is, theoretically, an attractive option early in an outbreak, while assessing transmissibility and severity of a novel influenza virus. In contrast, we found that county-wide PSCs of longer durations (8 to 12 weeks) would result in the most averted cases (31-47 million) and deaths (105,000-156,000), albeit at considerably more cost ($125-$150 billion net of averted illness costs) for the national-level, 1957-like analysis. The estimated net costs per death averted ($1.0 to $1.2 million) for these scenarios compare favorably to the range of values recommended for regulatory impact analyses ($4.6 to 15.0 million). Hence, economic benefits of such PSCs would exceed the population impacts and economic costs.
An immune correlate of SARS-CoV-2 infection and severity of reinfections
Authors: Maier Hannah E. , Balmaseda Angel , Ojeda Sergio , Cerpas Cristiam , Sanchez Nery , Plazaola Miguel , van Bakel Harm , Kubale John , Lopez Roger , Saborio Saira , Barilla Carlos ,   PSP Study Group, Harris Eva , Kuan Guillermina , Gordon Aubree
Published: November 2021

Background

An immune correlate of protection from SARS-CoV-2 infection is urgently needed.

Methods

We used an ongoing household cohort with an embedded transmission study that closely monitors participants regardless of symptom status. Real-time reverse-transcription polymerase chain reaction (RT-PCR) and Enzyme-linked immunosorbent assays (ELISAs) were used to measure infections and seropositivity. Sequencing was performed to determine circulating strains of SARS-CoV-2. We investigated the protection associated with seropositivity resulting from prior infection, the anti-spike antibody titers needed for protection, and we compared the severity of first and second infections.

Results

In March 2021, 62.3% of the cohort was seropositive. After March 2021, gamma and delta variants predominated. Seropositivity was associated with 69.2% protection from any infection (95% CI: 60.7%-75.9%), with higher protection against moderate or severe infection (79.4%, 95% CI: 64.9%-87.9%). Anti-spike titers of 327 and 2,551 were associated with 50% and 80% protection from any infection; titers of 284 and 656 were sufficient for protection against moderate or severe disease. Second infections were less severe than first infections (Relative Risk (RR) of moderated or severe disease: 0.6, 95% CI: 0.38-0.98; RR of subclinical disease:1.9, 95% CI: 1.33-2.73).

Conclusions

Prior infection-induced immunity is protective against infection when predominantly gamma and delta SARS-CoV-2 circulated. The protective antibody titers presented may be useful for vaccine policy and control measures. While second infections were somewhat less severe, they were not as mild as ideal. A strategy involving vaccination will be needed to ease the burden of the SARS-CoV-2 pandemic.
Antiviral activity of Molnupiravir precursor NHC against SARS-CoV-2 Variants of Concern (VOCs) and implications for the therapeutic window and resistance
Authors: Prince Tessa , Donovan-Banfield I’ah , Goldswain Hannah , Penrice-Randal Rebekah , Hartley Catherine , Khoo Saye , Fletcher Tom , Hiscox Julian A.
Published: November 2021

Several regulatory agencies have either licensed or given emergency use approval for treatment of patients at risk of developing severe COVID-19 with the anti-viral drug, Molnupiravir. Recent trials involving Molnupiravir suggested the drug was not as efficacious as earlier studies suggested. This study aimed to: (i) determine the effectiveness of the Molnupiravir active metabolite (NHC) against different SARS-CoV-2 Variants of Concern (VoCs), (ii) establish the therapeutic window of NHC in a human lung cell model, and (iii) and evaluate the genetic barrier to resistance. Dose response assays were performed in parallel to determine the IC50 (the concentration required to inhibit virus titre by 50%) of NHC against different variants. Human ACE-2 A549 cells were treated with NHC at different time points either before, during or after infection with SARS-CoV-2. Multiple passaging in the presence or absence of drug was used to evaluate whether resistance occurred. To obtain genomic information, virus was sequenced at regular intervals. After 20 passages in the presence of the drug, dose response assays and sequencing showed the virus did not appear to have developed resistance. The drug had equivalent activity against four VOCs ranging from 0.04 to 0.16μM IC50. The efficacy of the drug diminished when applied after 24 hours post-infection. Our results suggest that earlier administration in patients, perhaps pre- or post-exposure rather than symptom onset, would be a more effective treatment option.
Smoking-dependent expression alterations in nasal epithelium reveal immune impairment linked to germline variation and lung cancer risk
Authors: de Biase Maria Stella , Massip Florian , Wei Tzu-Ting , Giorgi Federico M. , Stark Rory , Stone Amanda , Gladwell Amy , O’Reilly MarJn , Schütte Daniel , de Santiago Ines , Meyer Kerstin B. , Markowetz Florian , Ponder Bruce A J , Rintoul Robert C , Schwarz Roland F
Published: November 2021

Lung cancer is the leading cause of cancer-related death in the world. In contrast to many other cancers, a direct connection to modifiable lifestyle risk in the form of tobacco smoke has long been established. More than 50% of all smoking-related lung cancers occur in former smokers, often many years after smoking cessation. Despite extensive research, the molecular processes for persistent lung cancer risk are unclear.

To examine whether risk stratification in the clinic and in the general population can be improved upon by the addition of genetic data, and to explore the mechanisms of the persisting risk in former smokers, we have analysed transcriptomic data from accessible airway tissues of 487 subjects, including healthy volunteers and clinic patients of different smoking status. We developed a model to assess smoking associated gene expression changes and their reversibility after smoking is stopped, comparing healthy subjects to clinic patients with and without lung cancer. We find persistent smoking-associated immune alterations to be a hallmark of the clinic patients. Integrating previous GWAS data using a transcriptional network approach, we demonstrate that the same immune and interferon related pathways are strongly enriched for genes linked to known genetic risk factors, demonstrating a causal relationship between immune alteration and lung cancer risk. Finally, we used accessible airway transcriptomic data to derive a non-invasive lung cancer risk classifier.

Our results provide initial evidence for germline-mediated personalised smoke injury response and risk in the general population, with potential implications for managing long-term lung cancer incidence and mortality.
A genome-wide association study of COVID-19 related hospitalization in Spain reveals genetic disparities among sexes
Authors: Carracedo Ángel ,   Spanish COalition to Unlock Research on host GEnetics on COVID-19 (SCOURGE)
Published: November 2021

Abstract

We describe the results of the Spanish Coalition to Unlock Research on Host Genetics on COVID-19 (SCOURGE). In sex-disaggregated genome-wide studies of COVID-19 hospitalization, we found two known loci associated among males (SLC6A20-LZTFL1 and IFNAR2), and a novel one among females (TLE1). Meta-analyses with independent studies revealed two novel associations (AQP3 and ARHGAP33) and replicated ELF5. A genetic risk score predicted COVID-19 severity, especially among younger males. We found less SNP-heritability and larger heritability differences by age (<60/≥60 years) among males than females. Inbreeding depression was associated with COVID-19 hospitalization and severity, and the effect was stronger among older males.
Severe COVID-19 induces molecular signatures of aging in the human brain
Authors: Mavrikaki Maria , Lee Jonathan D. , Solomon Isaac H. , Slack Frank J.
Published: November 2021

Coronavirus disease 2019 (COVID-19) is predominantly an acute respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and remains a significant threat to public health. COVID-19 is accompanied by neurological symptoms and cognitive decline, but the molecular mechanisms underlying this effect remain unclear. As aging induces distinct molecular signatures in the brain associated with cognitive decline in healthy populations, we hypothesized that COVID-19 may induce molecular signatures of aging. Here, we performed whole transcriptomic analysis of human frontal cortex, a critical area for cognitive function, in 12 COVID-19 cases and age- and sex-matched uninfected controls. COVID-19 induces profound changes in gene expression, despite the absence of detectable virus in brain tissue. Pathway analysis shows downregulation of genes involved in synaptic function and cognition and upregulation of genes involved in immune processes. Comparison with five independent transcriptomic datasets of aging human frontal cortex reveals striking similarities between aged individuals and severe COVID-19 patients. Critically, individuals below 65 years of age exhibit profound transcriptomic changes not observed among older individuals in our patient cohort. Our data indicate that severe COVID-19 induces molecular signatures of aging in the human brain and emphasize the value of neurological follow-up in recovered individuals.
Fast surveillance response and genome sequencing reveal the circulation of a new Yellow Fever Virus sublineage in 2021, in Minas Gerais, Brazil
Authors: Andrade Miguel S. , Campos Fabrício S. , de Oliveira Cirilo H. , Oliveira Ramon Silva , Campos Aline A. S. , Almeida Marco A. B. , Simonini-Teixeira Danilo , Sevá Anaiá da P. , Temponi Andrea Oliveira Dias , Magalhães Fernando Maria , Chaves Danielle Costa Capistrano , Pereira Maira Alves , Lamounier Ludmila Oliveira , de Menezes Givaldo Gomes , Teixeira Sandy Micaele Aquino , dos Santos Maria Eduarda Gonçalves , Bernal-Valle Sofía , Müller Nicolas F. D. , Cardoso Jader da C. , dos Santos Edmilson , Mares-Guia Maria A. , Albuquerque George R. , Romano Alessandro P. M. , Franco Ana C. , Ribeiro Bergmann M. , Roehe Paulo M. , Abreu Filipe V. S.
Published: November 2021

Yellow fever virus (YFV) exhibits a sylvatic cycle of transmission involving wild mosquitoes and non-human primates (NHP). In Brazil, YFV is endemic in the Amazon region, from where waves of epidemic expansion towards other Brazilian states eventually occur. During such waves, the virus usually follows the route from North to the Central-West and Southeast Brazilian regions. Amidst these journeys, outbreaks of Yellow Fever (YF) in NHPs, with spillovers to humans have been observed. In the present work, we describe a surveillance effort encompassing the technology of smartphone applications and the coordinated action of several research institutions and health services that succeeded in the first confirmation of YFV in NHPs in the state of Minas Gerais (MG), Southeast region, in 2021, followed by genome sequencing in an interval of only ten days. Samples from two NHPs (one of the species Alouatta caraya in the municipality of Icaraí de Minas and the other of the species Callithrix penicillata in the municipality of Ubaí) were collected and the presence of YFV was confirmed by RT-qPCR. We generated three near-complete by Nanopore sequencer MinION. Phylogenetic analysis revealed that all viral genomes recovered are equal and related to lineage South America 1, clustering with a genome detected in the Amazon region (Pará state) in 2017. These findings reveal the occurrence of a new wave of viral expansion in MG, six years after the beginning of the major outbreak in the state, between 2015-2018. No human cases were reported to date, showing the importance of coordinated work between local surveillance based on available technologies and support laboratories to ensure a quick response and implementation of contingency measures towards avoiding the occurrence of YF cases in humans.
Single-cell RNA sequencing ofPlasmodiumvivax sporozoites reveals stage- and species-specific transcriptomic signatures
Authors: Ruberto Anthony A. , Bourke Caitlin , Vantaux Amélie , Maher Steven P. , Jex Aaron , Witkowski Benoit , Snounou Georges , Mueller Ivo
Published: November 2021

Plasmodium vivaxsporozoites reside in the salivary glands of a mosquito before infecting a human host. Previous transcriptome-wide studies in populations of these forms were limited in their ability to elucidate cell-to-cell variation, thereby masking cellular states potentially important in understanding transmission outcomes. In this study, we performed transcription profiling on 9,947P. vivaxsporozoites to assess the extent to which they differ at single-cell resolution. We show that sporozoites residing in the mosquito’s salivary glands exist in distinct developmental states, as defined by their transcriptomic signatures. Additionally, relative toP. falciparum, P. vivaxdisplays overlapping and unique gene usage patterns, highlighting conserved and species-specific gene programs. Notably, distinguishingP. vivaxfromP. falciparumwere a subset ofP. vivaxsporozoites expressing genes associated with translational regulation and repression. Finally, our comparison of single-cell transcriptomic data fromP. vivaxsporozoite and erythrocytic forms reveals gene usage patterns unique to sporozoites. In defining the transcriptomic signatures of individualP. vivaxsporozoites, our work provides new insights into the factors driving their developmental trajectory and lays the groundwork for a more comprehensiveP. vivaxcell atlas.
Neurotoxic Amyloidogenic Peptides Identified in the Proteome of SARS-COV2: Potential Implications for Neurological Symptoms in COVID-19
Authors: Islam Saba , Charnley Mirren , Bindra Guneet , Ratcliffe Julian , Zhou Jiangtao , Mezzenga Raffaele , Hulett Mark , Han Kyunghoon , Berryman Joshua T. , Reynolds Nicholas P.
Published: November 2021

COVID-19 is primarily known as a respiratory disease caused by the virus SARS-CoV-2. However, neurological symptoms such as memory loss, sensory confusion, cognitive and psychiatric issues, severe headaches, and even stroke are reported in as many as 30% of cases and can persist even after the infection is over (so-called ‘long COVID’). These neurological symptoms are thought to be caused by brain inflammation, triggered by the virus infecting the central nervous system of COVID-19 patients, however we still don’t fully understand the mechanisms for these symptoms. The neurological effects of COVID-19 share many similarities to neurodegenerative diseases such as Alzheimer’s and Parkinson’s in which the presence of cytotoxic protein-based amyloid aggregates is a common etiological feature. Following the hypothesis that some neurological symptoms of COVID-19 may also follow an amyloid etiology we performed a bioinformatic scan of the SARS-CoV-2 proteome, detecting peptide fragments that were predicted to be highly amyloidogenic. We selected two of these peptides and discovered that they do rapidly self-assemble into amyloid. Furthermore, these amyloid assemblies were shown to be highly toxic to a neuronal cell line. We introduce and support the idea that cytotoxic amyloid aggregates of SARS-CoV-2 proteins are causing some of the neurological symptoms commonly found in COVID-19 and contributing to long COVID, especially those symptoms which are novel to long COVID in contrast to other post-viral syndromes.
Age-specific survival in an English Twite population
Authors: Gkourtsouli-Antoniadou Ismini , Ewing Steven R. , Hudson George , Pearson Michael A. , Schroeder Julia , Welch Peter E. , Wilkinson Nicholas , Dunning Jamie
Published: November 2021

Like many bird species associated with agricultural habitats in the UK, the Twite Linaria flavirostris has undergone severe declines over recent decades due to habitat degradation, with populations in England, Wales and Ireland now restricted to a few small pockets. However, the demographic drivers of these declines are still largely unresolved. We estimated the survival of Twite from a small population at the southernmost edge of the English range in Derbyshire using capture-mark-recapture data from 2016–2019. Annual apparent survival for juveniles (0.14-0.34) was lower than for adults (0.29-0.56) and less than that of other Cardueline finches. Our results suggest that low juvenile survival may be one demographic driver underpinning the recent decline of the Derbyshire Twite population, although we also cannot rule out the possibility that differences in emigration of juveniles and adults from the population also contribute to the observed age-specific apparent survival rates.
Recombination of standing variation in a multi-hybrid swarm drove adaptive radiation in a fungal pathogen and gave rise to two pandemic plant diseases
Authors: Rahnama Mostafa , Condon Bradford , Ascari Joao P. , Dupuis Julian R. , Del Ponte Emerson , Pedley Kerry F. , Martinez Sebastián , Valent Barbara , Farman Mark L.
Published: November 2021

Adaptive radiations fuel speciation and are characterized by rapid genetic diversification and expansion into new ecological niches. Historically, these processes were believed to be driven by selection on novel mutations but genomic analyses now indicate that standing variation and gene flow often have prominent roles. How “old” variation is combined, however, and its resulting genetic architecture within newly-adapted populations is not well understood. We reconstructed a recent radiation in the fungus, Pyricularia oryzae, that spawned a population pathogenic to eleven grass genera, and caused two new plant diseases: wheat blast - already a serious threat to global agriculture - and gray leaf spot of ryegrasses. We show that the new population evolved in a multi-hybrid swarm using only the standing variation that was present in seven individuals from five distinct, host-specialized lineages. Sexual and parasexual recombination within the swarm reassorted key host-specificity factors and generated more diversity in possibly just a few weeks than existing lineages had accumulated over hundreds to thousands of years. We suggest that the process was initiated by sexual opportunity arising when a fertile fungal strain was imported into Brazil on Urochloa introduced as forage for beef production; and we further contend that the host range expansion was largely fortuitous, with host selection playing little, if any, role in driving the process. Finally, we believe that our findings point to an overlooked role for happenstance in creating situations that allow organisms to skirt rules that would normally hold evolution in check.

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Atazanavir is a competitive inhibitor of SARS-CoV-2 Mpro, impairing variants replication in vitro and in vivo
Authors: Chaves Otávio Augusto , Sacramento Carolina Q. , C. Ferreira André , Mattos Mayara , Fintelman-Rodrigues Natalia , Temerozo Jairo R. , Pinto Douglas Pereira , da Silveira Gabriel P. E. , da Fonseca Laís Bastos , Pereira Heliana Martins , Carlos Aluana Santana , Pinto d’Ávila Joana da Costa , Viola João P.B. , Monteiro Robson Q. , Vazquez Leonardo , Bozza Patrícia T. , Castro-Faria-Neto Hugo Caire , Souza Thiago Moreno L.
Published: November 2021

Atazanavir (ATV) has already been considered as a potential repurposing drug to 2019 coronavirus disease (COVID-19), however, there are controversial reports on its mechanism of action and effectiveness as anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Through the pre-clinical chain of experiments: enzymatic, molecular docking, cell-based, and in vivo assays, it is demonstrated here that both SARS-CoV-2 B.1 lineage and variant of concern gamma are susceptible to this antiretroviral. Enzymatic assays and molecular docking calculations showed that SARS-CoV-2 main protease (Mpro) was inhibited by ATV, with Morrison’s inhibitory constant (Ki) 1.5-fold higher than boceprevir (GC376, a positive control). ATV was a competitive inhibition, increasing the Mpro’s Michaelis-Menten (Km) more than 6-fold. Cell-based assays indicated that SARS-CoV-2 gamma is more susceptible to ATV than its predecessor strain B.1. Using oral administration of ATV in mice to reach plasmatic exposure similar to humans, transgenic mice expression in human angiotensin converting enzyme 2 (K18-hACE2) were partially protected against lethal challenge with SARS-CoV-2 gamma. Moreover, less cell death and inflammation were observed in the lung from infected and treated mice. Our studies may contribute to a better comprehension of the Mpro/ATV interaction, which could pave the way to the development of specific inhibitors of this viral protease.