bluuebunny/crossref_metadata_2025 huggingface dataset:
Species richness promotes ecosystem carbon storage: evidence from biodiversity-ecosystem functioning experiments
Authors: Xu Shan , Eisenhauer Nico , Ferlian Olga , Zhang Jinlong , Zhou Guoyi , Lu Xiankai , Liu Chengshuai , Zhang Deqiang
Published: November 2020

Plant diversity has a strong impact on a plethora of ecosystem functions and services, especially ecosystem carbon (C) storage. However, the potential context-dependency of biodiversity effects across ecosystem types, environmental conditions and carbon pools remains largely unknown. In this study, we performed a meta-analysis by collecting data from 95 biodiversity-ecosystem functioning (BEF) studies across 60 sites to explore the effects of plant diversity on different C pools, including aboveground and belowground plant biomass, soil microbial biomass C and soil C content across different ecosystem types. The results showed that ecosystem C storage was significantly enhanced by plant diversity, with stronger effects on aboveground biomass than on soil C content. Moreover, the response magnitudes of ecosystem C storage increased with the level of species richness and experimental duration across all ecosystems. The effects of plant diversity were more pronounced in grasslands than in forests. Furthermore, the effects of plant diversity on belowground plant biomass increased with aridity index in grasslands and forests, suggesting that climate change might modulate biodiversity effects, which are stronger under wetter conditions but weaker under more arid conditions. Taken together, these results provide novel insights into the important role of plant diversity in ecosystem C storage across critical C pools, ecosystem types and environmental contexts.
Limited phenological and pollinator-mediated isolation among selfing and outcrossing
Arabidopsis lyrata
populations
Authors: Gorman Courtney E. , Bond Lindsay , van Kleunen Mark , Dorken Marcel E. , Stift Marc
Published: November 2020

Transitions from outcrossing to selfing have been a frequent evolutionary shift in plants and clearly play a role in species divergence. However, many questions remain about the initial mechanistic basis of reproductive isolation during the evolution of selfing. For instance, how important are pre-zygotic pre-pollination mechanisms (e.g. changes in phenology and pollinator visitation) in maintaining reproductive isolation between newly arisen selfing populations and their outcrossing ancestors? To test whether changes in phenology and pollinator visitation isolate selfing populations of
Arabidopsis lyrata
from outcrossing populations, we conducted a common garden experiment with plants from selfing and outcrossing populations as well as their between-population hybrids. Specifically, we asked whether there was isolation between outcrossing and selfing plants and their between-population hybrids through differences in (1) the timing or intensity of flowering; and/or (2) pollinator visitation. We found that phenology largely overlapped between plants from outcrossing and selfing populations. There were also no differences in pollinator preference related to mating system. Additionally, pollinators preferred to visit flowers on the same plant rather than exploring nearby plants, creating a large opportunity for self-fertilization. Overall, this suggests that pre-zygotic pre-pollination mechanisms do not strongly reproductively isolate plants from selfing and outcrossing populations of
Arabidopsis lyrata
.
Strategies for integrating disparate social information
Authors: Molleman Lucas , Tump Alan N. , Gradassi Andrea , Herzog Stefan , Jayles Bertrand , Kurvers Ralf H. J. M. , van den Bos Wouter
Published: November 2020

Social information use is widespread in the animal kingdom, helping individuals rapidly acquire useful knowledge and adjust to novel circumstances. In humans, the highly interconnected world provides ample opportunities to benefit from social information but also requires navigating complex social environments with people holding disparate or conflicting views. It is, however, still largely unclear how people integrate information from multiple social sources that (dis)agree with them, and among each other. We address this issue in three steps. First, we present a judgement task in which participants could adjust their judgements after observing the judgements of three peers. We experimentally varied the distribution of this social information, systematically manipulating its variance (extent of agreement among peers) and its skewness (peer judgements clustering either near or far from the participant's judgement). As expected, higher variance among peers reduced their impact on behaviour. Importantly, observing a single peer confirming a participant's own judgement markedly decreased the influence of other—more distant—peers. Second, we develop a framework for modelling the cognitive processes underlying the integration of disparate social information, combining Bayesian updating with simple heuristics. Our model accurately accounts for observed adjustment strategies and reveals that people particularly heed social information that confirms personal judgements. Moreover, the model exposes strong inter-individual differences in strategy use. Third, using simulations, we explore the possible implications of the observed strategies for belief updating. These simulations show how confirmation-based weighting can hamper the influence of disparate social information, exacerbate filter bubble effects and deepen group polarization. Overall, our results clarify what aspects of the social environment are, and are not, conducive to changing people's minds.
Active responses to outbreaks of infectious wildlife diseases: objectives, strategies and constraints determine feasibility and success
Authors: Bozzuto Claudio , Schmidt Benedikt R. , Canessa Stefano
Published: November 2020

Emerging wildlife diseases are taking a heavy toll on animal and plant species worldwide. Mitigation, particularly in the initial epidemic phase, is hindered by uncertainty about the epidemiology and management of emerging diseases, but also by vague or poorly defined objectives. Here, we use a quantitative analysis to assess how the decision context of mitigation objectives, available strategies and practical constraints influences the decision of whether and how to respond to epidemics in wildlife. To illustrate our approach, we parametrized the model for European fire salamanders affected byBatrachochytrium salamandrivorans, and explored different combinations of conservation, containment and budgetary objectives. We found that in approximately half of those scenarios, host removal strategies perform equal to or worse than no management at all during a local outbreak, particularly where removal cannot exclusively target infected individuals. Moreover, the window for intervention shrinks rapidly if an outbreak is detected late or if a response is delayed. Clearly defining the decision context is, therefore, vital to plan meaningful responses to novel outbreaks. Explicitly stating objectives, strategies and constraints, if possible before an outbreak occurs, avoids wasting precious resources and creating false expectations about what can and cannot be achieved during the epidemic phase.
Identification of miRNAs encoded by Autographa californica nucleopolyhedrovirus
Authors: Wang Jinwen , Xing Ke , Xiong Peiwen , Liang Hai , Zhu Mengxiao , Zhao Jin , Yu Xinghua , Ning Xiaolian , Li Runcai , Wang Xunzhang
Published: November 2020

Two Autographa californica nucleopolyhedrovirus (AcMNPV) encoded miRNAs, AcMNPV-miR-1 and AcMNPV-miR-3, have been reported by us in 2013 and 2019, respectively. Here, we present an integrated investigation of AcMNPV-encoded miRNAs, which include the above two miRNAs and three additional newly identified miRNAs. Six candidate miRNAs were predicted through small RNA deep sequencing and bioinformatics, of which, five were validated. Three miRNAs are located opposite the coding sequences, the other two are located in the coding sequences of viral genes. Targets in both virus and host were predicted and subsequently tested using dual-luciferase reporter assays. The validated targets were found mainly in AcMNPV, except for the targets of AcMNPV-miR-4, which are all host genes. Based on reporter assays, the five miRNAs predominantly function by down-regulating their targets. The transcription start sites of these miRNAs were bioinformatic screened based on known baculovirus promoter motifs. Our study reveals that AcMNPV-encoded miRNAs function as fine modulators of the interactions between host and virus by regulating viral and/or host genes.
Two mutations in the SARS-CoV-2 spike protein and RNA polymerase complex are associated with COVID-19 mortality risk
Authors: Hahn Georg , Wu Chloe M. , Lee Sanghun , Hecker Julian , Lutz Sharon M. , Haneuse Sebastien , Qiao Dandi , DeMeo Dawn , Choudhary Manish C. , Etemad Behzad , Mohammadi Abbas , Esmaeilzadeh Elmira , Cho Michael H. , Tanzi Rudolph E. , Li Jonathan Z. , Randolph Adrienne G. , Laird Nan M. , Weiss Scott T. , Silverman Edwin K. , Ribbeck Katharina , Lange Christoph
Published: November 2020

Background

SARS-CoV-2 mortality has been extensively studied in relation to host susceptibility. How sequence variations in the SARS-CoV-2 genome affect pathogenicity is poorly understood. Whole-genome sequencing (WGS) of the virus with death in SARS-CoV-2 patients is one potential method of early identification of highly pathogenic strains to target for containment.

Methods

We analyzed 7,548 single stranded RNA-genomes of SARS-CoV-2 patients in the GISAID database (Elbe and Buckland-Merrett, 2017; Shu and McCauley, 2017) and associated variants with reported patient’s health status from COVID-19, i.e. deceased versus non-deceased. We probed each locus of the single stranded RNA of the SARS-CoV-2 virus for direct association with host/patient mortality using a logistic regression.

Results

In total, evaluating 29,891 loci of the viral genome for association with patient/host mortality, two loci, at 12,053bp and 25,088bp, achieved genome-wide significance (p-values of 4.09e-09 and 4.41e-23, respectively).

Conclusions

Mutations at 25,088bp occur in the S2 subunit of the SARS-CoV-2 spike protein, which plays a key role in viral entry of target host cells. Additionally, mutations at 12,053bp are within the ORF1ab gene, in a region encoding for the protein nsp7, which is necessary to form the RNA polymerase complex responsible for viral replication and transcription. Both mutations altered amino acid coding sequences, potentially imposing structural changes that could enhance viral infectivity and symptom severity, and may be important to consider as targets for therapeutic development. Identification of these highly significant associations, unlikely to occur by chance, may assist with COVID-19 early containment of strains that are potentially highly pathogenic.
Use of alternative RNA storage and extraction reagents and development of a hybrid PCR-based method for SARS-CoV-2 detection
Authors: Yang Julie , Salfati Elias , Kao Damian , Mihaylova Yuliana
Published: November 2020

The COVID-19 pandemic has presented multiple healthcare challenges, one of which is adequately meeting the need for large-scale diagnostic testing. The most commonly used assays for detection of SARS-CoV-2, including those recommended by the Center for Disease Control and Prevention (CDC), rely on a consistent set of core reagents. This has put a serious strain on the reagent supply chain, resulting in insufficient testing. It has also led to restricted animal testing, even though there are now multiple reports of animals, particularly cats, ferrets and minks, contracting the disease. We aimed to address the diagnostic bottleneck by developing a PCR-based SARS-CoV-2 detection assay for cats (and, potentially, other animals) which avoids the use of most common reagents, such as collection kits optimized for RNA stabilization, RNA isolation kits and TaqMan-based RT-PCR reagents. We demonstrated that an inexpensive solid-phase reversible immobilization (SPRI) method can be used for RNA extraction from feline samples collected with DNAGenotek’s ORAcollect RNA OR-100 and PERFORMAgene DNA PG-100 sample collection kits, optimized for RNA or DNA stabilization, respectively. We developed a dual method SARS-CoV-2 detection assay relying on SYBR RT-PCR and Sanger sequencing, using the same set of custom synthesized oligo primers. We validated our test’s specificity with a commercially available SARS-CoV-2 plasmid positive control, as well as two in-house positive control RNA samples. Our assay’s sensitivity was determined to be 10 viral copies per reaction. Our results suggest that a simple SPRI-dependent RNA extraction protocol and certain sample collection kits not specifically optimized for RNA stabilization could potentially be used in cases where reagent shortages are hindering adequate COVID-19 testing. These ‘alternative’ reagents could be used in combination with our COVID-19 testing method, which relies on inexpensive and readily available SYBR RT-PCR and non-fluorescent PCR reagents. Depending on the detection goals and the laboratory setup available, the SYBR RT-PCR method and the Sanger sequencing based method can be used alone or in conjunction, for improved accuracy. Although the test is intended for animal use, it is, in theory, possible to use it with human samples, especially those with higher viral loads.
Maternal obesity before pregnancy predicts offspring blood pressure at 18 years of age: A causal mediation analysis
Authors: Brunton Nicole , Dufault Brenden , Dart Allison , Azad Meghan B. , McGavock Jonathan M
Published: November 2020

Importance

Hypertension is the second most common pediatric chronic disease in Westernized countries. Understanding the natural history of hypertension is key to identifying prevention strategies.

Objective

Examine the relationship between maternal pre-pregnancy body mass index (BMI) and offspring blood pressure at 18 years and the mediating role of growth throughout childhood and adolescence.

Design, Setting, and Participants

We performed multivariable regression and causal mediation analyses within 3217 mother - offspring pairs from the Avon Longitudinal Study of Parents and Children (ALSAPC) prospective birth cohort. Latent trajectory analysis (LTA) was used to quantify the mediating variable of offspring BMI from 7 to 18 years of age.

Exposures

The main exposure was maternal pre-pregnancy BMI. Analyses were adjusted for relevant confounders including maternal education, maternal blood pressure, and weeks gestation at delivery.

Main Outcomes and Measures

The main outcome was offspring blood pressure at 18 years of age categorized as normal (SBP < 120 mmHg or DBP < 80mmHg) or elevated (SBP ≥ 120 mmHg or DBP ≥ 80 mmHg) as per the 2017 American Academy of Pediatrics guidelines.

Results

At 18 years of age, among 3217 offspring, 676 (21%) were overweight or obese, 865 (27%) had elevated blood pressure, and 510 (16%) were hypertensive. LTA identified five distinct offspring BMI trajectories. Multivariate logistic regression revealed that for every 1 unit increase in maternal BMI the risk of elevated blood pressure at 18 years of age increased by 5% (aOR: 1.05, 95% CI: 1.03 – 1.07; p <0.001) and this effect was reduced after adjusting for offspring BMI trajectory (aOR: 1.03, 95% CI: 1.00 – 1.05; p = 0.017). Causal mediation analysis confirmed offspring BMI trajectory as a mediator accounting for 46% of the total effect of maternal BMI on elevated offspring blood pressure (aOR 1.22; 95% CI: 1.07-1.39).

Conclusion and Relevance

Maternal BMI prior to pregnancy is associated with an increased risk of elevated blood pressure in offspring at 18 years of age and is mediated, in part, by offspring BMI trajectory throughout childhood and adolescence.
The effectiveness of the three-tier system of local restrictions for control of COVID-19
Authors: Hunter Paul R , Brainard Julii , Grant Alastair
Published: November 2020

Despite it being over 10 months since COVID-19 was first reported to the world and it having caused over 1.3 million deaths it is still uncertain how the virus can be controlled whilst minimising the negative impacts on society and the economy. On the 14th October, England introduced a three-tier system of regional restrictions in an attempt to control the epidemic. This lasted until the 5th November when a new national lockdown was imposed. Tier 1 was the least and Tier 3 the most restrictive tiers. We used publicly available data of daily cases by local authority (local government areas) and estimated the reproductive rate (R value) of the epidemic over the previous 14 days at various time points after the imposition of the tier system or where local authorities were moved into higher tiers at time points after reallocation. At day 0 there vas very little difference in the R value between authorities in the different groups but by day 14 the R value in Tier 3 authorities had fallen to about 0.9, in Tier 2 to about 1.0 and in Tier 1 the R value was about 1.5. The restrictions in Tier 1 had little impact on transmission and allowed exponential growth in the large majority of authorities. By contrast the epidemic was declining in most Tier 3 authorities. In Tier 2, exponential growth was being seen in about half of authorities but declining in half. We concluded that the existing three tier system would have been sufficient to control the epidemic if all authorities had been moved out of Tier 1 into tier 2 and there had been more rapid identification and transfer of those authorities where the epidemic was increasing out of Tier 2 into Tier 3. A more restrictive tier than Tier 3 may be needed but only by a small number of authorities.
HIV status alters disease severity and immune cell responses inβvariant SARS-CoV-2 infection wave
Authors: Karim Farina , Gazy Inbal , Cele Sandile , Zungu Yenzekile , Krause Robert , Bernstein Mallory , Ganga Yashica , Rodel Hylton , Mthabela Ntombifuthi , Mazibuko Matilda , Khan Khadija , Muema Daniel , Ramjit Dirhona , Ndung’u Thumbi , Hanekom Willem , Gosnell Bernadett I. ,   COMMIT-KZN Team, Lessells Richard , Wong Emily , de Oliveira Tulio , Moosa Mahomed-Yunus S. , Lustig Gila , Leslie Alasdair , Kløverpris Henrik , Sigal Alex
Published: November 2020

There are conflicting reports on the effects of HIV on COVID-19. Here we analyzed disease severity and immune cell changes during and after SARS-CoV-2 infection in 236 participants from South Africa, of which 39% were people living with HIV (PLWH), during the first and second (βdominated) infection waves. The second wave had more PLWH requiring supplemental oxygen relative to HIV negative participants. Higher disease severity was associated with low CD4 T cell counts and higher neutrophil to lymphocyte ratios (NLR). Yet, CD4 counts recovered and NLR stabilized after SARS-CoV-2 clearance in wave 2 infected PLWH, arguing for an interaction between SARS-CoV-2 and HIV infection leading to low CD4 and high NLR. The first infection wave, where severity in HIV negative and PLWH was similar, still showed some HIV modulation of SARS-CoV-2 immune responses. Therefore, HIV infection can synergize with the SARS-CoV-2 variant to change COVID-19 outcomes.
Systematic Review of Studies on Telomere Lengths in Patients with Multiple Sclerosis
Authors: Bühring Jan , Hecker Michael , Fitzner Brit , Zettl Uwe Klaus
Published: November 2020

BACKGROUND

Telomeres are protective cap structures at the end of chromosomes that are essential for maintening genomic stability. Accelerated telomere shortening is related to premature cellular senescence. Shortened telomere lengths (TL) have been implicated in the pathogenesis of various chronic immune-mediated and neurological diseases.

OBJECTIVE

We aimed to systematically review the current literature on the association of TL as a measure of biological age and multiple sclerosis (MS).

METHODS

A comprehensive literature search was conducted to identify original studies that presented data on TL in samples from MS patients. Quantitative and qualitative information was extracted from the articles to summarize and compare the studies.

RESULTS

A total of 51 articles were screened, and 7 of them were included in this review. In 6 studies, average TL were analyzed in peripheral blood cells, whereas in one study, bone marrow-derived cells were used. Four of the studies reported significantly shorter leukocyte TL in at least one MS subtype in comparison to healthy controls (p=0.003 in meta-analysis). Shorter telomeres in MS patients were found to be associated, independently of age, with greater disability, lower brain volume, increased relapse rate and more rapid conversion from relapsing to progressive MS. However, it remains unclear how telomere attrition in MS may be linked to oxidative stress, inflammation and age-related disease processes.

CONCLUSIONS

Despite few studies in this field, there is substantial evidence on the association of TL and MS. Variability in TL appears to reflect heterogeneity in clinical presentation and course. Further investigations in large and well-characterized cohorts are warranted. More detailed studies on TL of individual chromosomes in specific cell types may help to gain new insights into the pathomechanisms of MS.

Highlights

The relationship between aging and the pathophysiology and course of MS is not fully understood

We have identified seven studies that analyzed telomere lengths (TL) in patients with MS

Our meta-analysis revealed significantly shorter leukocyte TL in MS patients compared to healthy controls

There is evidence that individual variability in biological aging reflects clinical heterogeneity in MS

The potential use of TL as a biomarker of age-related disease mechanisms deserves further investigation
Rapid Microscopic Fractional Anisotropy Imaging via an Optimized Kurtosis Formulation
Authors: Arezza N. J. J. , Tse D. H. Y. , Baron C. A.
Published: November 2020

Water diffusion anisotropy in the human brain is affected by disease, trauma, and development. Microscopic fractional anisotropy (μFA) is a diffusion MRI (dMRI) metric that can quantify water diffusion anisotropy independent of neuron fiber orientation dispersion. However, there are several different techniques to estimate μFA and few have demonstrated full brain imaging capabilities within clinically viable scan times and resolutions. Here, we present an optimized spherical tensor encoding (STE) technique to acquire μFA directly from the 2nd order cumulant expansion of the dMRI signal (i.e. diffusion kurtosis) which requires fewer powder-averaged signals than other STE fitting techniques and can be rapidly computed. We found that the optimal dMRI parameters for white matter μFA imaging were a maximum b-value of 2000 s/mm2 and a ratio of isotropic to linear tensor encoded acquisitions of 1.7 for our system specifications. We then compared two implementations of the direct approach to the well-established gamma model in 4 healthy volunteers on a 3 Tesla system. One implementation of the direct cumulant approach used mean diffusivity (D) obtained from a 2nd order fit of the cumulant expansion, while the other used a linear estimation of D from the low b-values. Both implementations of the direct approach showed strong linear correlations with the gamma model (ρ=0.97 and ρ=0.90) but mean biases of −0.11 and −0.02 relative to the gamma model were also observed, respectively. All three μFA measurements showed good test-retest reliability (ρ≥0.79 and bias=0). To demonstrate the potential scan time advantage of the direct approach, 2 mm isotropic resolution μFA was demonstrated over a 10 cm slab using a subsampled data set with fewer powder-averaged signals that would correspond to a 3.3-minute scan. Accordingly, our results introduce an optimization procedure that has enabled clinically relevant, nearly full brain μFA in only several minutes.

Highlights

Demonstrated method to acquire optimal parameters for regression μFA imaging

μFA measured using an optimized linear regression method at 3T

First μFA comparison between direct regression approach and the gamma model

Both approaches correlated strongly in white matter in healthy volunteers

Nearly full brain μFA demonstrated in a 3.3-minute scan at 2 mm isotropic resolution
Experimental efficacy of the face shield and the mask against emitted and potentially received particles
Authors: Wendling Jean-Michel , Fabacher Thibault , Pebay Philippe-Pierre , Cosperec Isabelle , Rochoy Michael
Published: November 2020

There is currently not sufficient evidence to support the effectiveness of face shields for source control. In order to evaluate the comparative barrier performance effect of face masks versus face shields, we used an aerosol generator and a particle counter to evaluate the performance of the various devices in comparable situations. We tested different configurations in an experimental setup with manikin heads wearing masks (surgical type I), face shields (22.5 cm high with overhang under the chin of 7 cm and circumference of 35 cm) on an emitter or a receiver manikin head, or both. The mannequins were face to face, 25 cm apart, with an intense particle emission (52.5 l/min) for 30 seconds. In our experimental conditions, when the receiver alone wore a protection, the face shield was more effective (reduction factor=54.8%), while reduction was lower with a mask (reduction factor=21.8%) (p=0.002). The wearing of a protective device by the emitter alone reduced the level of received particles by 96.8% for both the mask and face shield (p= NS). When both the emitter and receiver manikin heads wore a face shield, the ensuing double protection allowed for better results: 98% reduction for the face shields vs. 97.3% for the masks (p=0.01). Face shields offered an even better barrier effect than the mask against small inhaled particles (<0.3 microns - 0.3 to 0.5 microns - 0.5 to 1 microns) in all configurations. Therefore, it would be interesting to include face shields as used in our study as part of strategies to safely significantly reduce transmission within the community setting.
The sensitivity of SARS-CoV-2 antigen tests in the view of large-scale testing
Authors: Drevinek Pavel , Hurych Jakub , Kepka Zdenek , Briksi Ales , Kulich Michal , Zajac Miroslav , Hubacek Petr
Published: November 2020

Objectives

Antigen tests have recently emerged as an interesting alternative to SARS-CoV-2 diagnostic PCR, thought to be valuable especially for the screening of bigger communities. To check appropriateness of the antigen based testing, we determined sensitivity of two point-of-care antigen tests when applied to a cohort of COVID-19 symptomatic, COVID-19 asymptomatic and healthy persons.

Methods

We examined nasopharyngeal swabs with antigen test 1 (Panbio Covid-19 Ag Rapid Test, Abbott) and antigen test 2 (Standard F Covid-19 Ag FIA, SD Biosensor). An additional nasopharyngeal and oropharyngeal swab of the same individual was checked with PCR (Allplex SARS-nCoV-2, Seegene). Within a 4-day period in October 2020, we collected specimens from 591 subjects. Of them, 290 had COVID-19 associated symptoms.

Results

While PCR positivity was detected in 223 cases, antigen test 1 and antigen test 2 were found positive in 148 (sensitivity 0.664, 95% CI 0.599 - 0.722) and 141 (sensitivity 0.623, 95% CI 0.558 - 0.684) patients, respectively. When only symptomatic patients were analysed, sensitivity increased to 0.738 (95% CI 0.667 - 0.799) for the antigen test 1 and to 0.685 (95% CI 0.611 - 0.750) for the antigen test 2. The substantial drop in sensitivity to 12.9% (95% CI 0.067 - 0.234) was observed for samples with the PCR threshold cycle above > 30.

Conclusions

Low sensitivity of antigen tests leads to the considerable risk of false negativity. It is advisable to implement repeated testing with high enough frequency if the antigen test is used as a frontline screening tool.
Crystal Structure of a Retroviral Polyprotein: Prototype Foamy Virus Protease-Reverse Transcriptase (PR-RT)
Authors: Harrison Jerry Joe E. K. , Tuske Steve , Das Kalyan , Ruiz Francesc X. , Bauman Joseph D. , Boyer Paul , DeStefano Jeffrey J. , Hughes Stephen H. , Arnold Eddy
Published: November 2020

In most cases, proteolytic processing of the retroviral Pol portion of the Gag-Pol polyprotein precursor produces protease (PR), reverse transcriptase (RT), and integrase (IN). However, foamy viruses (FVs), express Pol separately from Gag and, when Pol is processed, only the IN domain is released. Here, we report a 2.9 Å resolution crystal structure of the mature PR-RT from prototype FV (PFV) that carries out both proteolytic processing and reverse transcription. PFV PR-RT is monomeric and the architecture of PFV PR is similar to one of the subunits of HIV-1 PR, which is a dimer. There is a C-terminal extension of PFV PR (101-145) that consists of two helices which are adjacent to the base of the RT palm subdomain, and anchors PR to RT. The polymerase domain of PFV RT consists of fingers, palm, thumb, and connection subdomains whose spatial arrangements are similar to the p51 subunit of HIV-1 RT. The RNase H and polymerase domains of PFV RT are connected by flexible linkers. Significant spatial and conformational (sub)domain rearrangements are therefore required for nucleic acid binding. The structure of PFV PR-RT provides insights into the conformational maturation of retroviral Pol polyproteins.

IMPORTANCE

Retroviruses such as HIV and other human and animal pathogens have evolved to maximize the protein-coding capacity of their genomes. Retroviruses synthesize large polyprotein precursors that are subsequently cleaved to produce mature functional enzymes and structural proteins from the same mRNA template. These polyproteins play an important role in the viral life cycle. We report the monomeric structure of the prototype foamy virus protease-reverse transcriptase fusion (PR-RT) which serves as both a protease and reverse transcriptase. The monomeric PR domain is folded in a similar way as a single subunit of dimeric HIV-1 PR. PR is anchored close to the fingers subdomain of the RT by a long C-terminal extension (CTE) that folds into two helices that pack against the palm subdomain of the RT. The RT is folded similarly to the p51 subunit of HIV-1 RT with the RNase H subdomain packed against the thumb and opposite the connection and palm subdomains. This structure offers insight into the structural arrangement of the domains and subdomains of immature retroviral polyproteins and provides support for the concept of developing drugs that target interfaces between immature enzymes that are present only in retroviral polyprotein precursors.
Protein kinases mediate anti-inflammatory effects of cannabidiol and estradiol against high glucose in cardiac sodium channels
Authors: Fouda Mohamed A. , Ruben Peter C.
Published: November 2020

Background and purpose

Cardiovascular anomalies are predisposing factors for diabetes-induced morbidity and mortality. Recently, we showed that high glucose induces changes in the biophysical properties of Nav1.5 that could be strongly correlated to diabetes-induced arrhythmia. However, the mechanisms underlying hyperglycemia-induced inflammation, and how inflammation provokes cardiac arrhythmia, are not well understood. We hypothesized that inflammation could mediate the high glucose-induced biophyscial changes on Nav1.5 through protein phosphorylation by protein kinases A and C. We also hypothesized that this signaling pathway is, at least partly, involved in the cardiprotective effects of CBD and E2.

Experimental approach

To test these ideas, we used Chinese hamster ovarian (CHO) cells transiently co-transfected with cDNA encoding human Nav1.5 α-subunit under control, a cocktail of inflammatory mediators or 100 mM glucose conditions (for 24 hours). We used electrophysiological experiments and action potential modelling.

Key Results

Inflammatory mediators, similar to 100 mM glucose, right shifted the voltage dependence of conductance and steady state fast inactivation and increased persistent current leading to computational prolongation of action potential (hyperexcitability) which could result in long QT3 arrhythmia. In addition, activators of PK-A or PK-C replicated the inflammation-induced gating changes of Nav1.5. Inhibitors of PK-A or PK-C, CBD or E2mitigated all the potentially deleterious effects provoked by high glucose/inflammation.

Conclusions and implications

These findings suggest that PK-A and PK-C may mediate the anti-inflammatory effects of CBD and E2against high glucose-induced arrhythmia. CBD, via Nav1.5, may be a cardioprotective therapeutic approach in diabetic postmenopausal population.

Bullet points

What is already known:

Arrhythmias are among the common cardiac causes of morbidity and mortality in diabetes-related hyperglycemia.

One of the diabetes-induced arrhythmias is long-QT syndrome, caused by gating defects in the cardiac voltage-gated sodium channel (Nav1.5).

What this study adds:

Inflammation and subsequent activation of PK-A and PK-C mediate the high glucose-induced electrophysiological changes of Nav1.5 in a manner consistent with the gating defects that underlie long-QT arrhythmia.

Cannabidiol and estradiol rescue the high glucose induced Nav1.5 gating defects through, at least partly, this signaling pathway.

Clinical significance:

Inflammation/PK-A and PK-C signaling pathway could be a potential therapeutic target to prevent arrhythmias associated with diabetes.

Cannabidiol may be a therapeutic approach to prevent cardiac complications in diabetes, especially in postmenopausal populations due to the decreased levels of the cardioprotective estrogen.
Reference-Aided Full-length Transcript Assembly, cDNA Cloning, and Molecular Characterization ofCoronatine-insensitive 1b(COI1b) Gene in Coconut (Cocos nuciferaL.)
Authors: Pammit Frenzee Kroeizha L. , Manohar Anand Noel C. , Lantican Darlon V. , Gardoce Roanne R. , Galvez Hayde F.
Published: November 2020

In the Philippines, 26% of the total agricultural land is devoted to coconut production making coconut one of the most valuable industrial crop in the country. However, the country’s multimillion-dollar coconut industry is threatened by the outbreak of coconut-scale insect (CSI) and other re-emerging insect pests promoting national research institutes to work jointly on developing new tolerant coconut varieties. Here, we report the cloning and characterization ofcoronatine-insensitive 1(COI1) gene, one of the candidate insect defense genes, using ‘Catigan Green Dwarf’ (CATD) genome sequence assembly as reference. Two (2) splicing variants were identified and annotated – CnCOI1b-1 and CnCOI1b-2. The full-length cDNA of CnCOI1b-1 was 7,919 bp with an ORF of 1,176 bp encoding for a deduced protein of 391 amino acids while CnCOI1b-2 has 2,360 bp full-length cDNA with an ORF of 1,743 bp encoding a deduced protein of 580 amino acids. The 3D structural model for the two (2) isoforms were generated through homology modelling. Functional analysis revealed that both isoforms are involved in various physiological and developmental plant processes including defense response of plants to insects and pathogens. Phylogenetic analysis confirms high degree of COI1 protein conservation during evolution, especially among monocot species.

Key Message

This paper reports the molecular cloning and characterization ofcorononatine-insensitive I(COI1)gene in coconut using reference-guided transcript assembly approach. As a well-known insect defense-response gene in other crops, the results of this study are expected to assist in the development of new resistant coconut varieties as one of the strategies to address threats in coconut production.
Pro108Ser mutant of SARS-CoV-2 3CLpro reduces the enzymatic activity and ameliorates COVID-19 severity in Japan
Authors: Abe Kodai , Kabe Yasuaki , Uchiyama Susumu , Iwasaki Yuka W. , Ishizu Hirotsugu , Uwamino Yoshifumi , Takenouchi Toshiki , Uno Shunsuke , Ishii Makoto , Maruno Takahiro , Noda Masanori , Murata Mitsuru , Hasegawa Naoki , Saya Hideyuki , Kitagawa Yuko , Fukunaga Koichi , Amagai Masayuki , Siomi Haruhiko , Suematsu Makoto , Kosaki Kenjiro ,   Keio Donner Project
Published: November 2020

SARS-CoV-2 genome accumulates point mutations constantly. However, whether non-synonymous mutations affect COVID-19 severity through altering viral protein function remains unknown. SARS-CoV-2 genome sequencing revealed that the number of non-synonymous mutations correlated inversely with COVID-19 severity in Tokyo Metropolitan area. Phylogenic tree analyses identified two predominant groups which were differentiated by a set of six-point mutations (four non-synonymous amino acid mutations). Among them, Pro108Ser in 3 chymotrypsin-like protease (3CLpro) and Pro151Leu in nucleocapsid protein occurred at conserved locations among β-coronaviruses. Patients with these mutations (N = 48) indicated significantly lower odds ratio for developing hypoxia which required supplemental oxygen (odds ratio 0.24 [95% CI 0.07-0.88, p-value = 0.032]) after adjustments for age and sex, versus those lacking this haplotype in the canonical Clade 20B (N = 37). The Pro108Ser 3CLpro enzyme in vitro decreases in the activity by 58%, and the hydrogen/deuterium exchange mass spectrometry reveals that mechanisms for reduced activities involve structural perturbation at the substrate-binding region which is positioned behind and distant from the 108th amino acid residue of the enzyme. This mutant strain rapidly outcompeted pre-existing variants to become predominant in Japan. Our results may benefit the efforts underway to design small molecular compounds or antibodies targeting 3CLpro.
Associations between alcohol use and accelerated biological ageing
Authors: Bøstrand Sunniva M. K. , Vaher Kadi , De Nooij Laura , Harris Mathew A. , Cole James H. , Cox Simon R. , Marioni Riccardo E. , McCartney Daniel L. , Walker Rosie M. , McIntosh Andrew M. , Evans Kathryn L. , Whalley Heather C. , Wootton Robyn E. , Clarke Toni-Kim
Published: November 2020

Background

Harmful alcohol use is a leading cause of premature death, and is associated with age-related disease. Ageing is highly variable between individuals, and may deviate from chronological ageing, suggesting that biomarkers of biological ageing (based on DNA methylation or brain structural measures) may be clinically relevant. Here, we investigated the relationships between alcohol phenotypes and both brain and DNA methylation age estimates.

Methods

First, using data from UK Biobank and Generation Scotland, we tested the association between alcohol consumption (units/week) or hazardous use (AUDIT scores), and accelerated brain and epigenetic ageing in 20,258 and 8,051 individuals, respectively. Second, we used Mendelian randomization to test for a causal effect of alcohol consumption levels and alcohol use disorder (AUD) on biological ageing.

Results

Alcohol use showed a consistent positive association with higher predicted brain age (AUDIT-C: β=0.053, p=3.16×10−13; AUDIT-P: β=0.052, p=1.6×10−13; total AUDIT score: β=0.062, p=5.52×10−16; units/week: β=0.078, p=2.20×10−16), and DNA methylation GrimAge (Units/week: β=0.053, p=1.48×10− 7) and PhenoAge (Units/week: β=0.077, p=2.18×10−10). Mendelian randomization analyses revealed some evidence for a causal effect of AUD on accelerated brain ageing (β=0.272, p=0.044), and no evidence for a causal effect of alcohol consumption levels on accelerated biological ageing.

Conclusions

We provide consistent phenotypic evidence linking alcohol use with accelerated biological ageing. There is possible evidence for a causal effect of AUD on brain age, but not for any other alcohol-related trait on brain or epigenetic age acceleration. Future studies investigating the mechanisms associating alcohol use with accelerated biological ageing are warranted.
Demography, social contact patterns and the COVID-19 burden in different settings of Ethiopia: a modeling study
Authors: Trentini Filippo , Guzzetta Giorgio , Galli Margherita , Zardini Agnese , Manenti Fabio , Putoto Giovanni , Marziano Valentina , Gamshie Worku Nigussa , Tsegaye Ademe , Greblo Alessandro , Melegaro Alessia , Ajelli Marco , Merler Stefano , Poletti Piero
Published: November 2020

Background

COVID-19 spread may have a dramatic impact in countries with vulnerable economies and limited availability of, and access to, healthcare resources and infrastructures. However, in sub-Saharan Africa a low prevalence and mortality have been observed so far.

Methods

We collected data on individuals’ social contacts in Ethiopia across geographical contexts characterized by heterogeneous population density, work and travel opportunities, and access to primary care. We assessed how socio-demographic factors and observed mixing patterns can influence the COVID-19 disease burden, by simulating SARS-CoV-2 transmission in remote settlements, rural villages, and urban neighborhoods, under the current school closure mandate.

Results

From national surveillance data, we estimated a net reproduction number of 1.62 (95%CI 1.55-1.70). We found that, at the end of an epidemic mitigated by school closure alone, 10-15% of the overall population would have been symptomatic and 0.3-0.4% of the population would require mechanical ventilation and/or possibly result in a fatal outcome. Higher infection attack rates are expected in more urbanized areas, but the highest incidence of critical disease is expected in remote subsistence farming settlements.

Conclusions

The relatively low burden of COVID-19 in Ethiopia can be explained by the estimated mixing patterns, underlying demography and the enacted school closures. Socio-demographic factors can also determine marked heterogeneities across different geographical contexts within the same country. Our findings can contribute to understand why sub-Saharan Africa is experiencing a relatively lower attack rate of severe cases compared to high income countries.
Nurses’ burnout and associated risk factors during the COVID-19 pandemic: a systematic review and meta-analysis
Authors: Galanis Petros , Vraka Irene , Fragkou Despoina , Bilali Angeliki , Kaitelidou Daphne
Published: November 2020

Background

During the COVID-19 pandemic, physical and mental health of the nurses is greatly challenged since they work under unprecedented pressure and they are more vulnerable to the harmful effects of the disease.

Aim

To examine the impact of the COVID-19 pandemic on nurses’ burnout and to identify associated risk factors.

Methods

We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines for this systematic review and meta-analysis. PubMed, Scopus, ProQuest and pre-print services (medRχiv and PsyArXiv) were searched from January 1, 2020 to November 15, 2020 and we removed duplicates. We applied a random effect model to estimate pooled effects since the heterogeneity between results was very high.

Findings

Fourteen studies, including 17,390 nurses met the inclusion criteria. Five standardized and valid questionnaires were used to measure burnout among nurses; Maslach Burnout Inventory, Copenhagen Burnout Inventory, Professional Quality of Life Scale version 5, Mini-Z, and Spanish Burnout Inventory. The overall prevalence of emotional exhaustion was 34.1% (95% confidence interval [CI]: 22.5-46.6%), of depersonalization was 12.6% (95% CI: 6.9-19.7%), and of lack of personal accomplishment was 15.2% (95% CI: 1.4-39.8%). The following factors were associated with increased nurses’ burnout: younger age, higher educational level, higher degree, decreased social support, having a relative/friend diagnosed with COVID-19, low family and colleagues readiness to cope with COVID-19 outbreak, increased perceived threat of Covid-19, longer working time in quarantine areas, working in a high-risk environment (a COVID-19 designated hospital, a COVID-19 unit, etc.), working in hospitals with inadequate and insufficient material and human resources, decreased working safety while caring for COVID-19 patients, increased workload, decreased self-confidence in self-protection, and lower levels of specialized training regarding COVID-19, job experience, and self-confidence in caring for COVID-19.

Conclusion

Nurses experience high levels of burnout during the COVID-19 pandemic, while several sociodemographic, social and occupational factors affect this burnout. Several interventions need to be implemented to mitigate mental health impact of the COVID-19 pandemic on nurses, e.g. screening for mental health illness and early supportive interventions for high-risk nurses, immediate access to mental health care services, social support to reduce feelings of isolation, sufficient personal protective equipment for all nurses to provide security etc. Governments, health care organizations and policy makers should act in this direction to prepare health care systems, individuals and nurses for a better response against the COVID-19 pandemic.
Protein coevolution and physicochemical adaptation in the APAF-1/apoptosome: structural and functional implications
Authors: Sánchez-Borbón José A , Massey Steven E , Hernández-Martich José D
Published: November 2020

The apoptosome is involved in the mitochondrial pathway of apoptosis, consisting of APAF-1, caspase 9 and cytochrome c, forming a heptamer that activates effector caspases, causing cell death. This protein complex has also been characterized in Drosophila melanogaster (DARK) and Caenorhabditis elegans (CED-4). Here we present an evolutionary guided in silico characterization of the APAF-1/apoptosome. The evolutionary history of the apoptosome was determined, taking the possible orthologs of the APAF-1 version, and executing a protein coevolution and a positive selection analysis, to make structural and functional inferences and identify residues under destabilizing changes, respectively. Results suggests that the APAF-1/apoptosome is not unique to vertebrates, but also some basal invertebrates could possess orthologous copies. New possible versions were also detected in other taxa. Not all insects and other arthropods have the DARK version, just as not all nematodes have the CED-4 version. In the APAF-1 version, amino acid clusters with coevolution signal located in the interior, gave more insights on new potential interactions, allowing us to infer a more detailed model that includes allosterism, of how cytochrome c associates with β propellers during APAF-1 activation, as well as interactions essential for nucleotide exchange, activation of CASP9, the molecular timer and other pathways in mitochondria to induce apoptosis. Residues on the surface under destabilizing changes have guided the protein complex in adaptations necessary for conformational changes, interactions and folding.
Shaking hands is a putative terminal selector and controls axon outgrowth of central complex neurons in the insect modelTribolium
Authors: Garcia-Perez Natalia Carolina , Bucher Gregor , Buescher Marita
Published: November 2020

Individual cell types are specified by transcriptional programs which act during development. Gene regulatory mechanisms which specify subtype identity of central complex (CX) neurons are the subject of intense investigation. The CX is a compartment within the brain common to all insect species. The CX functions as a “command center” by initiating motor actions in response to incoming information. The CX is made up of several thousand neurons with more than 60 morphologically distinct identities. Accordingly, transcriptional programs must effect the specification of at least as many neuronal subtypes. Here we demonstrate a role for the transcription factor Shaking hands (Skh) in the specification of embryonic CX neurons inTribolium. The developmental dynamics ofTc-skhexpression are characteristic for terminal selectors of neuronal subtype identity. In the embryonic brainTc-skhexpression is restricted to a subset of neurons, many of which survive to adulthood and contribute to the mature CX.Tc-skhexpression is maintained throughout the lifetime of the respective CX neurons.Tc-skhknock-down results in severe axon outgrowth defects thus preventing the formation of an embryonic CX primordium. The as yet unstudiedDrosophila skhshows a similar embryonic expression pattern suggesting that subtype specification of CX neurons may be conserved.