bluuebunny/crossref_metadata_2025 huggingface dataset:
Inequalities in antenatal care coverage and quality: an analysis from 63 low and middle-income countries using the ANCq content-qualified coverage indicator
Authors: Arroyave Luisa , Saad Ghada E , Victora Cesar G , Barros Aluisio J D
Published: November 2020

Objective

to conduct a global analysis of socioeconomic inequalities in antenatal care (ANC) using national surveys from low- and middle-income countries.

Methods

ANC was measured using the ANCq, a novel content-qualified ANC coverage indicator, created and validated using national surveys, based upon contact with the health services and content of care received. We performed stratified analysis to explore the socioeconomic inequalities in ANCq. We also estimated the slope index of inequality, which measures the difference in coverage along the wealth spectrum.

Results

We analyzed 63 national surveys carried out from 2010 to 2017. There were large inequalities between and within countries. Higher ANCq scores were observed among women living in urban areas, with secondary or more level of education, belonging to wealthier families and with higher empowerment in nearly all countries. Countries with higher ANCq mean presented lower inequalities; while countries with average ANCq scores presented wide range of inequality, with some managing to achieve very low inequality.

Conclusions

Despite all efforts in ANC programs, important inequalities in coverage and quality of ANC services persist. If maternal and child mortality Sustainable Development Goals are to be achieved, those gaps we documented must be bridged.
Age differential analysis of COVID-19 second wave in Europe reveals highest incidence among young adults
Authors: Aleta Alberto , Moreno Yamir
Published: November 2020

Most of the western nations have been unable to suppress the COVID-19 and are currently experiencing second or third surges of the pandemic. Here, we analyze data of incidence by age groups in 25 European countries, revealing that the highest incidence of the current second wave is observed for the group comprising young adults (aged 18-29 years old) in all but 3 of the countries analyzed. We discuss the public health implications of our findings.
Failure of VITEK2 to reliably detectvanB- mediated vancomycin resistance inEnterococcus faecium
Authors: Walker Sarah V. , Wolke Martina , Plum Georg , Weber Robert E. , Werner Guido , Hamprecht Axel
Published: November 2020

Objectives

The increasing prevalence of vancomycin resistant enterococci (VRE) necessitates a reliable detection of VRE especially for low level resistance mediated byvanBinEnterococcus faecium. In this prospective study we analyzed ifvanBmediated vancomycin resistance can be reliably detected by Vitek2.

Methods

1344 enterococcal isolates from routine clinical specimens were tested by Vitek2 (bioMérieux, Nürtingen, Germany). Additionally, a bacterial suspension (0.5 McFarland) was inoculated on a chromID VRE screening agar (bioMérieux) and incubated for 48 hours. If vancomycin was tested susceptible by Vitek2 but growth was detected on the screening agar a PCR forvanA/vanBwas performed (GeneXpertvanA/Btest kit, Cepheid, Frankfurt, Germany). MICs of vancomycin susceptible by Vitek butvanA/Bpositive isolates were determined before and after cultivation in a broth with increasing concentration of vancomycin.

Results

156/492 ofE. faeciumwere VRE, predominantlyvanB(87.0%) of which 14 were not identified as VRE by Vitek2 (sensitivity 91.0%). The majority (9/14) demonstrated high-level MICs by broth dilution. Even after exposure to increasing vancomycin concentrations MICs remained nearly identical. Three of the undetected isolates demonstrated initial growth on chromID VRE, after the vancomycin exposure additional 7 isolates demonstrated growth on chromID VRE.

Conclusions

Vitek2 fails to detectvanBmediated vancomycin resistance consistently, especially but not limited to low-level resistance. As this may lead to treatment failure and further dissemination of vanB VRE, additional methods (e.g. culture on VRE screening agar or PCR) are necessary to reliably identifyvanB-positive enterococci in clinical routine.
Association of Herpesvirus Response Burden with Long-Term Mortality Differs Between Older Males and Females
Authors: Strandberg Timo E , Seppänen Mikko , Pitkälä Kaisu H , Kivimäki Mika , Tienari Pentti J
Published: November 2020

Background

Sex-specific immune responses may contribute to variable vulnerability for Covid-19 between females and males. We tested whether there is a long-term mortality difference between sexes for other microbes (viral and bacterial) response burden among older people.

Methods

Seven-year follow-up study consisted of 382 home-dwelling people aged 75-90 years (65.2% females) with a history cardiovascular disease. At baseline, serum immunoglobulin G antibodies were assayed against herpesviruses (CMV, HSV-1 and HSV-2) and bacteria (Chlamydophila pneumoniae, Mycoplasma pneumonia, and Helicobacter pylori). Titers were summed up as herpes (HB) or bacterial response burden (BB) and divided into tertiles. Hazard ratios (HR) of total mortality with 95% CIs were calculated using Cox regression.

Results

The overall HB was lower and BB higher among males than females (P<0.001). There was a significant sex/HB (P=0.01) and sex/BB (P=0.03) interaction with mortality. Multivariable-adjusted (age, body mass index, C-reactive protein, and comorbidity index) mortality HRs for increasing HB sex-specific tertiles were 1.0 (reference), 1.34 (95% CI 0.62-2.88), and 2.66 (1.25-5.64) for males and 1.0, 1.30 (0.76-2.21), and 1.30 (0.77-2.22) for females. The significant age-adjusted association between BB and mortality in males attenuated after multivariable adjustments, HR (top-vs-bottom tertile) 1.74 (0.93-3.25). In females, no association with BB was observed. Using HB and BB as continuous variables supported the findings with tertiles.

Conclusions

Although being lower in older males than females, higher Herpesviridae response burden was associated with increased 7-year mortality risk among males, not among females. Immune responses to common microbes may contribute to sex differences in longevity and mortality.

Key points

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Gender differences in vulnerability during Covid-19 has increased interested in sex-related responses to infections

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We used IgG titers of Herpesviridae and bacteria as surrogate markers for variably recurrent reactivation

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Although Herpesviridae response burden was generally lower among males than females, within sexes higher Herpesviridae burden strongly predicted 7-year mortality among males but not females

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Long-term virus burden, like Herpesviridae, may partly explain shorter longevity and higher mortality among males with weaker immune systems
Comparison of seven commercial SARS-CoV-2 rapid Point-of-Care Antigen tests
Authors: Corman Victor M. , Haage Verena Claudia , Bleicker Tobias , Schmidt Marie Luisa , Mühlemann Barbara , Zuchowski Marta , Jó Lei Wendy Karen , Tscheak Patricia , Möncke-Buchner Elisabeth , Müller Marcel A. , Krumbholz Andi , Drexler Jan Felix , Drosten Christian
Published: November 2020

Background

Antigen point of care tests (AgPOCT) can accelerate SARS-CoV-2 testing. As first AgPOCT are becoming available, there is a growing interest in their utility and performance.

Methods

Here we compare AgPOCT products by seven suppliers: the Abbott Panbio™ COVID-19 Ag Rapid Test; the RapiGEN BIOCREDIT COVID-19 Ag; the Healgen® Coronavirus Ag Rapid Test Cassette (Swab); the Coris Bioconcept Covid.19 Ag Respi-Strip; the R-Biopharm RIDA®QUICK SARS-CoV-2 Antigen; the NAL von minden NADAL COVID19-Ag Test; and the Roche/SD Biosensor SARS-CoV Rapid Antigen Test. Tests were evaluated on recombinant nucleoprotein, cultured endemic and emerging coronaviruses, stored clinical samples with known SARS-CoV-2 viral loads (n=138), stored samples from patients with respiratory agents other than SARS-CoV-2 (n=100), as well as self-sampled swabs from healthy volunteers (n=35).

Findings

Limits of detection in six of seven tested products ranged between 2.08 × 106 and 2.88 × 107 copies per swab, the outlier at 1.58 × 1010 copies per swab. Specificities ranged between 98.53% and 100% in five products, with two outliers at 94.85% and 88.24%. False positive results were not associated with any specific respiratory agent. As some of the tested AgPOCT were early production lots, the observed issues with specificity are unlikely to persist.

Interpretation

The sensitivity range of most AgPOCT overlaps with viral load figures typically observed during the first week of symptoms, which marks the infectious period in the majority patients. AgPOCTs with a limit of detection that approximates the virus concentration above which patients are infectious may enable shortcuts in decision-making in various areas of healthcare and public health.
Type 2 diabetes as a determinant of Parkinson’s disease risk and progression
Authors: Chohan Harneek , Senkevich Konstantin , Patel Radhika K , Bestwick Jonathan P , Jacobs Benjamin M , Ciga Sara Bandres , Gan-Or Ziv , Noyce Alastair J
Published: November 2020

Objective

To investigate type 2 diabetes mellitus (T2DM) as a determinant of Parkinson’s disease (PD) through a meta-analysis of observational and genetic summary data.

Methods

A systematic review and meta-analysis of observational studies was undertaken by searching six databases. We selected the highest quality studies investigating the association of T2DM with PD risk and progression. We then used Mendelian randomization (MR) to investigate causal effects of genetic liability towards T2DM on PD risk and progression, using summary data derived from genome-wide association studies.

Results

In the observational part of the study, nine studies were included in the risk meta-analysis and four studies were included in the progression meta-analysis. Pooled effect estimates revealed that T2DM was associated with an increased risk of PD (OR 1.21, 95% CI 1.07-1.36), and there was some evidence that T2DM was associated with faster progression of motor symptoms (SMD 0.55, 95% CI 0.39-0.72) and cognitive decline (SMD −0.92, 95% CI −1.50 – −0.34). Using MR we found supportive evidence for a causal effect of diabetes on PD risk (IVW OR 1.08, 95% CI 1.02-1.14; p=0.010) and some evidence of an effect on motor progression (IVW OR 1.10, 95% CI 1.01-1.20; p=0.032), but not for cognitive progression.

Conclusion

Using meta-analysis of traditional observational studies and genetic data, we observed convincing evidence for an effect of T2DM on PD risk, and new evidence to support a role in PD progression. Treatment of diabetes may be an effective strategy to prevent or slow progression of PD.
Association of Obstructive Sleep Apnea and severity of COVID-19: A hospital based observational study
Authors: Kar Avishek , Saxena Khushboo , Goyal Abhishek , Pakhare Abhijit , Khurana Alkesh , Saigal Saurabh
Published: November 2020

Introduction

OSA has been postulated to be associated with mortality in COVID19, but studies are lacking thereof. This study was done to estimate prevalence of OSA in patients with COVID-19 using various screening questionnaires and to assess effect of OSA on outcome of disease.

Methodology

In this prospective observational study, consecutive patients with RTPCR confirmed COVID 19 patients were screened for OSA by different questionnaires (STOPBANG, Berlin Questionnaire, NoSAS and Epworth Scale). Association between OSA and outcome (mortality) and requirement for respiratory support was assessed.

Results

In study of 213 patients; screening questionnaires for OSA {STOPBANG, Berlin Questionnaire (BQ), NoSAS} were more likely to be positive in patients who died compared to patients who survived. On binary logistic yregression analysis, age≥55 and STOPBANG score ≥5 were found to have small positive but independent effect on mortality even after adjusting for other variables. Proportion of patients who were classified as high risk for OSA by various OSA screening tools significantly increased with increasing respiratory support (p<0.001 for STOPBANG, BQ, ESS and p=0.004 for NoSAS).

Conclusion

This is one of the first prospective studies of sequentially hospitalized patients with confirmed COVID 19 status who were screened for possible OSA. This study shows that OSA could be an independent risk factor for poor outcome in patients with COVID19.
Polygenic transcriptome risk scores improve portability of polygenic risk scores across ancestries
Authors: Liang Yanyu , Pividori Milton , Manichaikul Ani , Palmer Abraham A. , Cox Nancy J. , Wheeler Heather , Im Hae Kyung
Published: November 2020

Polygenic risk scores (PRS) are on course to translate the results of genome-wide association studies (GWAS) into clinical practice. To date, most GWAS have been based on individuals of European-ancestry, meaning that the utility of PRS for non-European populations is limited because SNP effects and LD patterns may not be conserved across populations. We hypothesized that cross population prediction at the level of genes rather than SNPs would be more effective, since the effect of genes on traits is likely to be more highly conserved. Therefore, we developed a framework to convert effect sizes at SNPs into effect sizes for genetically predicted transcript abundance, which we used for prediction in non-European populations. We compared this approach, which we call polygenic transcriptome risk scores (PTRS), to PRS, using data from 17 quantitative traits that were measured in multiple ancestries (European, African, East Asian, and South Asian) by UK Biobank. On average, PTRS using whole blood predicted transcriptome had lower absolute prediction accuracy than PRS, as we expected since not all regulatory processes were captured by a single tissue. However, as hypothesized, we found that in the African target set, the portability (prediction accuracy relative to the European reference set) was significantly higher for PTRS than PRS (p=0.03) with additional gain when transcriptomic prediction models ancestry matched the target population (p=0.021). Taken together, our results suggest that using PTRS can improve prediction in underrepresented populations and that increasing the diversity of transcriptomic data may be an effective way to improve portability of GWAS results between populations and help reduce health disparities.
Rhipicephalus microplusand its vector-borne haemoparasites in Guinea: further species expansion in West Africa
Authors: Makenov MT , Toure AH , Korneev MG , Sacko N , Porshakov AM , Yakovlev SA , Radyuk EV , Zakharov KS , Shipovalov AV , Boumbaly S , Zhurenkova OB , Grigoreva YaE , Morozkin ES , Fyodorova MV , Boiro MY , Karan LS
Published: November 2020

Abstract

Rhipicephalus microplusis an ixodid tick with a pantropical distribution that represents a serious threat to livestock. West Africa was free of this tick until 2007, when its introduction into Benin was reported. Shortly thereafter, the further invasion of this tick into West African countries was demonstrated. In this paper, we describe the first detection ofR. microplusin Guinea and list the vector-borne haemoparasites that were detected in the invader and indigenousBoophilusspecies.

In 2018, we conducted a small-scale survey of ticks infesting cattle in three administrative regions of Guinea: N`Zerekore, Faranah, and Kankan. The tick species were identified by examining their morphological characteristics and by sequencing their COI gene and ITS-2 gene fragments.R. micropluswas found in each studied region. In the ticks, we found DNA ofBabesia bigemina,Anaplasma marginale, Anaplasma platys, andEhrlichia spp. The results of this study indicate thatR. micropluswas introduced into Guinea with cows from Mali and/or Ivory Coast.
Genetic variation at theCyp6m2putative insecticide resistance locus inAnopheles gambiaeandAnopheles coluzzii
Authors: Wagah Martin G. , Korlević Petra , Clarkson Christopher , Miles Alistair ,   The Anopheles gambiae 1000 Genomes Consortium, Lawniczak Mara K. N. , Makunin Alex
Published: November 2020

Background

The emergence of insecticide resistance is a major threat to malaria control programmes in Africa, with many different factors contributing to insecticide resistance in its vectors,Anophelesmosquitoes.CYP6M2has previously been recognized as an important candidate in cytochrome P450-mediated detoxification inAnophelesmosquitoes. As it has been implicated in resistance against pyrethroids, organochlorines and carbamates, its broad metabolic activity makes it a potential agent in insecticide cross-resistance. Currently, allelic variation within theCyp6m2gene remains unknown.

Results

Here, we use Illumina whole-genome sequence data from Phase 2 of theAnopheles gambiae1000 Genomes Project (Ag1000G) to examine genetic variation in theCyp6m2gene across 16 populations in 13 countries comprisingAnopheles gambiaeandAnopheles coluzziimosquitoes. We find 15 missense biallelic substitutions at high frequency (defined as >5% frequency in one or more populations), that fall into five distinct haplotype groups that carry the main high frequency variants: A13T, D65A, E328Q, Y347F, I359V and A468S. We examine whether these alleles show evidence of selection either through potentially modified enzymatic function or by being linked to variants that change the transcriptional profile of the gene. Despite consistent reports ofCyp6m2upregulation and metabolic activity in insecticide resistant Anophelines, we find no evidence of directional selection occurring on these variants or on the haplotype clusters in which they are found.

Conclusion

Our results imply that emerging resistance associated withCyp6m2is potentially driven by distant regulatory loci such as transcriptional factors rather than by its missense variants, or that other genes are playing a more significant role in conferring metabolic resistance.
Characterization of LC-MS based urine metabolomics in healthy subjects across the life span
Authors: Liu Xiaoyan , Tian Xiaoyi , Shi Qinghong , Sun Haidan , Li Jing , Tang Xiaoyue , Guo Zhengguang , Liu Ying , Ma Jie , Ren Na , Jin Fang , He Chengyan , Song Wenqi , Sun Wei
Published: November 2020

Previous studies reported that gender and age could influence urine metabolomics, which should be considered in biomarker discovery. As a consequence, for the baseline of urine metabolomics characteristics, it becomes critical to avoid confounding effects in clinical cohort studies. In this study, we provided a comprehensive lifespan characterization of urine metabolomics in a cohort of 348 healthy children and 315 adults aged 1 to 70 years using liquid chromatography coupled with high resolution mass spectrometry. Our results suggested that gender-dependent urine metabolites are much greater in adults than in children. The pantothenate and CoA biosynthesis and alanine metabolism pathways were enriched in early life. Androgen and estrogen metabolism showed high activity during adolescence and youth stages. Pyrimidine metabolism was enriched in the old stage. Based on the above analysis, metabolomic characteristics of each age stage were provided. This work could help us understand the baseline of urine metabolism characteristics and contribute to further studies of clinical disease biomarker discovery.
Antisense oligonucleotide therapy forKCNT1encephalopathy
Authors: Burbano Lisseth Estefania , Li Melody , Jancovski Nikola , Jafar-Nejad Paymaan , Richards Kay , Sedo Alicia , Soriano Armand , Rollo Ben , Jia Linghan , Gazina Elena , Piltz Sandra , Adikusuma Fatwa , Thomas Paul Q. , Rigo Frank , Reid Christopher A. , Maljevic Snezana , Petrou Steven
Published: November 2020

Developmental and epileptic encephalopathies (DEE) are characterized by pharmacoresistant seizures with concomitant intellectual disability. Epilepsy of infancy with migrating focal seizures (EIMFS) is one of the most severe of these syndromes.De novomutations in ion channels, including gain-of-function variants inKCNT1, have been found to play a major role in the etiology of EIMFS. Here, we test a potential precision therapeutic approach inKCNT1-associated DEE using a gene silencing antisense oligonucleotide (ASO) approach. The homozygous p.P924L (L/L) mouse model recapitulates the frequent, debilitating seizures and developmental compromise that are seen in patients. After a single intracerebroventricular bolus injection of aKcnt1gapmer ASO in symptomatic mice at postnatal day 40, seizure frequency was significantly reduced, behavioral abnormalities improved, and overall survival was extended compared to mice treated with a control ASO (non-hybridizing sequence). ASO administration at neonatal age was also well-tolerated and effective in controlling seizures and extending the lifespan of treated animals. The data presented here provides a proof of concept for ASO-based gene silencing as a promising therapeutic approach inKCNT1-associated epilepsies.
Ten-year projection of white-nose syndrome disease dynamics at the southern leading-edge of infection in North America
Authors: Meierhofer Melissa B. , Lilley Thomas M. , Ruokolainen Lasse , Johnson Joseph S. , Parratt Steven , Morrison Michael L. , Pierce Brian L. , Evans Jonah W. , Anttila Jani
Published: November 2020

Predicting the emergence and spread of infectious diseases is critical for effective conservation of biodiversity. White-nose syndrome (WNS), an emerging infectious disease of bats, has resulted in high mortality in eastern North America. Because the fungal causative agentPseudogymnoascus destructansis constrained by temperature and humidity, spread dynamics may vary greatly by geography. Environmental conditions in the southern part of the continent, where disease dynamics are typically studied, making it difficult to predict how the disease will manifest. Herein, we modeled the spread of WNS in Texas based on available cave densities and average dispersal distances of species occupying these sites, and projected these results out to 10 years. We parameterized a predictive model of WNS epidemiology and its effects on hibernatory bat populations with observed environmental data from bat hibernation sites in Texas. Our model suggests that bat populations in northern Texas will be more affected by WNS mortality than southern Texas. As such, we recommend prioritizing the preservation of large overwintering colonies of bats in north Texas through management actions. Our model further illustrates that infectious disease spread and infectious disease severity can become uncoupled over a gradient of environmental variation. Finally, our results highlight the importance of understanding host, pathogen and environmental conditions in various settings to elucidate what may happen across a breadth of environments.
Micromanipulation of amyloplasts with optical tweezers inArabidopsisstems
Authors: Abe Yoshinori , Meguriya Keisuke , Matsuzaki Takahisa , Sugiyama Teruki , Yoshikawa Hiroshi Y. , Morita Miyo Terao , Toyota Masatsugu
Published: November 2020

Intracellular sedimentation of highly dense, starch-filled amyloplasts toward the gravity vector is likely a key initial step for gravity sensing in plants. However, recent live-cell imaging technology revealed that most amyloplasts continuously exhibit dynamic, saltatory movements in the endodermal cells ofArabidopsisstems. These complicated movements led to questions about what type of amyloplast movement triggers gravity sensing. Here we show that a confocal microscope equipped with optical tweezers can be a powerful tool to trap and manipulate amyloplasts noninvasively, while simultaneously observing cellular responses such as vacuolar dynamics in living cells. A near-infrared (λ = 1064 nm) laser that was focused into the endodermal cells at 1 mW of laser power attracted and captured amyloplasts at the laser focus. The optical force exerted on the amyloplasts was theoretically estimated to be up to 1 pN. Interestingly, endosomes and trans-Golgi networks were trapped at 30 mW but not at 1 mW, which is probably due to lower refractive indices of these organelles than that of the amyloplasts. Because amyloplasts are in close proximity to vacuolar membranes in endodermal cells, their physical interaction could be visualized in real time. The vacuolar membranes drastically stretched and deformed in response to the manipulated movements of amyloplasts by optical tweezers. Our new method provides deep insights into the biophysical properties of plant organelles in vivo and opens a new avenue for studying gravity-sensing mechanisms in plants.
GSAP Regulates Amyloid Beta Production through Modulation of Amyloid Precursor Protein Trafficking
Authors: Chang Jerry C. , Xu Peng , Wong Eitan , Flajolet Marc , Li Yue-Ming , Greengard Paul
Published: November 2020

In addition to participating in γ-secretase activity, presenilin 1 (PS1) regulates trafficking and subcellular localization of β-amyloid precursor protein (APP). We previously showed that gamma-secretase activating protein (GSAP) selectively modulates γ-secretase activity by inducing conformational change in PS1. However, little is known whether and how GSAP might influence APP trafficking and consequent generation of β-amyloid (Aβ) peptides. Here, to explore whether GSAP has any role in regulating APP trafficking, and to systematically investigate the intracellular trafficking routes of APP, we paired total internal reflection fluorescence microscopy, high-speed line scanning microscopy, and 4D microscopy with comprehensive imaging analysis methodologies to depict the elusive modes of APP trafficking at a single-vesicle level. Mobility and diffusivity changes reveal the existence of two kinetically distinct pathways, classified into mobile and immobile pools, for vesicular APP trafficking, suggesting high association between immobile vesicle pool and amyloidogenic processing. GSAP knockdown significantly lowers immobile pool without overturning APP vesicle diffusivity, suggesting that GSAP affects vesicular APP trafficking by retaining APP in membrane microdomains known to favor amyloidogenic processing. Our study reveals a novel role of GSAP in the regulation of Aβ-peptide formation that modulates switching of APP vesicles between immobile and mobile pools, which may help identifying new therapeutic strategies to treat Alzheimer’s disease.
A simplified workflow for the analysis of whole-genome sequencing data fromPristionchus pacificusmutant lines
Authors: Rödelsperger Christian
Published: November 2020

Nematodes are attractive model systems to understand the genetic basis of various biological processes ranging from development to complex behaviors. In particular, mutagenesis experiments combined with whole-genome sequencing has been proven as one of the most effective methods to identify core players of multiple biological pathways. To enable experimentalists to apply such integrative genetic and bioinformatic analysis in the case of the satellite model organismPristionchus pacificus, I present a simplified workflow for the analysis of whole-genome data from mutant lines and corresponding mapping panels. Individual components are based on well-maintained and widely used software packages and are extended by 50 lines of code for the analysis and visualization of allele frequencies. The effectiveness of this workflow is demonstrated by an application to recently generated data of aP. pacificusmutant line, where it reduced the number of candidate mutations from an initial set of 3,500 single nucleotide variants to ten.
Encoding multiple virtual signals in DNA barcodes with single-molecule FRET
Authors: Kim Sung Hyun , Kim Hyunwoo , Jeong Hawoong , Yoon Tae-Young
Published: November 2020

DNA barcoding provides a way to label a huge number of different biological molecules using the extreme programmability in DNA sequence synthesis. Fluorescence imaging is an easy-to-access method to detect individual DNA barcodes, which can be scaled up to a massively high-throughput format. Large overlaps between emission spectra of fluorescence dyes, however, severely limit the numbers of DNA barcodes–and thus its signal space–that can be detected in a simultaneous manner. We here demonstrate the use of single-molecule fluorescence resonance energy transfer (FRET) to encode virtual signals in DNA barcodes using conventional two-color fluorescence microscopy. By optimizing imaging and biochemistry conditions for weak hybridization events for DNA barcodes, we markedly enhanced accuracy in our determination of the efficiency by which single-molecule FRET occurred. This allowed us to unambiguously differentiate six DNA barcodes exhibiting different FRET values without involving probe sequence exchanges. Our method can be directly incorporated with previous DNA barcode techniques, and may thus be widely adopted to expand the signal space of the DNA barcode techniques.
DarkQ: Continuous genomic monitoring using message queues
Authors: Viehweger A. , Brandt C. , Hölzer M.
Published: November 2020

Motivation

Newly sequenced genomes are often not noticed by potential stakeholders because submission to public databases is delayed, and search options are limited. However, the discovery of genomes can be vital: In pathogen outbreaks, fast updates are essential to coordinate containment efforts and prevent spread.

Results

Here we introduce DarkQ, a message queue that allows for instant sharing and discovery of genomes.

Availability

DarkQ is released under the BSD-2 license atgithub.com/phiweger/darkq.
The population genomics of transposable element activation in the highly repressive genome of an agricultural pathogen
Authors: Pereira Danilo , Oggenfuss Ursula , McDonald Bruce A. , Croll Daniel
Published: November 2020

The activity of transposable elements (TEs) can be an important driver of genetic diversity with TE-mediated mutations having a wide range of fitness consequences. To avoid deleterious effects of TE activity, some fungi evolved highly sophisticated genomic defences to reduce TE proliferation across the genome. Repeat-induced point (RIP) mutations is a fungal-specific TE defence mechanism efficiently targeting duplicated sequences. The rapid accumulation of RIP mutations is expected to deactivate TEs over the course of a few generations. The evolutionary dynamics of TEs at the population level in a species with highly repressive genome defences is poorly understood. Here, we analyze 366 whole-genome sequences ofParastagonospora nodorum, a fungal pathogen of wheat with efficient RIP. A global population genomics analysis revealed high levels of genetic diversity and signs of frequent sexual recombination. Contrary to expectations for a species with RIP, we identified recent TE activity in multiple populations. The TE composition and copy numbers showed little divergence among global populations regardless of the demographic history. Miniature inverted-repeat transposable elements (MITEs) and terminal repeat retrotransposons in miniature (TRIMs) were largely underlying recent intra-species TE expansions. We inferred RIP footprints in individual TE families and found that recently active, high-copy TEs have possibly evaded genomic defences. We find no evidence that recent positive selection acted on TE-mediated mutations rather that purifying selection maintained new TE insertions at low insertion frequencies in populations. Our findings highlight the complex evolutionary equilibria established by the joint action of TE activity, selection and genomic repression.

Data Summary

All Illumina sequence data is available from the NCBI SRA BioProject numbers PRJNA606320, PRJNA398070 and PRJNA476481 (https://www.ncbi.nlm.nih.gov/bioproject). The Methods and Supplementary Figures S1-S11 and Supplementary Tables S1-S4 provide all information on strain locations and outcomes of genome analyses.
Modelling Citrus Huanglongbing Spread in Scenarios involving Alternative Hosts, Vector Populations and Removal of Symptomatic Plants
Authors: Ternes Sônia , Vilamiu Raphael G. d’A. , Moreira Alécio S. , Rossi Marcelo , de C. Santos Tâmara T. , Laranjeira Francisco F.
Published: November 2020

Huanglongbing (HLB, ex-greening) is the most devastating citrus disease around the world. We modelled HLB spread in scenarios with different populational levels of the main alternative host (Murraya paniculata) andDiaphorina citriKuwayama, vector of HLB associated bacteria; and removal of HLB-symptomatic plants. A compartmental deterministic mathematical model was built for representing the HLB dynamics in the Reconcavo Baiano, Bahia State, Brazil. The model encompasses delays on latency and incubation disease periods and on theD. citrinymphal stages. The simulations indicated that the presence of alternative hosts at low proportion would not play a crucial role in HLB dynamics in situations of poorD. citrimanagement, regardless of HLB-symptomatic plants eradication. Symptomatic citrus plants contribute more to increase the HLB-incidence than the alternative host in scenarios without a suitableD. citrimanagement.
MetamORF: A repository of unique short Open Reading Frames identified by both experimental and computational approaches for gene-level and meta-analysis
Authors: Choteau Sebastien A. , Wagner Audrey , Pierre Philippe , Spinelli Lionel , Brun Christine
Published: November 2020

The development of high-throughput technologies revealed the existence of non-canonical short open reading frames (sORFs) on most eukaryotic RNAs. They are ubiquitous genetic elements highly conserved across species and suspected to be involved in numerous cellular processes. MetamORF (http://metamorf.hb.univ-amu.fr/) aims to provide a repository of unique sORFs identified in the human and mouse genomes with both experimental and computational approaches. By gathering publicly available sORF data, normalizing it and summarizing redundant information, we were able to identify a total of 1,162,675 unique sORFs. Despite the usual characterization of ORFs as short, upstream or downstream, there is currently no clear consensus regarding the definition of these categories. Thus, the data has been reprocessed using a normalized nomenclature. MetamORF enables new analyses at loci, gene, transcript and ORF levels, that should offer the possibility to address new questions regarding sORF functions in the future. The repository is available through an user-friendly web interface, allowing easy browsing, visualization, filtering over multiple criteria and export possibilities. sORFs could be searched starting from a gene, a transcript, an ORF ID, or looking in a genome area. The database content has also been made available through track hubs at UCSC Genome Browser.
Compensation Strategies for Bioelectric Signal Changes in Chronic Selective Nerve Cuff Recordings: A Simulation Study
Authors: Sammut Stephen , Koh Ryan G.L. , Zariffa José
Published: November 2020

Peripheral nerve interfaces (PNIs) allow us to extract motor, sensory and autonomic information from the nervous system and use it as control signals in neuroprosthetic and neuromodulation applications. Recent efforts have aimed to improve the recording selectivity of PNIs, including by using spatiotemporal patterns from multi-contact nerve cuff electrodes as input to a convolutional neural network (CNN). Before such a methodology can be translated to humans, its performance in chronic implantation scenarios must be evaluated. In this simulation study, approaches were evaluated for maintaining selective recording performance in the presence of two chronic implantation challenges: the growth of encapsulation tissue and rotation of the nerve cuff electrode. Performance over time was examined in three conditions: training the CNN at baseline only, supervised re-training with explicitly labeled data at periodic intervals, and a semi-supervised self-learning approach. This study demonstrated that a selective recording algorithm trained at baseline will likely fail over time due to changes in signal characteristics resulting from the chronic challenges. Results further showed that periodically recalibrating the selective recording algorithm can maintain its performance over time, and that a self-learning approach has the potential to reduce the frequency of recalibration.
Protein-Protein Interactions Shape Genomic Autoimmunity in the Adaptively-Evolving Rhino-Deadlock-Cutoff (RDC) Complex
Authors: Kelleher Erin S.
Published: November 2020

The piRNA pathway is a genomic defense system that controls the movement of transposable elements (TEs) through transcriptional and post-transcriptional silencing. While TE defense is critical to ensuring germline genome integrity, it is equally critical that the piRNA pathway avoids autoimmunity in the form of silencing host genes. Ongoing cycles of selection for expanded control of invading TEs, followed by selection for increased specificity to reduce impacts on host genes, are proposed to explain the frequent signatures of adaptive evolution among piRNA pathway proteins. However, empirical tests of this model remain limited, particularly with regards to selection against genomic autoimmunity.

I examined three adaptively evolving piRNA proteins, Rhino, Deadlock and Cutoff, for evidence of interspecific divergence in autoimmunity betweenDrosophila melanogasterandD. simulans. I tested a key prediction of the autoimmunity hypothesis: that foreign heterospecific piRNA proteins will exhibit enhanced autoimmunity, due to the absence of historical selection against off-target effects. Consistent with this prediction, full-lengthD. simulansCutoff, as well as theD. simulanshinge domain of Rhino, exhibit expanded regulation ofD. melanogastergenes. I further demonstrate that this autoimmunity is dependent on known incompatibilities betweenD. simulansproteins or domains and their interacting partners inD. melanogaster. My observations reveal that the same protein-protein interaction domains that are interfaces of adaptive evolution in Rhino and Cutoff also determine their potential for autoimmunity.
Functional phenomics and genetics of the root economics space in winter wheat using high-throughput phenotyping of respiration and architecture
Authors: Guo Haichao , Ayalew Habtamu , Seethepalli Anand , Dhakal Kundan , Griffiths Marcus , Ma Xue-Feng , York Larry M.
Published: November 2020

The root economics space is a useful framework for plant ecology, but rarely considered for crop ecophysiology. In order to understand root trait integration in winter wheat, we combined functional phenomics with trait economic theory utilizing genetic variation, high-throughput phenotyping, and multivariate analyses.

We phenotyped a diversity panel of 276 genotypes for root respiration and architectural traits using a novel high-throughput method for CO2flux and the open-source software RhizoVision Explorer for analyzing scanned images.

We uncovered substantial variation for specific root respiration (SRR) and specific root length (SRL), which were primary indicators of root metabolic and construction costs. Multiple linear regression estimated that lateral root tips had the greatest SRR, and the residuals of this model were used as a new trait. SRR was negatively correlated with plant mass. Network analysis using a Gaussian graphical model identified root weight, SRL, diameter, and SRR as hub traits. Univariate and multivariate genetic analyses identified genetic regions associated with aspects of the root economics space, with underlying gene candidates.

Combining functional phenomics and root economics is a promising approach to understand crop ecophysiology. We identified root traits and genomic regions that could be harnessed to breed more efficient crops for sustainable agroecosystems.
Lost in translation: the pitfalls of Ensembl Gene annotations between human genome assemblies and their impact on diagnostics
Authors: Abdallah Mohammed O.E , Koko Mahmoud , Ramesar Raj
Published: November 2020

Background

The GRCh37 human genome assembly is still widely used in genomics despite the fact an updated human genome assembly (GRCh38) has been available for many years. A particular issue with relevant ramifications for clinical genetics currently is the case of the GRCh37 Ensembl gene annotations which has been archived, and thus not updated, since 2013. These Ensembl GRCh37 gene annotations are just as ubiquitous as the former assembly and are the default gene models used and preferred by the majority of genomic projects internationally. In this study, we highlight the issue of genes with discrepant annotations, that have been recognized as protein coding in the new but not the old assembly. These genes are ignored by all genomic resources that still rely on the archived and outdated gene annotations. Moreover, the majority if not all of these discrepant genes (DGs) are automatically discarded and ignored by all variant prioritization tools that rely on the GRCh37 Ensembl gene annotations.

Methods

We performed bioinformatics analysis identifying Ensembl genes with discrepant annotations between the two most recent human genome assemblies, hg37, hg38, respectively. Clinical and phenotype gene curations have been obtained and compared for this gene set. Furthermore, matching RefSeq transcripts have also been collated and analyzed.

Results

We found hundreds of genes (N=267) that were reclassified as “protein-coding” in the new hg38 assembly. Notably, 169 of these genes also had a discrepant HGNC gene symbol between the two assemblies. Most genes had RefSeq matches (N=199/267) including all the genes with defined phenotypes in Ensembl genes GRCh38 assembly (N=10). However, many protein-coding genes remain missing from the current known RefSeq gene models (N=68)

Conclusion

We found many clinically relevant genes in this group of neglected genes and we anticipate that many more will be found relevant in the future. For these genes, the inaccurate label of “non-protein-coding” hinders the possibility of identifying any causal sequence variants that overlap them. In addition, Important additional annotations such as evolutionary constraint metrics are also not calculated for these genes for the same reason, further relegating them into oblivion.
Beating your Neighbor to the Berry Patch
Authors: Rogers Alan R.
Published: November 2020

Foragers often compete for resources that ripen (or otherwise improve) gradually. What strategy is optimal in this situation? It turns out that there is no optimal strategy. There is no evolutionarily stable strategy (ESS), and the only Nash equilibrium (NE) is unstable: strategies similar to the NE can always invade. But in spite of this instability, the NE is predictive. If harvesting attempts are costly or there are many competitors, the process tends to remain near the unstable NE. In this case, the resource often goes unharvested. Harvesting attempts—when they happen at all—usually occur when the resource is barely ripe enough to offset costs. The more foragers there are, the lower the chance that the resource will be harvested and the greater its mean value when harvested. This counterintuitive behavior is exhibited not only by theoretical models and computer simulations, but also by human subjects in an experimental game.
StrongestPath: a Cytoscape application for protein-protein interaction analysis
Authors: Mousavian Zaynab , Khodabandeh Mehran , Sharifi-Zarchi Ali , Nadafian Alireza , Mahmoudi Alireza
Published: November 2020

Background

StrongestPath is a Cytoscape 3 application that enables to look for one or more cascades of interactions connecting two single or groups of proteins in a collection of protein-protein interaction (PPI) network or signaling network databases. When there are different levels of confidence over the interactions, it is able to process them and identify the cascade of interactions having the highest total confidence score. Given a set of proteins, StrongestPath can extract and show the network of interactions among them from the given databases, and expand the network by adding new proteins having the most interactions with highest total confidence to the current proteins. The application can also identify any activation or inhibition regulatory paths between two distinct sets of transcription factors and target genes. This application can be either used with a set of built-in human and mouse PPI or signaling databases, or any user-provided database for some organism.

Results

Our results on 12 signaling pathways from the NetPath database demonstrate that the application can be used for indicating proteins which may play significant roles in the middle of the pathway by finding the strongest path(s) in the PPI or signaling network.

Conclusion

Easy access to multiple public large databases, generating output in a short time, addressing some key challenges in one platform and providing a user-friendly graphical interface make the StrongestPath easy to use.
Accumbens D2-MSN hyperactivity drives behavioral supersensitivity
Authors: Kruyer Anna , Parilla-Carerro Jeffrey , Powell Courtney , Brandt Lasse , Gutwinski Stefan , Angelis Ariana , Chalhoub Reda , Amato Davide
Published: November 2020

Antipsychotic-induced behavioral supersensitivity is a problematic consequence of long-term treatment with antipsychotic drugs and is characterized by emergence of refractory symptoms and dyskinesias. The underlying mechanisms are unknown, and no rational approaches exist to prevent or reverse antipsychotic-induced supersensitivity. Here we describe major adaptations impacting populations of striatal medium spiny neurons (MSNs) during the development of behavioral supersensitivity and reveal a prominent role played by D2 receptor expressing MSNs. We show that enhanced D2-MSN activity underlies several symptoms spanning from psychostimulant sensitization, to antipsychotic treatment resistance and drug addiction. Our data warn against severe adverse events following antipsychotic treatment discontinuation and offer insight that may inform therapeutic approaches to overcome antipsychotic-induced supersensitivity.
Developmental Single-cell transcriptomics in theLytechinus variegatusSea Urchin Embryo
Authors: Massri Abdull J. , Greenstreet Laura , Afanassiev Anton , Escobar Alejandro Berrio , Wray Gregory M. , Schiebinger Geoffrey , McClay David R.
Published: November 2020

Here we employed scRNA-seq coupled with computational approaches to examine molecular changes in cells during specification and differentiation. We examined the first 24 hours of development of the sea urchinLytechinus variegatus(Lv) with 18 time points during which the embryo develops to the larval stage. Using Waddington-OT, the time points were computationally “stitched” together to calculate developmental trajectories. Skeletogenic cells displayed the expected immediate early divergence while other lineages diverged asynchronously, with many cells retaining an intermediate specification status until late in gastrulation. TheLv-scRNA-seq dataset was compared to the developmental Gene Regulatory Network (dGRN) model of specification inStrongylocentrotus purpuratus(Sp). 79 of 80 genes (98%) in that dGRN are present in theLv-scRNA-seq dataset, and expressed in the correct lineages in which the dGRN circuits operate. Surprisingly, however, many heterochronies in timing of first expression of dGRN genes have evolved between the two species. Replotting the two dGRNs with precise attention to time of expression revealed a number of feedback inputs that likely buffer the dGRNs, allowing them to maintain function in the face of accumulating heterochronies.

Summary statement

The early development of the sea urchin embryo was followed using scRNA-seq plus computational methods to trace lineage diversifications. These were matched to gene regulatory network changes over time.