bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of the rapid ResaPolymyxin Acinetobacter/Pseudomonas NP test for rapid colistin resistance detection in lactose non-fermenting Gram-negative bacteria
Authors: Jung Hyunsul , Pitout Johann D. D. , Mitton Barend C. , Strydom Kathy-Anne , Kingsburgh Chanel , Coetzee Jennifer , Ehlers Marthie M. , Kock Marleen
Published: June 2021

Introduction. Colistin is one of the last-resort antibiotics for treating multidrug-resistant (MDR) or extensively drug-resistant (XDR) lactose non-fermenting Gram-negative bacteria such as

Pseudomonas aeruginosa

and

Acinetobacter baumannii

.

Gap Statement. As the rate of colistin resistance is steadily rising, there is a need for rapid and accurate antimicrobial susceptibility testing methods for colistin. The Rapid ResaPolymyxin

Acinetobacter

/

Pseudomonas

NP test has recently been developed for rapid detection of colistin resistance in

P. aeruginosa

and

A. baumannii

.

Aim. The present study aimed to evaluate the performance of the Rapid ResaPolymyxin

Acinetobacter

/

Pseudomonas

NP test in comparison with the reference broth microdilution (BMD) method.

Methodology. The Rapid ResaPolymyxin

Acinetobacter

/

Pseudomonas

NP test was performed using a total of 135

P

.

aeruginosa

(17 colistin-resistant and 118 colistin-susceptible) and 66

A. baumannii

isolates (32 colistin-resistant and 34 colistin-susceptible), in comparison with the reference BMD method.

Results. The categorical agreement of the Rapid ResaPolymyxin

Acinetobacter

/

Pseudomonas

NP test with the reference BMD method was 97.5 % with a major error rate of 0 % (0/152) and a very major error (VME) rate of 10.2 %. The VME rate was higher (23.5 %) when calculated separately for

P. aeruginosa

isolates. The overall sensitivity and specificity were 89.8 and 100 %, respectively.

Conclusion. The Rapid ResaPolymyxin

Acinetobacter

/

Pseudomonas

NP test performed better for

A. baumannii

than for

P. aeruginosa

.
Signature transcriptome analysis of stage specific atherosclerotic plaques of patients
Authors: Verma Sonia , Kumar Abhay , Narang Rajiv , Bisoi Akshay K , Mitra Dipendra K
Published: June 2021

Background

Inflammation plays an important role in all the stages of atherosclerotic plaque development. The current study aimed at assessing the altered expression of genes functioning in inflammation within the early stage (ES)and advanced stage (AS) atherosclerotic plaques obtained from patients undergoing coronary artery bypass grafting (CABG) surgery and identifying biomarker panel/sthat may detect the status of plaque stages using peripheral blood samples.

Methods

A section of ES and ASplaques and normal left internal mammary arteries (LIMA) were obtained from 8 patients undergoing theCABG surgery. Total RNA isolated was analysed for mRNA and miRNAexpression profile by Affymetrix arrays. Significant number of mRNAs was found to be differentially expressed in ES and ASplaque tissues relative to LIMA. The pathway analysis of differentially expressed mRNAs in the two plaque stages was also performed using DAVID Bioinformatics Database.

Results

The mRNAs were found to be involved in critical inflammatory processes such as Toll-like receptor signalling pathway and cytokine-cytokine receptor interaction. Few miRNAs targeting these mRNAs were also altered in the two plaque conditions. QRT-PCR results showedsimilar expression pattern of few of themRNAs and miRNAsin peripheral blood of same patients relative to healthy controls.

Conclusion

Changes in mRNA and miRNA expression associated with various inflammatory processes occur in different atherosclerotic stage plaques as well as peripheral blood. Detection of such variations in patients’ blood can be used as a possible prognostic tool to detect and/or predict the risk and stage of atherosclerosis.
Improving prediction of amyloid deposition in Mild Cognitive Impairment with a timed motor task
Authors: Schaefer Sydney Y. , Duff Kevin , Hooyman Andrew , Hoffman John M.
Published: June 2021

Cortical amyloid deposition is one of the hallmark biomarkers of Alzheimer’s disease. However, given how cost- and time-intensive amyloid imaging can be, there is a continued need for a low-cost, non-invasive, and accessible enrichment strategy to pre-screen individuals for their likelihood of amyloid prior to imaging. Previous work supports the use of coordinated limb movement as a potential screening tool, even after controlling for cognitive and daily function. Thirty-six patients diagnosed with amnestic Mild Cognitive Impairment over the age of 65 underwent 18F-Flutemetamol amyloid-positron emission tomography imaging, then completed a timed motor task involving upper limb coordination. This task takes ∼5 minutes to administer and score. Multivariate linear regression and Receiver Operator Characteristic analyses showed that including motor task performance improved model prediction of amyloid burden. Results support the rationale for including functional upper extremity motor assessment as a cost- and time-effective means to screen participants for amyloid deposition.
The Impact of Legislation on Covid-19 Mortality in a Brazilian Federative Unit was Mediated by Social Isolation
Authors: Diaz-Quijano Fredi A. , Ribeiro Tatiane Bomfim , da Rosa Aléxia Viana , Reis Rossana , Aith Fernando , Ventura Deisy F. L.
Published: June 2021

Background

This study aimed to estimate the effect of restrictive laws on actual social isolation and COVID-19 mortality. Moreover, we evaluated how community adherence, measured with an index of social isolation, would mediate the lockdown effect on COVID-19 mortality.

Methods

This ecological study assessed the legislations published until June 30, 2020, in the Brazilian state of Ceará. We performed a systematic review and classification of restrictive norms and estimated their immediate effect on social isolation, measured by an index based on mobile data, and the subsequent impact on COVID-19 mortality (three weeks later). A mediation analysis was performed to estimate the effect of rigid lockdown on mortality that was explained for effective social isolation.

Results

The social isolation index showed an increase of 11.9% (95% CI: 2.9% - 21%) during the days in which a rigid isolation norm (lockdown) was implemented. Moreover, this rigid lockdown was associated with a reduction of 26% (95% CI: 21% - 31%) in the three-week-delayed mortality. We also calculated that the rigid lockdown had the indirect effect, i.e., mediated by adherence to social isolation, of reducing COVID-19 mortality by 38.24% (95% CI: 21.64% to 56.07%). Therefore, the preventive effect of this norm was fully explained by the actual population adherence, reflected in the social isolation index. On the other hand, mandatory mask use was associated with 11% reduction in COVID-19 mortality (95% CI: 8% −13%).

Conclusions

We estimated the effect of quarantine regulations on social isolation and evidenced that a rigid lockdown law led to a reduction of COVID-19 mortality in one state of Brazil. In addition, the mandatory masks norm was an additional determinant of the reduction of this outcome.
Safe in my heart: resting heart rate variability longitudinally predicts emotion regulation, worry and sense of safeness during COVID-19 lockdown
Authors: Makovac Elena , Carnevali Luca , Hernandez-Medina Sonia , Sgoifo Andrea , Petrocchi Nicola , Ottaviani Cristina
Published: June 2021

Due to its ability to reflect the capacity to engage in context-appropriate responses, tonic heart rate variability (HRV) is considered a putative biomarker of stress resilience. However, most studies are cross-sectional, precluding causal inferences. The high levels of uncertainty and fear at a global level that characterize the COVID-19 pandemic offer a unique opportunity to investigate the longitudinal role of HRV in stress resilience. The present study examined whether HRV, measured about 2 years earlier (Time 0), could predict emotion regulation strategies and daily affect in healthy adults during the May 2020 lockdown (Time 1). Moreover, we evaluated the association between HRV measures, emotion regulation strategies, subjective perception of COVID-19 risk, and self-reported depressive symptoms at Time 1. Higher tonic HRV at Time 0 resulted a significant predictor of a stronger engagement in more functional emotion regulation strategies, as well as of higher daily feelings of safeness and reduced daily worry at Time 1. Moreover, depressive symptoms negatively correlated with HRV and positively correlated with the subjective perception of COVID-19 risk at Time 1. Current data support the view that HRV might be not only a marker but also a precursor of resilience under stressful times.
The mental health of NHS staff during the COVID-19 pandemic: a two-wave cohort study
Authors: De Kock Johannes H. , Latham Helen Ann , Cowden Richard G. , Cullen Breda , Narzisi Katia , Jerdan Shaun , Munoz Sarah-Anne , Leslie Stephen J. , Boggon Adam , Humphry Roger W.
Published: June 2021

Background

Health and social care workers(HSCWs) are at risk of experiencing adverse mental health (MH) outcomes (e.g., higher levels of anxiety and depression) as a result of the COVID-19 pandemic. This can have a detrimental impact on quality of care, the national response to the pandemic and its aftermath.

Aims

A longitudinal design provided follow-up evidence on the MH(changes in the prevalence of disease over time) of NHS staff working in a remote health board in Scotland during the COVID-19 pandemic and investigated the determinants of MH outcomes over time.

Method

A two-wave longitudinal study was conducted from July to September 2020. Participants self-reported levels of depression(PHQ-9), anxiety(GAD-7), and mental well-being(WEMWBS) at baseline and again 1.5 months later.

Results

The analytic sample of 169 participants, working in community(43%) and hospital(44%) settings reported substantial levels of probable clinical depression, anxiety and low mental well-being(MWB) at baseline(depression:30.8%, anxiety:20.1%, low-MWB:31.9%). Whilst the MH of participants remained mostly constant over time, the proportion of participants meeting the threshold for clinical anxiety increased to 27.2% at follow-up. Multivariable modelling indicated that working with, and disruption due to COVID-19 were associated with adverse MH changes over time.

Conclusions

HSCWs working in a remote area with low COVID-19 prevalence, reported similar levels of substantial anxiety and depression as those working in areas of the UK with high rates of COVID-19 infections. Efforts to support HSCW MH must remain a priority and should minimize the adverse effects of working with, and the disruption caused by the COVID-19 pandemic.
Prevalence and Risk Factors of Stroke in Bangladesh: A Nationwide Population-Based Survey
Authors: Mondal Md Badrul Alam , Hasibul Hasan A T M , Khan Nushrat , Mohammad Quazi Deen
Published: June 2021

Background

This community survey was conducted to estimate the prevalence of stroke and its associated common risk factors among the Bangladeshi population.

Methods

This was a population-based cross-sectional study, carried out in 8 administrative divisions and 64 districts to estimate the prevalence of stroke throughout the country. The study adopted a two-stage cluster random sampling approach. The calculated sample size was 25,287. A semi-structured questionnaire was used to identify suspected stroke patients who were subsequently confirmed by consultant neurologists.

Result

In the first stage, Interviewers identified 561 respondents as suspected stroke in 64 districts. Of the 25,287 respondents, 54.9% were male. The mean age was 39.9 years. In the second stage of the study; among all the respondents, 288 were confirmed as stroke patients which provided a prevalence of 11.39 per 1000 population. The highest stroke prevalence (14.71 per thousand) was found in the Mymensingh division and the lowest (7.62 per thousand) found in the Rajshahi division. It was 30.10 per thousand in the age group of more than 60 years. The prevalence of stroke among males was twice that of females (13.62 versus 8.68 per thousand). The prevalence was slightly higher in rural areas (11.85 versus 11.07). Out of a total of 288 cases, 79.7% (213) patients had an ischemic stroke, 15.7% (42) had hemorrhagic, and 4.6% (12) were diagnosed as subarachnoid hemorrhage. The majority of the stroke patients had hypertension (79.2%), followed by dyslipidemia (38.9%), tobacco use in any form (37.2%), diabetes (28.8%), ischemic heart disease (20.1%).

Conclusion

We have found a stroke prevalence of 11.39 per 1000 population, the highest being in the Mymensingh division. The prevalence was much higher in the elderly and male population. More than three fourth had an ischemic stroke. Hypertension, dyslipidemia, tobacco use, diabetes, ischemic heart disease are the most common risk factors observed among stroke patients.

Summary Box

Already Known:

▪

The prevalence of stroke in Bangladesh was found to be 3 per thousand.

▪

Hypertension, diabetes, dyslipidemia, smoking, and ischemic heart disease were common risk factors.

New Findings:

▪

This is the first-ever nationwide survey in Bangladesh that revealed a stroke prevalence of 11.39 per thousand.

▪

There was a wide regional variation of stroke prevalence.

▪

The prevalence was twice among males.

Impact of the study result:

▪

The study result will help the policymakers in deciding what to do for which regions of this country to handle the stroke burden.

▪

It will also help the clinicians to identify common risk factors among stroke patients.
An empirical assessment of influenza intensity thresholds obtained from the moving epidemic and WHO methods
Authors: Bracher Johannes , Littek Jonas M.
Published: June 2021

The moving epidemic method (MEM) and the WHO method are widely used to determine intensity levels for seasonal influenza. The two approaches are conceptually similar, but differ in two aspects. Firstly, the MEM involves a log transformation of incidence data, while the WHO method operates on the original scale. Secondly, the MEM uses more than one observation from each past season to compute intensity thresholds, fixing the total number to include. The WHO method uses only the highest value from each season. To assess the impact of these choices on thresholds we perform simulation studies which are based on re-sampling of ILI data from France, Spain, Switzerland and the US. When no transformation is applied, a rather large proportion of season peaks are classified as high or very high intensity. This can be mitigated by a logarithmic transformation. When fixing the total number of included past observations, thresholds increase the more seasons are available. When only few are available, there is a high chance of classifying new season peaks as high or very high intensity. We therefore suggest using one observation per season and a log transformation, i.e. a hybrid of the default settings of the MEM and WHO methods.
Validation of the 4C Deterioration Model for COVID-19 in a UK teaching hospital during Wave 2
Authors: Cowan Sarah L. , Wiegand Martin , Preller Jacobus , Goudie Robert J. B.
Published: June 2021

The 4C Deterioration model was developed and validated on data collected in UK hospitals until August 26, 2020, but has not yet been validated in the presence of SARS-CoV-2 variants and novel treatment regimens that have emerged subsequently. In this first validation study of the 4C Deterioration model on patients admitted between August 27, 2020 and April 16, 2021 we found, despite a slightly overestimation of risk, that the discrimination (area under the curve 0.75, 95% CI 0.71-0.78) and calibration of the model remained consistent with the development study, strengthening the evidence for adopting this model into clinical practice.
Effect of Electronic Nicotine Delivery Systems on Cigarette Abstinence in Smokers with no Plans to Quit: Exploratory Analysis of a Randomized Placebo-Controlled Trial
Authors: Foulds Jonathan , Cobb Caroline O. , Yen Miao-Shan , Veldheer Susan , Brosnan Phoebe , Yingst Jessica , Hrabovsky Shari , Lopez Alexa A , Allen Sophia I. , Bullen Christopher , Wang Xi , Sciamanna Chris , Hammett Erin , Hummer Breianna L. , Lester Courtney , Richie John P. , Chowdhury Nadia , Graham Jacob T. , Kang Le , Sun Shumei , Eissenberg Thomas
Published: June 2021

Introduction

The extent to which use of electronic nicotine delivery systems (ENDS) for smoking reduction leads to cigarette abstinence in smokers with no plans to quit smoking is unclear. This exploratory analysis examined the effects of ENDS delivering different amounts of nicotine on cigarette abstinence up to 24-week follow-up, in comparison to placebo or a behavioral substitute.

Methods

This four-arm parallel-group, randomized placebo-controlled trial took place at two academic medical centers in USA (Penn State Hershey and Virginia Commonwealth University). Participants were current adult smokers (N=520) interested in reducing but not planning to quit. They received brief advice and were randomized to one of four 24-week conditions, receiving either an eGo-style ENDS paired with 0, 8 or 36 mg/ml nicotine liquid (double-blind) or a cigarette-shaped tube, as a cigarette substitute (CS). Self-reported daily cigarette consumption and exhaled carbon monoxide (CO) were measured at all study visits. Outcomes included intent-to-treat, self-reported 7-day cigarette abstinence, biochemically confirmed by exhaled CO at 24 weeks after randomization.

Results

At 24 weeks, significantly more participants in the 36 mg/ml condition (14/130, 10.8%) than in the 0 mg/ml condition (1/130, 0.8%) and the CS condition (4/130, 3.1%) were abstinent (relative risk = 14 [95% CI=1.9-104.9] and 3.5 [95% CI=1.2-10.4], respectively). The abstinence rate in the 8 mg/ml condition was 4.6% (6/130).

Conclusions

When smokers seeking to reduce smoking tried ENDS, few quit smoking in the short term. However, if smokers continued to use an ENDS with cigarette-like nicotine delivery, a greater proportion completely switched to ENDS, as compared with placebo or a cigarette substitute.

IMPLICATIONS

The extent to which use of electronic nicotine delivery systems (ENDS) for smoking reduction leads to cigarette abstinence in smokers with no plans to quit smoking was unclear. This randomized trial found that ENDS with nicotine delivery approaching that of a cigarette are more effective in helping ambivalent smokers to quit cigarette smoking.
Land-surface evapotranspiration derived from a first-principles primary production model
Authors: Tan Shen , Wang Han , Prentice Iain Colin , Yang Kun
Published: June 2021

We propose an application of eco-evolutionary optimality theory in the context of monitoring and modelling physical land-surface processes. Evapotranspiration (ET) links the water and carbon cycles in the atmosphere, hydrosphere, and biosphere. We develop an ET modelling framework based on the hypothesis that canopy conductance acclimates to plant growth conditions so that the total costs of maintaining carboxylation and transpiration capacities are minimized. This is combined with the principle of co-ordination between the light- and Rubisco-limited rates of photosynthesis to predict gross primary production (GPP). Transpiration (T) is predicted from GPP via canopy conductance. No plant type- or biome-specific parameters are required. ET is estimated from T by calibrating a site-specific (but time-invariant) ratio of modelled average T to observed average ET. Predicted seasonal cycles of GPP were well supported by (weekly) GPP data at 20 widely distributed eddy-covariance flux sites (228 site-years), with correlation coefficients (r) = 0.81 and root-mean-square error (RMSE) = 18.7 gC/week and Nash-Sutcliffe efficiency coefficient (NSE) = 0.61. Seasonal cycles of ET were also well supported, withr= 0.85, RMSE = 5.5 mm week−1and NSE = 0.66. Estimated T/ET ratios (0.52–0.92) showed significant positive relationships to radiation, precipitation and green vegetation cover and negative relationships to temperature and modelled T (r= 0.84). Although there are still uncertainties to be improved in the current framework, particularly in estimating T/ET, we see the application of eco-evolutionary principles as a promising direction for water resources research.

Highlights

Building an evapotranspiration estimation framework based ona prioriprimary productivity model (the P model).

Assessing the contribution of environmental indicators to the ratio of transpiration to evapotranspiration.

Proving the reliability of this approach to estimate evapotranspiration.
Sustained TREM2 stabilization accelerates microglia heterogeneity and Aβ pathology in a mouse model of Alzheimer’s disease
Authors: Dhandapani Rahul , Neri Marilisa , Bernhard Mario , Brzak Irena , Schweizer Tatjana , Rudin Stefan , Joller Stefanie , Berth Ramon , Waldt Annick , Cuttat Rachel , Naumann Ulrike , Keller Caroline Gubser , Roma Guglielmo , Feuerbach Dominik , Shimshek Derya R. , Neumann Ulf , Gasparini Fabrizio , Galimberti Ivan
Published: June 2021

TREM2 is a transmembrane protein expressed exclusively in microglia in the brain that regulates inflammatory responses to pathological conditions. Proteolytic cleavage of membrane TREM2 affects microglial function and is associated with Alzheimer’s disease, but the consequence of reduced TREM2 proteolytic cleavage has not been determined. We generated a transgenic mouse model of reduced TREM2 shedding (Trem2-IPD) through amino acid substitution of ADAM-protease recognition site. We found that Trem2-IPD mice displayed increased TREM2 cell surface receptor load, survival and function in myeloid cells. Using single cell transcriptomic profiling of mouse cortex we show that sustained TREM2 stabilization induces a shift of fate in microglial maturation and accelerates microglial responses to Aβ pathology in a mouse model of Alzheimer’s disease. Our data indicate that reduction of TREM2 proteolytic cleavage aggravates neuroinflammation during the course of AD pathology suggesting that TREM2 shedding is a critical regulator of microglial activity in pathological states.
Structural analysis of 3’UTRs in insect flaviviruses reveals novel determinant of sfRNA biogenesis and provides new insights into flavivirus evolution
Authors: Slonchak Andrii , Parry Rhys , Pullinger Brody , Sng Julian D.J. , Wang Xiaohui , Buck Teresa F , Torres Francisco J , Harrison Jessica J , Colmant Agathe M G , Hobson-Peters Jody , Hall Roy A , Tuplin Andrew , Khromykh Alexander A
Published: June 2021

Insect-specific flaviviruses (ISFs) circulate in nature due to vertical transmission in mosquitoes and do not infect vertebrates. ISFs include two distinct lineages – classical ISFs (cISFs) that evolved independently and dual host associated ISFs (dISFs) that are proposed to diverge from mosquito-borne flaviviruses (MBFs). Compared to pathogenic flaviviruses, ISFs are relatively poorly studied, and their molecular biology remains largely unexplored. In this study we focused on the characterisation of ISF 3’UTRs and their ability to produce subgenomic flaviviral RNAs – noncoding viral RNAs that are known as important determinants of transmission and replication of pathogenetic flaviviruses. We demonstrated that cISFs and dISFs produce sfRNAs by employing a highly conserved mechanism of resistance to degradation by the cellular 5’-3’ exoribonuclease XRN1. We determined the secondary structures of complete 3’UTRs and experimentally identified structured RNA elements that resist degradation by XRN1 (xrRNAs) in divergent representatives of cISF and dISF clades. We discovered a novel class of xrRNAs in dISFs and identified structurally divergent xrRNA in Anopheles-associated cISFs. Phylogenetic analyses based on sequences and secondary structures of xrRNAs and complete 3’UTRs reveal that xrRNAs of cISFs and MBFs/dISFs evolved from a common xrRNA ancestor similar to the xrRNA of Anopheles-associated cISFs. Additionally, we found that duplications of xrRNAs occurred independently in ISF and MBF clades. Using ISF mutants deficient in the production of sfRNAs, we found that individual sfRNAs of ISFs have redundant functions. We conclude that duplicated xrRNAs were selected in the evolution of flaviviruses to ensure that sfRNA is produced if one of the xrRNAs lose XRN1 resistance due to mutations or misfolding.
Protein crosslinking as a therapeutic strategy for SOD1-related ALS
Authors: Hossain Md Amin , Sarin Richa , Donnelly Daniel P. , Miller Brandon C. , Salisbury Joseph P. , Conway Jeremy B. , Watson Samantha , Winters Jenifer N. , Alam Novera , Sivasankar Durgalakshmi , Ponmudiyan Aparna C. , Gawde Tanvi , Kannapadi Sunanda , Auclair Jared R. , Makowski Lee , Petsko Gregory A. , Ringe Dagmar , Greenblatt David J. , Ondrechen Mary Jo , Chen Yunqiu , Manetsch Roman , Agar Jeffrey N.
Published: June 2021

Mutations in the gene encoding Cu-Zn superoxide dismutase 1 (SOD1) cause a subset of familial amyotrophic lateral sclerosis (fALS). One effect of these mutations is that SOD1, which is normally a stable dimer, dissociates into toxic monomers. Considerable research efforts have been devoted to developing compounds that stabilize the dimer of fALS SOD1 variants, but these have not yet resulted in an approved drug. We demonstrate that a cyclic thiosulfinate cross-linker can stabilize prevalent disease-causing SOD1 variants. The degree of stabilization afforded by cyclic thiosulfinates (up to 24 °C) is unprecedented. We show this compound works rapidly in vivo with a half-life of ~3 days. The efficacy, low toxicity, and pharmacodynamics of cross-linker mediated stabilization make it a promising therapeutic approach for SOD1-related fALS.

Significance statement

Cyclic thiosulfinate S-XL6 enables the kinetic stabilization of ALS-associated SOD1 variants, in vivo.
Accurate model of liquid-liquid phase behaviour of intrinsically-disordered proteins from optimization of single-chain properties
Authors: Tesei Giulio , Schulze Thea K. , Crehuet Ramon , Lindorff-Larsen Kresten
Published: June 2021

Many intrinsically disordered proteins (IDPs) may undergo liquidliquid phase separation (LLPS) and participate in the formation of membraneless organelles in the cell, thereby contributing to the regulation and compartmentalisation of intracellular biochemical reactions. The phase behaviour of IDPs is sequence-dependent, and its investigation through molecular simulations requires protein models that combine computational efficiency with an accurate description of intra- and intermolecular interactions. We developed a general coarse-grained model of IDPs, with residue-level detail, based on an extensive set of experimental data on single-chain properties. Ensemble-averaged experimental observables are predicted from molecular simulations, and a data-driven parameter-learning procedure is used to identify the residue-specific model parameters that minimize the discrepancy between predictions and experiments. The model accurately reproduces the experimentally observed conformational propensities of a set of IDPs. Through two-body as well as large-scale molecular simulations, we show that the optimization of the intramolecular interactions results in improved predictions of protein self-association and LLPS.
Ire1α-Regulated mRNA Translation Rate Controls the Identity and Polarity of Upper Layer Cortical Neurons
Authors: Ambrozkiewicz Mateusz C. , Borisova Ekaterina , Newman Andrew G. , Kraushar Matthew L. , Schaub Theres , Dannenberg Rike , Brockmann Marisa , Rosário Marta , Turko Paul , Jahn Olaf , Kaplan David R. , Iwawaki Takao , Spahn Christian M. T. , Rosenmund Christian , Tarabykin Victor
Published: June 2021

Evolutionary expansion of the neocortex is associated with the increase in upper layer neurons. Here, we present Inositol-Requiring Enzyme 1α, Ire1α, as an essential determinant of upper layer fate, neuronal polarization and cortical lamination. We demonstrate a non-canonical function of Ire1α in the regulation of global translation rates in the developing neocortex through its dynamic interaction with the ribosome and regulation of eIF4A1 and eEF-2 expression. Inactivation of Ire1α engenders lower protein synthesis rates associated with stalled ribosomes and decreased number of translation start sites. We show unique sensitivity of upper layer fate to translation rates. Whereas eEF-2 is required for cortical lamination, eIF4A1 regulates acquisition of upper layer fate downstream of Ire1α in a mechanism of translational control dependent on 5’UTR-embedded structural elements in fate determinant genes. Our data unveil developmental regulation of ribosome dynamics as post-transcriptional mechanisms orchestrating neuronal diversity establishment and assembly of cortical layers.

HIGHLIGHTS

Small molecule screening reveals Ire1α upstream of upper layer neuronal identity

Polarization and proper lamination of layer II/III neurons require Ire1α

Development of upper layers requires high translation rates driven by eIF4A1 and eEF-2 downstream of Ire1α

eIF4A1-dependent Satb2 mRNA translation initiation is a mechanism of upper layer fate acquisition
3D UNet with GAN discriminator for robust localisation of the fetal brain and trunk in MRI with partial coverage of the fetal body
Authors: Uus Alena , Grigorescu Irina , van Poppel Milou , Hughes Emer , Steinweg Johannes , Roberts Thomas , Lloyd David , Pushparajah Kuberan , Deprez Maria
Published: June 2021

In fetal MRI, automated localisation of the fetal brain or trunk is a prerequisite for motion correction methods. However, the existing CNN-based solutions are prone to errors and may require manual editing. In this work, we propose to combine a multi-label 3D UNet with a GAN discriminator for localisation of both fetal brain and trunk in fetal MRI stacks. The proposed method is robust for datasets with both full and partial coverage of the fetal body.
High quality, phased genomes of Phytophthora ramorum clonal lineages NA1 and EU1
Authors: Carleson Nicholas C. , Press Caroline M. , Grünwald Niklaus J.
Published: June 2021

Phytophthora ramorum is the causal agent of sudden oak death in West Coast forests and currently two clonal lineages, NA1 and EU1, cause epidemics in Oregon forests. Here, we report on two high-quality genomes of individuals belonging to the NA1 and EU1 clonal lineages respectively, using PacBio long-read sequencing. The NA1 strain Pr102, originally isolated from coast live oak in California, is the current reference genome and was previously sequenced independently using either Sanger (P. ramorum v1) or PacBio (P. ramorum v2) technology. The EU1 strain PR-15-019 was obtained from tanoak in Oregon. These new genomes have a total size of 57.5 Mb, with a contig N50 length of ~3.5-3.6 Mb and encode ~15,300 predicted protein-coding genes. Genomes were assembled into 27 and 28 scaffolds with 95% BUSCO scores and are considerably improved relative to the current JGI reference genome with 2,575 or the PacBio genomes with 1,512 scaffolds. These high-quality genomes provide a valuable resource for studying the genetics, evolution, and adaptation of these two clonal lineages.
A critical period of translational control during brain development at codon resolution
Authors: Harnett Dermot , Ambrozkiewicz Mateusz C. , Zinnall Ulrike , Rusanova Alexandra , Borisova Ekaterina , Dannenberg Rike , Imami Koshi , Münster-Wandowski Agnieszka , Fauler Beatrix , Mielke Thorsten , Selbach Matthias , Landthaler Markus , Spahn Christian M.T. , Tarabykin Victor , Ohler Uwe , Kraushar Matthew L.
Published: June 2021

Translation modulates the timing and amplification of gene expression after transcription. Brain development requires uniquely complex gene expression patterns, but large-scale measurements of translation directly in the prenatal brain are lacking. We measure the reactants, synthesis, and products of translation spanning mouse neocortex neurogenesis, and discover a transient window of dynamic regulation at mid-gestation. Timed translation upregulation of chromatin binding proteins like Satb2, which is essential for neuronal subtype differentiation, restricts protein expression in neuronal lineages despite broad transcriptional priming in progenitors. In contrast, translation downregulation of ribosomal proteins sharply decreases ribosome number, coinciding with a major shift in protein synthesis dynamics at mid-gestation. Changing levels of eIF4EBP1, a direct inhibitor of ribosomal protein translation, are concurrent with ribosome downregulation and controls Satb2 fate acquisition during neuronal differentiation. Thus, the refinement of transcriptional programs by translation is central to the molecular logic of brain development. Modeling of the developmental neocortex translatome is provided as an open-source searchable resource: https://shiny.mdc-berlin.de/cortexomics/.
SLC1A5provides glutamine and asparagine necessary for bone development in mice
Authors: Sharma Deepika , Yu Yilin , Shen Leyao , Zhang Guo-Fang , Karner Courtney
Published: June 2021

Osteoblast differentiation is sequentially characterized by high rates of proliferation followed by increased protein and matrix synthesis, processes that require substantial amino acid acquisition and production. How osteoblasts obtain or maintain intracellular amino acid production is poorly understood. Here we identifySlc1a5as a critical amino acid transporter during bone development. Using a genetic and metabolomic approach, we showSlc1a5acts cell autonomously in osteoblasts to import glutamine and asparagine. DeletingSlc1a5or reducing either glutamine or asparagine availability prevents protein synthesis and osteoblast differentiation. Mechanistically, glutamine and asparagine metabolism support amino acid biosynthesis. Thus, osteoblasts depend onSlc1a5to provide glutamine and asparagine, which are subsequently used to produce non-essential amino acids and support osteoblast differentiation and bone development.
Mapping the corticoreticular pathway from cortex-wide anterograde axonal tracing in the mouse
Authors: Boyne Pierce , Awosika Oluwole O. , Luo Yu
Published: June 2021

The corticoreticular pathway (CRP) has been implicated as an important mediator of motor recovery and rehabilitation after central nervous system damage. However, its origins, trajectory and laterality are not well understood. This study mapped the mouse CRP in comparison with the corticospinal tract (CST). We systematically searched the Allen Mouse Brain Connectivity Atlas (© 2011 Allen Institute for Brain Science) for experiments that used anterograde tracer injections into the right isocortex in mice. For each eligible experiment (N=607), CRP and CST projection strength were quantified by the tracer volume reaching the reticular formation motor nuclei (RFmotor) and pyramids respectively. Tracer density in each brain voxel was also correlated with RFmotor versus pyramids projection strength to explore the relative trajectories of the CRP and CST. We found significant CRP projections originating from the primary and secondary motor cortices, anterior cingulate, primary somatosensory cortex and medial prefrontal cortex. Compared with the CST, the CRP had stronger projections from each region except the primary somatosensory cortex. Ipsilateral projections were stronger than contralateral for both tracts (above the pyramidal decussation), but the CRP projected more bilaterally than the CST. The estimated CRP trajectory was anteromedial to the CST in the internal capsule and dorsal to the CST in the brainstem. Our findings reveal a widespread distribution of CRP origins and confirm strong bilateral CRP projections, theoretically increasing the potential for partial sparing after brain lesions and contralesional compensation after unilateral injury.

SIGNIFICANCE

The corticoreticular pathway (CRP) provides volitional input to brainstem nuclei that generate walking command signals, facilitate balance and direct limb movements. Upregulation of this pathway appears to be a central mechanism of movement recovery after brain and spinal cord injury, but its anatomy is not well understood. We showed that the mouse CRP originates from widespread parts of the cortex, including non-motor regions, that it projects strongly to both sides of the brainstem, and that its projections are more distributed and bilateral than the corticospinal tract. These findings suggest that the CRP may be particularly resilient to complete disruption.
Polygenic variation in sexual investment across an ephemerality gradient inDaphnia pulex
Authors: Barnard-Kubow Karen , Becker Dörthe , Murray Connor S. , Porter Robert , Gutierrez Grace , Erickson Priscilla , Nunez Joaquin C. B. , Voss Erin , Suryamohan Kushal , Ratan Aakrosh , Beckerman Andrew , Bergland Alan O.
Published: June 2021

Species across the tree of life can switch between asexual and sexual reproduction. In facultatively sexual species, the ability to switch between reproductive modes is often environmentally dependent and subject to local adaptation. However, the ecological and evolutionary factors that influence the maintenance and turnover of polymorphism associated with facultative sex remain unclear. To address this basic question, we studied the ecological and evolutionary dynamics of polymorphism in reproductive strategy in a metapopulation of the model facultative sexual,Daphnia pulex, located in the southern United Kingdom. We found that patterns of clonal diversity, but not genetic diversity varied with ephemerality. Reconstruction of a multi-year pedigree demonstrated the co-existence of clones that were found to differ in their investment into male production. Mapping of quantitative variation in male production using lab-generated and field-collected individuals identified multiple putative QTL underlying this trait, and we identified a plausible candidate gene. The evolutionary history of these QTL suggests that they are relatively young, and male limitation in this system is a rapidly evolving trait. Our work highlights the dynamic nature of the genetic structure and composition of facultative sex across space and time and suggests that quantitative genetic variation in reproductive strategy can undergo rapid evolutionary turnover.
An empirically-driven guide on using Bayes Factors for M/EEG decoding
Authors: Teichmann Lina , Moerel Denise , Baker Chris , Grootswagers Tijl
Published: June 2021

Bayes Factors can be used to provide quantifiable evidence for contrasting hypotheses and have thus become increasingly popular in cognitive science. However, Bayes Factors are rarely used to statistically assess the results of neuroimaging experiments. Here, we provide an empirically-driven guide on implementing Bayes Factors for time-series neural decoding results. Using real and simulated Magnetoencephalography (MEG) data, we examine how parameters such as the shape of the prior and data size affect Bayes Factors. Additionally, we discuss benefits Bayes Factors bring to analysing multivariate pattern analysis data and show how using Bayes Factors can be used instead or in addition to traditional frequentist approaches.
The impact of mutation L138F/L210F on the Orai channel: a molecular dynamics simulation study
Authors: Zhang Xiaoqian , Yu Hua , Liu Xiangdong , Song Chen
Published: June 2021

The calcium release-activated calcium (CRAC) channel, composed of the Orai channel and the STIM protein, plays a crucial role in maintaining the Ca2+ concentration in cells. Previous studies showed that the L138F mutation in the human Orai1 creates a constitutively open channel independent of STIM, causing severe myopathy, but how the L138F mutation activates Orai1 is still unclear. Here, based on the crystal structure of Drosophila melanogaster Orai (dOrai), molecular dynamics simulations for the wild-type (WT) and the L210F (corresponding to L138F in the human Orai1) mutant were conducted to investigate their structural and dynamical properties. The results showed that the L210F dOrai mutant tends to have a more hydrated hydrophobic region (V174 to F171), as well as more dilated basic region (K163 to R155) and selectivity filter (E178). Sodium ions were located deeper in the mutant than in the WT. Further analysis revealed two local but essential conformational changes that may be the key to the activation. A rotation of F210, a previously undescribed feature, was found to result in the opening of the K163 gate through hydrophobic interactions. At the same time, a counter-clockwise rotation of F171 occurred more frequently in the mutant, resulting in a wider hydrophobic gate with more hydration. Ultimately, the opening of the two gates may facilitate the opening of the Orai channel independent of STIM.
Norepinephrine activates β1-adrenergic receptors localized to the inner nuclear membrane in cortical astrocytes
Authors: Benton Kelsey C. , Wheeler Daniel S. , Kurtoglu Beliz , Bagher Zadeh Ansari Mahshid , Cibich Daniel P. , Gonzalez Dante A. , Herbst Matthew R. , Khursheed Saema , Knorr Rachel C. , Lobner Doug , Maglasang Jenree G. , Rohr Kayla E. , Taylor Analisa , Witt Paul J. , Gasser Paul J.
Published: June 2021

Studies in cardiomyocytes have established that adrenergic receptors, conventionally thought to initiate signaling events exclusively from the plasma membrane, can also localize to and signal from the nuclear membrane. Activation of these receptors by their endogenous cationic ligands requires transmembrane uptake mediated by organic cation transporter 3 (OCT3). We have demonstrated that OCT3 is densely localized to outer nuclear membranes in neurons and astrocytes, suggesting that nuclear adrenergic signaling is also present in the central nervous system. In this study, we examined the subcellular localization of β1-adrenergic receptors, their G-protein signaling partners, and catecholamine transporters in mouse astrocytes. We identified a population of β1-adrenergic receptors localized to astrocyte inner nuclear membranes. We demonstrated that key components of Gs-mediated signaling are localized to the nuclear compartment and identified OCT3 and other catecholamine transporters localized to plasma and nuclear membranes. Treatment of astrocytes with norepinephrine induced rapid increases in nuclear PKA activity which were blocked by pretreatment with inhibitors of catecholamine transport. These data indicate that nuclear β1-adrenergic receptors are functionally coupled to Gs-coupled signaling mediators and that their activation by norepinephrine requires transporter-mediated uptake. These receptors represent a powerful mechanism by which norepinephrine may alter astrocyte gene expression and brain function.
Genome-wide profiling reveals functional interplay of DNA sequence composition, transcriptional activity, and nucleosome positioning in driving DNA supercoiling and helix destabilization in C. elegans
Authors: Krassovsky Kristina , Ghosh Rajarshi P. , Meyer Barbara J.
Published: June 2021

DNA topology and alternative DNA structures are implicated in regulating diverse biological processes. Although biomechanical properties of these structures have been studied extensively in vitro, characterization in vivo, particularly in multicellular organisms, is limited. We devised new methods to map DNA supercoiling and single-stranded DNA in Caenorhabditis elegans embryos and diapause larvae. To map supercoiling, we quantified the incorporation of biotinylated psoralen into DNA using high-throughput sequencing. To map single-stranded DNA, we combined permanganate treatment with genome-wide sequencing of induced double-stranded breaks. We found high levels of negative supercoiling at transcription start sites (TSSs) in embryos. GC-rich regions flanked by a sharp GC-to-AT transition delineate boundaries of supercoil propagation. In contrast to TSSs in embryos, TSSs in diapause larvae showed dramatic reductions in negative supercoiling without concomitant attenuation of transcription, suggesting developmental-stage-specific regulation. To assess whether alternative DNA structures control chromosome architecture and gene expression, we examined DNA supercoiling in the context of X-Chromosome dosage compensation. We showed that the condensin dosage compensation complex creates negative supercoils locally at its highest-occupancy binding sites but found no evidence for large-scale supercoiling domains along X Chromosomes. In contrast to transcription-coupled negative supercoiling, single-strandedness, which is most pronounced at transcript end sites, is dependent on high AT content and symmetrically positioned nucleosomes. We propose that sharp transitions in sequence composition at functional genomic elements constitute a common regulatory code and that DNA structure and propagation of torsional stress at regulatory elements are critical parameters in shaping important developmental events.
Optimal propeller blade design, computation, manufacturing and experimental testing
Authors: Kovačević Aleksandar , Svorcan Jelena , Hasan Mohammad Sakib , Ivanov Toni , Jovanović Miroslav
Published: June 2021

Purpose

Modern unmanned air vehicles (UAVs) are usually equipped with rotors connected to electric motors that enable them to hover and fly in all directions. The purpose of the paper is to design optimal composite rotor blades for such small UAVs and investigate their aerodynamic performances both computationally and experimentally.

Design/methodology/approach

Artificial intelligence method (genetic algorithm) is used to optimize the blade airfoil described by six input parameters. Furthermore, different computational methods, e.g. vortex methods and computational fluid dynamics, blade element momentum theory and finite element method, are used to predict the aerodynamic performances of the optimized airfoil and complete rotor as well the structural behaviour of the blade, respectively. Finally, composite blade is manufactured and the rotor performance is also determined experimentally by thrust and torque measurements.

Findings

Complete process of blade design (including geometry definition and optimization, estimation of aerodynamic performances, structural analysis and blade manufacturing) is conducted and explained in detail. The correspondence between computed and measured thrust and torque curves of the optimal rotor is satisfactory (differences mostly remain below 15%), which validates and justifies the used design approach formulated specifically for low-cost, small-scale propeller blades. Furthermore, the proposed techniques can easily be applied to any kind of rotating lifting surfaces including helicopter or wind turbine blades.

Originality/value

Blade design methodology is simplified, shortened and made more flexible thus enabling the fast and economic production of propeller blades optimized for specific working conditions.