bluuebunny/crossref_metadata_2025 huggingface dataset:
Dopamine signaling in wake promoting clock neurons is not required for the normal regulation of sleep inDrosophila
Authors: Fernandez-Chiappe Florencia , Hermann-Luibl Christiane , Peteranderl Alina , Reinhard Nils , Hieke Marie , Selcho Mareike , Shafer Orie T. , Muraro Nara I. , Helfrich-Förster Charlotte
Published: May 2020

Dopamine is a wakefulness promoting neuromodulator in mammals and fruit flies. InD. melanogaster, the network of clock neurons that drives sleep/activity cycles comprises both wake and sleep promoting cell types, indicating that the sleep-wake circuitry is intimately linked to the circadian clock. The large and small ventrolateral neurons (l-LNvs and s-LNvs) have been identified as wake-promoting neurons within the clock neuron network. The l-LNvs are innervated by dopaminergic neurons, and earlier work proposed that dopamine signaling raises cAMP levels in the l-LNvs and thus induces excitatory electrical activity (action potential firing), which results in wakefulness and inhibits sleep. Here, we test this hypothesis by combining cAMP imaging and patch-clamp recordings in isolated brains. We find that dopamine application indeed increases cAMP levels and depolarizes the l-LNvs, but surprisingly, it does not result in increased firing rates. Down-regulation of the excitatory dopamine receptor, Dop1R1 in the l-and s-LNvs, but not of Dop1R2, abolished the depolarization of l-LNvs in response to dopamine. This indicates that dopamine signals via Dop1R1 to the l-LNvs. Down-regulation of Dop1R1 or Dop1R2 receptors in the l- and s-LNvs does not affect sleep. Unexpectedly, we find a moderate decrease of daytime sleep with down-regulation of Dop1R1 and of nighttime sleep with down-regulation of Dop1R2. Since the l-LNvs do not utilize Dop1R2 receptors and the s-LNvs respond also to dopamine, we conclude that the s-LNvs are responsible for the observed decrease in nighttime sleep. In summary, dopamine signaling in the wake-promoting LNvs is not required for daytime arousal, but likely promotes nighttime sleep via the s-LNvs.

Significance statement

In insect and mammalian brains, sleep promoting networks are intimately linked to the circadian clock, and the mechanisms underlying sleep and circadian timekeeping are evolutionarily ancient and highly conserved. Here we show that dopamine, one important sleep modulator in flies and mammals, plays surprisingly complex roles in the regulation of sleep by clock containing neurons. Dopamine inhibits neurons in a central brain sleep center to promote sleep and excites wake-promoting circadian clock neurons. It is therefore predicted to promote wakefulness through both of these networks. Nevertheless, our results reveal that dopamine acting on wake promoting clock neurons promotes sleep, revealing a previously unappreciated complexity in the dopaminergic control of sleep.
Methodological priorities in assessing wild edible plant knowledge and use – a case study among the Baka in Cameroon
Authors: Gallois Sandrine , Heger Thomas , Henry Amanda G. , van Andel Tinde
Published: May 2020

Freelisting and dietary recalls are frequently used methods in ethnobotany to assess wild edible plant (WEP) knowledge and use. Though theseex-situinterviewing methods are practical to perform and may yield large datasets in a short time, they are known to be limited by the informant’s memory and cognitive bias. Alternatively, the much more laborious walk-in-the-woods method may be used, in which informants point out edible plantsin-situ. Few studies, however, examine quantitatively how these different methods influence results. In this study, we assessed how these methods capture the diversity of wild edible plant knowledge and use among the Baka, a group of forager-horticulturalists from southeastern Cameroon. We show that within a single population, and when data on consumption frequency are collected simultaneously, the walk-in-the-woods method results in more detailed information of WEP knowledge and use than do freelisting or dietary recalls. Ourin-situmethod yielded 91 species of WEP, much more than theex-situmethods of freelisting (34 spp.) and dietary recalls (12 spp.). Our results imply that previous studies based only onex situsurveys may have underestimated the importance of WEP for local communities. We propose that future studies on WEP knowledge and use frequency should rely on mixed methods, taking anin-situmethod as the starting point of their approach.
Non-denaturing bisulfite treatment and single-molecule real-time sequencing reveals d-loop footprints, their length, position and distribution
Authors: Shah Shanaya Shital , Hartono Stella , Chédin Frédéric , Heyer Wolf-Dietrich
Published: May 2020

Displacement loops (D-loops) are signature intermediates formed during homologous recombination. Numerous factors regulate D-loop formation and disruption, thereby influencing crucial aspects of DNA repair, including donor choice and the possibility of a crossover outcome. While D-loop detection methods exist, it is currently unfeasible to assess the relationship between D-loop editors and D-loop characteristics such as length and position. Here, we developed a novel in vitro assay to characterize the length and position of individual D-loop with base-pair resolution and deep coverage, while also revealing their distribution in a population. Non-denaturing bisulfite treatment modifies the cytosines on the displaced strand of the D-loop to uracil, leaving a permanent signature for the displaced strand. Subsequent single-molecule real-time sequencing uncovers the cytosine conversion patch as a D-loop footprint, revealing D-loop characteristics at unprecedented resolution. The D-loop Mapping Assay is widely applicable with different substrates and donor types and can be used to study factors that influence D-loop properties.
Rapid divergence of the copulation proteins in theDrosophila dunnigroup is associated with hybrid post-mating-prezygotic incompatibilities
Authors: Hill Tom , Rosales-Stephens Hazel-Lynn , Unckless Robert L.
Published: May 2020

Proteins involved in post-copulatory interactions between males and females are among the fastest evolving genes in many species and this has been attributed to reproductive conflict. Likely as a result, these proteins are frequently involved in cases of post-mating-prezygotic isolation between species. TheDrosophila dunnisubgroup consists of a dozen recently diverged species found across the Caribbean islands with varying levels of hybrid incompatibility. We sought to examine how post-mating-prezygotic factors are involved in isolation among members of this species group. We performed experimental crosses between species in thedunnigroup and find evidence of hybrid inviability. We also find an insemination reaction-like response preventing egg laying and leading to reduced female survival post-mating. To identify that genes may be involved in these incompatibilities, we sequenced and assembled the genomes of four species in thedunnisubgroup and looked for signals of rapid evolution between species. Despite low levels of divergence, we found evidence of rapid evolution and divergence of some reproductive proteins, specifically the seminal fluid proteins. This suggests post-mating-prezygotic isolation as a barrier for gene flow between even the most closely related species in this group and seminal fluid proteins as a possible culprit.
A large accessory genome, high recombination rates, and selection of secondary metabolite genes help maintain global distribution and broad host range of the fungal plant pathogenClaviceps purpurea
Authors: Wyka Stephen A. , Mondo Stephen J. , Liu Miao , Nalam Vamsi , Broders Kirk D.
Published: May 2020

Pangenome analyses are increasingly being utilized to study the evolution of eukaryotic organisms, which is often governed by variable gene content. While pangenomes can provide insight into polymorphic gene content, inferences about the ecological and adaptive potential of such organisms also need to be accompanied by additional supportive genomic analyses. In this study we constructed a pangenome ofClaviceps purpureafrom 24 genomes and examined the positive selection and recombination landscape of an economically important fungal organism for pharmacology and agricultural research. Together, these analyses revealed thatC. purpureahas a relatively large accessory genome (∼ 38%) that is likely maintained by high recombination rates (ρ = 0.044) and transposon mediated gene duplication. However, due to observations of relatively low transposable element (TE) content (8.8%) and a lack of variability in genome sizes, prolific TE expansion is likely controlled by these high recombination rates, which may additionally be influencing the overall trend of purifying selection across the genome. Despite this trend, we observed a strong positive selection pressure on secondary metabolite genes, particularly within the ergoline biosynthetic cluster where we also revealed that thelpsA1andlpsA2genes were the result of a recombination event. These results indicate that secondary metabolites are primary factors affecting the diversification of the species into new ecological niches and help maintain its global distribution and broad host range. These results showcase the use of selection and recombination landscapes to identify mechanisms contributing to pangenome structure and primary factors influencing the evolution of an organism.

Author Summary

The use of genomic data to better understand the lifestyle of a pathogen and its relationship with its host has expanded our ability to investigate the evolutionary history of these organisms. This in turn has allowed us to decipher and understand the ambiguity surrounding the true nature of the fungal plant pathogenClaviceps purpurea. By combining three different types of broad genomic analyses we identified primary factors affecting the evolution and adaptive potential of this pathogen; particularly a large accessory genome, high recombination rates, and positive selection of genes associated with stress tolerance. These factors likely contribute to the pathogen’s global distribution and broad host range. Furthermore, these findings will influence the direction of future research into optimal control methods.
Chronic high dietary sucrose induces sexually dimorphic metabolic adaptations in liver and adipose tissue
Authors: Stephenson Erin J , Stayton Amanda S , Sethuraman Aarti , Rao Prahlad K , Gomes Charles Klazer , Mulcahy Molly C , McAllan Liam , Puchowicz Michelle A , Pierre Joseph F , Bridges Dave , Han Joan C
Published: May 2020

Almost all effective treatments for non-alcoholic fatty liver disease (NAFLD) involve reduction of adiposity, which suggests the metabolic axis between liver and adipose tissue is essential to NAFLD development. Since excessive dietary sugar intake may be an initiating factor for NAFLD, we have characterized the metabolic effects of liquid sucrose intake at concentrations relevant to typical human consumption in mice. We report that sucrose intake induces sexually dimorphic effects in liver, adipose tissue, and the microbiome; differences concordant with steatosis severity. We show that when steatosis is decoupled from impairments in insulin responsiveness, sex is a moderating factor that influences sucrose-driven lipid storage and the contribution ofde novofatty acid synthesis to the overall hepatic triglyceride pool. Our findings provide physiologic insight into how sex influences the regulation of adipose-liver crosstalk and highlight the importance of extrahepatic metabolism in the pathogenesis of diet-induced steatosis and NAFLD.
Structural Basis for Negative Regulation of ABA Signaling by ROP11 GTPase
Authors: Zhao Chuankai , Shukla Diwakar
Published: May 2020

Abscisic acid (ABA) is an essential plant hormone responsible for plant development and stress responses. Recent structural and biochemical studies have identified the key components involved in ABA signaling cascade, including PYR/PYL/RCAR receptors, protein phosphatases PP2C, and protein kinases SnRK2. The plant-specific, Roh-like (ROPs) small GTPases are negative regulators of ABA signal transduction by interacting with PP2C, which can shut off “leaky” ABA signal transduction caused by constitutive activity of monomeric PYR/PYL/RCAR receptors. However, the structural basis for negative regulation of ABA signaling by ROP GTPases remain elusive. In this study, we have utilized large-scale coarse-grained (10.05 milliseconds) and all-atom molecular dynamics simulations and standard protein-protein binding free energy calculations to predict the complex structure of AtROP11 and phosphatase AtABI1. In addition, we have elucidated the detailed complex association pathway and identified the critical residue pairs in AtROP11 and AtABI1 for complex stability. Overall, this study has established a powerful framework of using large-scale molecular simulations to predict unknown protein complex structures and elucidated the molecular mechanism of the negative regulation of ABA signal transduction by small GTPases.
Perforin-2 limits pathogen proliferation at the maternal-fetal interface
Authors: Gayle Petoria , McGaughey Vanessa , Hernandez Rosmely , Wylie Marina , Colletti Rachel C. , Nguyen Ka Lam , Arons Marshall , Padula Laura , Strbo Natasa , Schesser Kurt
Published: May 2020

Placental immune responses are highly regulated to strike a balance between protection and tolerance. For relatively mild infections, protection encompasses both the mother and fetus; however, during worsening conditions, protection becomes exclusively reserved for the mother. Previously, we and others have shown that the host factor Perforin-2 plays a central role in protecting mice and cells against infection. Here, we analyzed Perforin-2 activity in the mouse placenta to determine whether Perforin-2 plays a similarly protective role. We show that Perforin-2 is critical for inhibitingListeria monocytogenescolonization of the placenta and fetus and that this protection is due to both maternal and fetal-encoded Perforin-2.Perforin-2mRNA is readily detectable in individual immune cells of the decidua and these levels are further enhanced specifically in decidual macrophages during high-dose infections that result in fetal expulsion. Unexpectedly, inductive Perforin-2 expression in decidual macrophages did not occur during milder infections in which fetal viability remained intact. This pattern of expression significantly differed from that observed in splenic macrophages in which inductive Perforin-2 expression was observed in both high and mild infection conditions. In the placenta, inductive Perforin-2 expression in decidual macrophages was co-incident with their polarization from a M2 to M1 phenotype that normally occurs in the placenta during high-burden infections. Our results suggest that Perforin-2 is part of a host response that is protective either for both the mother and fetus in milder infections or exclusively for the mother during high-dose infections.
Transcriptome and epigenome diversity and plasticity of muscle stem cells following transplantation
Authors: Evano Brendan , Gill Diljeet , Hernando-Herraez Irene , Comai Glenda , Stubbs Thomas M. , Commere Pierre-Henri , Reik Wolf , Tajbakhsh Shahragim
Published: May 2020

Adult skeletal muscles are maintained during homeostasis and regenerated upon injury by muscle stem cells (MuSCs). A heterogeneity in self-renewal, differentiation and regeneration properties has been reported for MuSCs based on their anatomical location. Although MuSCs derived from extraocular muscles (EOM) have a higher regenerative capacity than those derived from limb muscles, the molecular determinants that govern these differences remain undefined. Here we show that EOM and limb MuSCs have distinct DNA methylation signatures associated with enhancers of location-specific genes, and that the EOM transcriptome is reprogrammed following transplantation into a limb muscle environment. Notably, EOM MuSCs expressed host-site specific positionalHoxcodes after engraftment and self-renewal within the host muscle. However, about 10% of EOM-specific genes showed engraftment-resistant expression, pointing to cell-intrinsic molecular determinants of the higher engraftment potential of EOM MuSCs. Our results underscore the molecular diversity of distinct MuSC populations and molecularly define their plasticity in response to microenvironmental cues. These findings provide insights into strategies designed to improve the functional capacity of MuSCs in the context of regenerative medicine.
TET1 dioxygenase is required for FOXA2-associated chromatin remodeling in pancreatic beta-cell differentiation
Authors: Li Jianfang , Wu Xinwei , Lee Minjung , Ke Jie , Lan Qingping , Li Jia , Huang Yun , Sun De-Qiang , Xie Ruiyu
Published: May 2020

Existing knowledge of the role of epigenetic modifiers in pancreas development has exponentially increased. However, the function of TET dioxygenases in pancreatic endocrine specification remains obscure. We set out to tackle this issue using a human embryonic stem cell (hESC) differentiation system, in whichTET1/TET2/TET3triple knock-out cells display severe defects in pancreatic β-cell specification. Integrative whole-genome analysis identifies unique cell-type-specific hypermethylated regions (hyper-DMRs) displaying reduced chromatin activity and remarkable enrichment of FOXA2, a pioneer transcription factor essential for pancreatic endoderm specification. Intriguingly, TET depletion leads to significant changes in FOXA2 binding at pancreatic progenitor stage, in which gene loci with decreased FOXA2 binding features low levels of active chromatin modifications and enriches for bHLH motifs. Transduction of full-lengthTET1but not the TET1-catalytic-domain inTET-deficient cells effectively rescues β-cell differentiation accompanied by restoringPAX4hypomethylation. Taking these findings together with the defective generation of functional β-cells upon TET1-inactivation, our study unveils an essential role of TET1-dependent demethylation in establishing β-cell identity. Moreover, we discover a physical interaction between TET1 and FOXA2 in endodermal lineage intermediates, which provides a new mechanistic clue regarding the complex crosstalk between TET dioxygenases and pioneer transcription factors in epigenetic regulation during pancreas specification.
Trends of SARS-CoV-2 infection worldwide: Role of population density, age structure, and climate on transmission and case fatality
Authors: Endailalu Tewodros B , Hadgu Fitsum W
Published: May 2020

Introduction
The disease transmission pattern of COVID19 is highly heterogeneous, which suggests that the pandemic maybe driven by complex factors, which may include habitat suitability, region specific human mobility, and transmission related to susceptibility. The purpose of this study was to examine the effects of different spatial and demographic factors on COVID19 transmission and case fatality worldwide.
Methods
We assessed SARS CoV2 virus transmission and COVID19 related fatalities in 50 countries in all continents of the globe. Data from the COVID19 data repository of the Johns Hopkins Center for Systems Science and Engineering, the European center for disease control and prevention, and the World Health Organization were used to obtain the daily number of cases and organize the incidence data. Disease spread, was assessed using the reproduction number of the disease across the sampled countries. R0 package of R statistical software was used to estimate the reproduction number of the COVID19 using the exponential growth method. After computing the reproductive number of each country in the study, a multiple linear regression model was fitted by taking the R0 value as dependent variable, and latitude and population density as an independent variable. Disease severity was analyzed using the case fatality ratio of COVID19. The proportion of deaths to the total numbers of cases was meta analyzed using metaphor package of R statistical software using random effect inverse variance weighting to come up with the case fatality ratio.
Results
We found no statistically significant association between disease spread and latitude or population density. The regression model analysis that accounted for age, population density and latitude showed that age distribution remains an important driver shaping the current distribution of COVID19 cases. The relative frequency of people above 65 years old was positively correlated with the cumulative numbers of COVID19 cases as well as case fatality ratio in each country. The multiple linear regression model fitted between CFR and the three major covariates showed that, the demographic distribution of the sampled countries is strongly associated with the case fatality ratio. An increase in the elderly population proportion by 1 percent was associated with an increase in CFR by 0.32. Correlation with proportion of populations over 65 years old is concordant with the previous findings relationship between case fatality ratio and patient age.
Conclusion
This analysis provides important information that can inform the decisions of local and global health authorities. Particularly, as our study confirms that death and severity of COVID19 are associated with age, in countries with the biggest outbreaks, strategies must be employed to ensure that high risk groups, such as old people received adequate protection from COVID19.
A super-series of extracellular miRNA in cerebrospinal fluid reveals broad patterns associated with neurologic disease
Authors: Dhawan Andrew
Published: May 2020

Extracellular non-coding RNA are emerging biomarkers across diseases, as they may represent the functional state of the cells of origin, and have been robustly detected and associated with disease in many biofluids, but not yet at a large scale in cerebrospinal fluid (CSF). While there have been extracellular non-coding RNA (exmiRNA) identified in small associative studies involving the CSF and patients with neurologic conditions, much remains to be determined, including what constitutes healthy CSF. In this work, we aggregate 9 existing cohorts to define a super-series of 864 extracellular circulating microRNA (exmiRNA) samples in the CSF from patients with 16 neurologic diseases and healthy controls. Through this, we identify broad patterns of conserved expression of CSF exmiRNA in the healthy state and in neurologic diseases, and a set of robustly detectable miRNA that may be strong biomarker candidates for future studies. We show that the coexpression network of exmiRNA differs significantly between the malignant and non-malignant states, suggesting that widespread dysregulation of miRNA due to cancer can be detected in the CSF. The super series will serve as a resource for future research in CSF exncRNA biomarkers, and will continue to evolve as more data is generated in this burgeoning field.
Development and clinical application of a rapid and sensitive loop-mediated isothermal amplification test for SARS-CoV-2 infection
Authors: Hu Xuejiao , Deng Qianyun , Li Junmin , Chen Jierong , Wang Zixia , Zhang Xiqin , Fang Zhixin , Li Haijian , Zhao Yunhu , Yu Pan , Li Wenmin , Wang Xiaoming , Li Shan , Zhang Lei , Hou Tieying
Published: May 2020

Background

The SARS-CoV-2 outbreak urgently requires sensitive and convenient COVID-19 diagnostics for the containment and timely treatment of patients. We aimed to develop and validate a novel reverse transcription loop-mediated isothermal amplification (RT-LAMP) assay to detect SARS-CoV-2 in qualified laboratories and point-of-care settings.

Methods

Patients with suspected COVID-19 and close contacts were recruited from two hospitals between Jan 26 and April 8, 2020. Respiratory samples were collected and tested using the RT-LAMP assays, and the results were compared with those obtained by RT-qPCR. Samples yielding inconsistent results between these two methods were subjected to next-generation sequencing for confirmation. The RT-LAMP assay was also tested on an asymptomatic COVID-19 carrier and patients with other respiratory viral infections.

Results

Samples were collected from a cohort of 129 cases (329 nasopharyngeal swabs) and an independent cohort of 76 patients (152 nasopharyngeal swabs and sputum samples). The RT-LAMP assay was validated to be accurate (overall sensitivity and specificity: 88.89% and 99.00%; positive and negative predictive values: 94.74% and 97.78%, respectively) and diagnostically useful (positive and negative likelihood ratios: 88.89 and 0.11, respectively). RT-LAMP showed an increased sensitivity (88.89% vs 81.48%) and high consistency (kappa 0.92) compared with RT-qPCR for SARS-CoV-2 screening while requiring only constant temperature heating and visual inspection. The time required for RT-LAMP was less than 1 h from sample preparation to result. In addition, RT-LAMP was feasible for use with asymptomatic patients and did not cross-react with other respiratory pathogens.

Conclusion

The developed RT-LAMP assay offers rapid, sensitive and straightforward detection of SARS-CoV-2 infection and could aid the expansion of COVID-19 testing in the public domain and hospitals.
Neurons need no adaptation to optimally code arbitrarily complex stimuli
Authors: Forkosh Oren
Published: May 2020

Neural networks seem to be able to handle almost any task they face. This feat involves coping efficiently with different data types, at multiple scales, and with varying statistical properties. Here, we show that this so-called optimal coding can occur at the single-neuron level and does not require adaptation. Differentiator neurons, i.e., neurons that spike whenever there is an increase in the input stimuli, are capable of capturing arbitrary statistics and scale of practically any stimulus they encounter. We show this optimality both analytically and using simulations, which demonstrate how an ideal neuron can handle drastically different probability distributions. While the mechanism we present is an oversimplification of “real” neurons and does not necessarily capture all neuron types, this is also its strength since it can function alongside other neuronal goals such as data manipulation and learning. Depicting the simplicity of neural response to complex stimuli, this result may also indicate a straightforward way to improve current artificial neural networks.
Repeat length increases disease penetrance and severity in C9orf72 ALS/FTD BAC transgenic mice
Authors: Pattamatta Amrutha , Nguyen Lien , Olafson Hailey , Scotti Marina , Laboissonniere Lauren A. , Richardson Jared , Berglund J. Andrew , Zu Tao , Wang Eric.T. , Ranum Laura P.W.
Published: May 2020

C9orf72 ALS/FTD patients show remarkable clinical heterogeneity, but the complex biology of the repeat expansion mutation has limited our understanding of the disease. BAC transgenic mice were used to better understand the molecular mechanisms and repeat length effects of C9orf72 ALS/FTD. Genetic analyses of these mice demonstrate that the BAC transgene and not integration site effects cause ALS/FTD phenotypes. Transcriptomic changes in cell proliferation, inflammation and neuronal pathways are found late in disease and alternative splicing changes provide early molecular markers that worsen with disease progression. Isogenic sublines of mice with 800, 500 or 50 G4C2 repeats generated from the single-copy C9-500 line show longer repeats result in earlier onset, increased disease penetrance, and increased levels of RNA foci and RAN aggregates. These data demonstrate G4C2 repeat length is an important driver of disease and identify alternative splicing changes as early biomarkers of C9orf72 ALS/FTD.
Integration of multiple imaging platforms to uncover cardiac defects in adult zebrafish
Authors: Bensimon-Brito Anabela , Boezio Giulia L. M. , Cardeira-da-Silva João , Wietelmann Astrid , Helker Christian S. M. , Ramadass Radhan , Piesker Janett , Nauerth Arno , Mueller Clemens , Stainier Didier Y. R.
Published: May 2020

Mammalian models have been instrumental to investigate adult heart function and human disease. However, electrophysiological differences with human hearts and high costs emphasize the need for additional models. The zebrafish is a well-established genetic model to study cardiac development and function; however, analysis of cardiac phenotypes in adult specimens is particularly challenging as they are opaque. Here, we optimized and combined multiple imaging techniques including echocardiography, magnetic resonance imaging and micro-computed tomography to identify and analyze cardiac phenotypes in adult zebrafish. Usingalk5a/tgfbr1amutants as a case study, we observed morphological and functional cardiac defects, which were undetected with conventional approaches. Correlation analysis of multiple parameters revealed an association between hemodynamic defects and structural alterations of the heart, as observed clinically. Thus, we report a comprehensive and sensitive platform to identify otherwise indiscernible cardiac phenotypes in adult zebrafish, a model with clear advantages to study cardiac function and disease.
Dynamically evolving novel overlapping gene as a factor in the SARS-CoV-2 pandemic
Authors: Nelson Chase W. , Ardern Zachary , Goldberg Tony L. , Meng Chen , Kuo Chen-Hao , Ludwig Christina , Kolokotronis Sergios-Orestis , Wei Xinzhu
Published: May 2020

Understanding the emergence of novel viruses requires an accurate and comprehensive annotation of their genomes. Overlapping genes (OLGs) are common in viruses and have been associated with pandemics, but are still widely overlooked. We identify and characterizeORF3d, a novel OLG in SARS-CoV-2 that is also present in Guangxi pangolin-CoVs but not other closely related pangolin-CoVs or bat-CoVs. We then document evidence ofORF3dtranslation, characterize its protein sequence, and conduct an evolutionary analysis at three levels: between taxa (21 members ofSevere acute respiratory syndrome-related coronavirus), between human hosts (3978 SARS-CoV-2 consensus sequences), and within human hosts (401 deeply sequenced SARS-CoV-2 samples).ORF3dhas been independently identified and shown to elicit a strong antibody response in COVID-19 patients. However, it has been misclassified as the unrelated geneORF3b, leading to confusion. Our results likenORF3dto other accessory genes in emerging viruses and highlight the importance of OLGs.
A high-throughput neutralizing antibody assay for COVID-19 diagnosis and vaccine evaluation
Authors: Muruato Antonio E. , Fontes-Garfias Camila R. , Ren Ping , Garcia-Blanco Mariano A. , Menachery Vineet D. , Xie Xuping , Shi Pei-Yong
Published: May 2020

Virus neutralization remains the gold standard for determining antibody efficacy. Therefore, a high-throughput assay to measure SARS-CoV-2 neutralizing antibodies is urgently needed for COVID-19 serodiagnosis, convalescent plasma therapy, and vaccine development. Here we report on a fluorescence-based SARS-CoV-2 neutralization assay that detects SARS-CoV-2 neutralizing antibodies in COVID-19 patient specimens and yields comparable results to plaque reduction neutralizing assay, the gold standard of serological testing. Our approach offers a rapid platform that can be scaled to screen people for antibody protection from COVID-19, a key parameter necessary to safely reopen local communities.
pH-Dependent Transcriptional Profile Changes in Iron-DeficientArabidopsisRoots
Authors: Tsai Huei-Hsuan , Schmidt Wolfgang
Published: May 2020

Iron is an essential element for plants and abundantly present in most mineral soils. The mobility of iron is, however, dependent on the redox potential and hydrogen activity (pH) of the soil, factors that may limit its availability to plants in particular at alkaline pHs. Iron deficiency triggers pronounced changes in the transcriptional profile of plants, inducing processes that aid in the acquisition, uptake, and translocation of iron. How ambient pH impact the transcriptional iron deficiency response has not yet been elucidated in detail. Here, we provide an RNA-seq data set that catalogs global gene expression changes of iron-deficient plants grown at either optimal (5.5) or high (7.0) pH. A suite of 857 genes changed significantly and more than twofold in expression; only 54 genes of this suite were also differentially expressed between iron-deficient and iron-sufficient plants grown at pH 5.5. Among the high pH-responsive genes, 186 were earlier shown to be responsive to short-term transfer to low pH, 91 genes of this subset were anti-directionally regulated by high and low pH. The latter subset contained genes involved in cell wall organization, auxin homeostasis, and potential hubs of yet undefined signaling circuits. Growing iron-deficient plants at high pH also modulated the transcriptional iron deficiency response observed at pH 5.5 by compromising the enzymatic reduction of ferric chelates and favoring the production of iron-mobilizing coumarins. It is concluded that ambient pH is an important determinant of global gene expression which tunes iron acquisition to the prevailing edaphic conditions.
Examining Interspecific density-dependent dispersal in forest small mammals
Authors: Denomme-Brown Simon T. , Cottenie Karl , Falls J. Bruce , Falls E. Ann , Brooks Ronald J. , McAdam Andrew G.
Published: May 2020

The effects of conspecific densities on dispersal have been well documented. However, while positive and negative density-dependent dispersal based on conspecific densities are often shown to be the result of intraspecific competition or facilitation respectively, the effects of heterospecific densities on dispersal are examined far less frequently. This despite the potential for the analogous processes of interspecific competition and heterospecific attraction to influence dispersal. Here we use 51 years of live-trapping data on deer mouse (Peromsycus maniculatus), eastern chipmunk (Tamias striatus), red-backed vole (Myodes gapperi), and jumping mice (Napaeozapus insignisandZapus hudsonius) to examine the effects of both conspecific and heterospecific densities on dispersal frequency. In terms of conspecific densities, jumping mice were more likely to disperse from areas of low conspecific densities, while red-backed voles and chipmunks did not respond to conspecific densities in their dispersal frequencies. When considering interspecific density effects, while there were no statistically clear effects of density on dispersal frequency, the effects of chipmunk and jumping mice densities on dispersal by red-backed vole were greater than the effects of conspecific densities, with voles more likely to disperse from areas of high chipmunk densities and low jumping mice densities. Likewise, the effect of chipmunk densities on dispersal by jumping mice was greater than the conspecific density effect. Conspecific densities clearly can affect dispersal by two of these four species, but the effects of heterospecific densities on dispersal frequency are less clear. Based on effect sizes it appears that there is potential for heterospecific effects on dispersal by some species in the community, but future experimental work could elucidate the strength and causes of these relationships.
Pathways of the COVID-19 Pandemic with Human Mobility across Countries
Authors: Zhang Cheng , Qian Li-Xian , Hu Jian-Qiang
Published: May 2020

This study develops a holistic view of the novel coronavirus (COVID-19) transmission worldwide through a spatial-temporal model with network dynamics. By using a unique human mobility dataset containing 547,166 flights with a total capacity of 101,455,913 passengers among 22 countries during the past three months, we analyze the associations between international travel movement in six continents and the new infections in these countries. Results show that policymakers should move away from the previous practices that focus only on restricting hotspot areas with high transmission rates. Instead, they should develop a new holistic view of global human mobility to adjust the international movement restriction. The study highlights that international human mobility is the key to understand the transmission pathways and the small world phenomenon in the global network of COVID-19 pandemic.
A pandemic at the Tunisian scale. Mathematical modelling of reported and unreported COVID-19 infected cases
Authors: Abdeljaoued-Tej Ines
Published: May 2020

Starting from the city of Wuhan in China in late December 2019, the pandemic quickly spread to the rest of the world along the main intercontinental air routes. At the time of writing this article, there are officially about five million infections and more than 300 000 deaths. Statistics vary widely from country to country, revealing significant differences in anticipation and management of the crisis. We propose to examine the COVID-19 epidemic in Tunisia through mathematical models, which aim to determine the actual number of infected cases and to predict the course of the epidemic. As of May 11, 2020, there are officially 1032 COVID-19 infected cases in Tunisia. 45 people have died. Using a mathematical model based on the number of reported infected cases, the number of deaths, and the effect of the 18-day delay between infection and death, this study estimates the actual number of COVID-19 cases in Tunisia as 2555 cases. This paper analyses the evolution of the epidemic in Tunisia using population dynamics with an SEIR model combining susceptible cases S(t), asymptomatic infected cases A(t), reported infected cases V (t), and unreported infected cases U(t). This work measures the basic reproduction number R0, which is the average number of people infected by a COVID-19 infected person. The model predicts an R0 = 2.73. Strict containment measures have led to a significant reduction in the reproduction rate. Contact tracing and respect for isolation have an impact: at the current time, we compute that Tunisia has an Rt = 0.42 (95% CI 0.14-0.70). These values depend on physical separation and can vary over time depending on the management of suspicious cases. Their objective estimation and the study of their evolution are however necessary to understand the pandemic and to reduce their unintended damage (due to an absence of symptoms, or the confusion of certain symptoms with less contagious diseases, or unavailable or unreliable tests).
Psychological Impact of COVID-19 on Pakistani University Students and How They Are Coping
Authors: Salman Muhammad , Asif Noman , Mustafa Zia Ul , Khan Tahir Mehmood , Shehzadi Naureen , Hussain Khalid , Tahir Humera , Raza Muhammad Husnnain , Khan Muhammad Tanveer
Published: May 2020

Background

COVID-19 is spreading quickly, causing great deal of fear and unrest in the public. We aimed to assess the psychological impact of COVID-19 on university students and their coping strategies.

Methods

This web-based, cross-sectional study was conducted among students of four Pakistani higher education institutions. Google forms were used to disseminate the online questionnaire to assess anxiety (GAD-7), depression (PHQ-9), sources of distress (14-items) and the coping strategies (Brief-COPE).

Results

A total of 1134 responses (age 21.7 ± 3.5 years) were included. The frequency of students having moderate-severe anxiety and depression (score ≥ 10) were ≈ 34% and 45%, respectively. The respondents’ aged ≥ 31 years had significantly lower depression score than those below 30 years. Males had significantly less anxiety and depression scores than females. Additionally, those having a family member, friend or acquaintance infected with the disease had significantly higher anxiety score. The main sources of distress were the changes in daily life due to the ongoing pandemic. Regarding coping strategies, majority of respondents were found to have adopted religious/spiritual coping (6.45 ± 1.68) followed by acceptance (5.58 ± 1.65).

Conclusions

COVID-19 have significant adverse impact on students’ mental health. The most frequent coping strategy adopted by them are religious/spiritual coping, acceptance, self-distraction and active coping. It is suggested that mental health of students should not be neglected during epidemics.
Forecasting trajectories of an emerging epidemic with mathematical modeling in an online dashboard: The case of COVID-19
Authors: Młocek Wojciech , Lew Robert
Published: May 2020

We offer an efficient mathematical model for forecasting the course of an emerging epidemic, with COVID-19 as a use case. We predict the future course of confirmed cases in a number of countries, and present the results in a modern online dashboard, updated daily and accessible to the public.
Immunity after COVID-19: protection or sensitization?
Authors: Danchin Antoine , Turinici Gabriel
Published: May 2020

Motivated by historical and present clinical observations, we discuss the possible unfavorable evolution of the immunity (similar to documented antibody-dependent enhancement scenarios) after a first infection with COVID-19. More precisely we ask the question of how the epidemic outcomes are affected if the initial infection does not provide immunity but rather sensitization to future challenges. We first provide background comparison with the 2003 SARS epidemic. Then we use a compartmental epidemic model structured by immunity level that we fit to available data; using several scenarios of the fragilization dynamics, we derive quantitative insights into the additional expected numbers of severe cases and deaths.
The role of school enjoyment in the association between externalising and depressive symptoms and academic attainment: findings from a UK prospective cohort study
Authors: Cadman Tim , Hughes Amanda , Wright Caroline , López-López José A , Morris Tim , Rice Frances , Smith George Davey , Howe Laura D
Published: May 2020

Previous research on the relationship between children’s externalising and depressive symptoms, experience of school, and later academic attainment is inconclusive. The present study uses data from the Avon Longitudinal Study of Parents and Children (n=6,409) to investigate bidirectional associations between school experience (enjoyment and connectedness) and externalising and depressive symptoms at age 10-11 and 13-14. We also investigate the relationship between school experience and academic attainment at 16 and test whether school experience mediates associations of externalising and depressive symptoms with later attainment. A cross-lagged structural equation model was employed. Externalising and depressive symptoms at 10-11 were negatively associated with school connectedness at 13-14 (externalizing: standardised β=−0.13, CI: −0.17, −0.08; depressive: β=−0.06, CI: −0.11, 0.01), and with school enjoyment at 13-14 (externalising: β=−0.08, CI: −0.13, −0.03; depressive β=−0.04, −0.08, 0.03). School enjoyment at 13-14 was positively associated with attainment at 16 (β=0.10, CI: 0.04, 0.15), and partially mediated associations between externalising and depressive symptoms at 10-11 and attainment at 16 (externalising: proportion mediated; 4.7%, CI: 0.7, 10.1, depressive: proportion mediated 2.2%, I: −1.5, 5.9). School enjoyment is a potentially modifiable risk factor that may affect educational attainment of adolescents with depressive and externalising symptoms.
Genomic Epidemiology ofEscherichia coliIsolates from a Tertiary Referral Center in Lilongwe, Malawi
Authors: Tegha Gerald , Ciccone Emily J. , Krysiak Robert , Kaphatika James , Chikaonda Tarsizio , Ndhlovu Isaac , van Duin David , Hoffman Irving , Juliano Jonathan J. , Wang Jeremy
Published: May 2020

Antimicrobial resistance (AMR) is a global threat, including in sub-Saharan Africa. However, little is known about the genetics of resistant bacteria in the region. In Malawi, there is growing concern about increasing rates of antimicrobial resistance to most empirically used antimicrobials. The highly drug resistantEscherichia colisequence type (ST) 131, which is associated with the extended spectrum β-lactamaseblaCTX-M-15, has been increasing in prevalence globally. Previous data from isolates collected between 2006-2013 in southern Malawi have shown the presence of ST131 and theblaCTX-M-15gene in the country. We performed whole genome sequencing (WGS) of 58 clinicalE. coliisolates at Kamuzu Central Hospital, a tertiary care center in central Malawi, collected from 2012-2018. We used Oxford Nanopore Technologies (ONT) sequencing, which was performed in Malawi. We show that ST131 has become more prevalent (14.9% increasing to 32.8%) and that theblaCTX-M-15gene is occurring at a higher frequency (21.3% increasing to 44.8%). Phylogenetics show isolates are highly related between the central and southern geographic regions and confirm that ST131 isolates are contained in a single group consistent with recent expansion. All AMR genes, includingblaCTX-M-15, were widely distributed across sequence types. We also identified an increased number of ST410 isolates, which in this study tend to carry a plasmid-located copy ofblaCTX-M-15gene at a higher frequency thanblaCTX-M-15occurs in ST131. This study confirms the expanding nature of ST131 and the wide distribution of theblaCTX-M-15gene in Malawi. We also highlight the feasibility of conducting longitudinal genomic epidemiology studies of important bacteria with the sequencing done on site using a nanopore platform that requires minimal infrastructure.

DATA SUMMARY

The sequencing data used for this analysis is available in public data repositories. Information on the sequences used is provided in Supplementary Table 2.
Proper names from story recall are associated with beta-amyloid in cognitively unimpaired adults at risk for Alzheimer's disease
Authors: Mueller Kimberly D , Koscik Rebecca , Du LianLian , Bruno Davide , Jonaitis Erin M , Koscik Audra Z , Christian Bradley , Betthauser Tobey J , Chin Nathaniel , Hermann Bruce P , Johnson Sterling C.
Published: May 2020

Due to advances in the early detection of Alzheimer's disease (AD) biomarkers including beta-amyloid (Aβ), neuropsychological measures that are sensitive to concurrent, subtle changes in cognition are critically needed. Story recall tasks have shown sensitivity to early memory declines in persons with Mild Cognitive Impairment and early stage dementia, as well as in persons with autosomal dominantly inherited AD up to 10 years prior to a dementia diagnosis. However, the evidence is inconclusive regarding relationships between evidence of Aβ and story recall measures. Because story recall tasks require the encoding and delayed retrieval of several lexical-semantic categories, such as proper names, verbs, and numerical expressions, and because lexical categories have been shown to be differentially impaired in persons with MCI, we focused on item-level analyses of lexical-semantic retrieval from a quintessential story recall task, Logical Memory from the Wechsler Memory Scale. Our objective was to investigate whether delayed recall of lexical categories (proper names, verbs and/or numerical expressions), as well as the traditional total score measure, was associated with 'preclinical AD,' or cognitively unimpaired adults with positive Aβ deposition on positron emission tomography (PET) neuroimaging using Pittsburgh Compound B. We developed an item-level scoring system, in which we parsed items into lexical categories and examined the immediate and delayed recall of these lexical categories from 217 cognitively unimpaired participants from the Wisconsin Registry for Alzheimer's Prevention. We performed binary logistic regression models with story recall score as predictor and Aβ status (positive/negative) as the outcome. Using baseline Logical Memory data, proper names from delayed story recall were significantly associated with Aβ status, such that participants who recalled more proper names were less likely to be classified as PiB(+) (odds ratio = .58, p=.01). None of the other story recall variables, including total score, were associated with PiB status. Secondary analyses determined that immediate recall of proper names was not significantly associated with Aβ, suggesting a retrieval deficit rather than that of encoding. The present findings suggest that lexical semantic retrieval measures from existing story recall tasks may be sensitive to Aβ deposition, and may provide added utility to a widely-used, long-standing neuropsychological test for early detection of cognitive decline on the AD continuum.