bluuebunny/crossref_metadata_2025 huggingface dataset:
Multi-Dimensional Event Data in Graph Databases
Authors: Esser Stefan , Fahland Dirk
Published: May 2021

Process event data is usually stored either in a sequential process event log or in a relational database. While the sequential, single-dimensional nature of event logs aids querying for (sub)sequences of events based on temporal relations such as “directly/eventually-follows,” it does not support querying multi-dimensional event data of multiple related entities. Relational databases allow storing multi-dimensional event data, but existing query languages do not support querying for sequences or paths of events in terms of temporal relations. In this paper, we propose a general data model for multi-dimensional event data based on labeled property graphs that allows storing structural and temporal relations in a single, integrated graph-based data structure in a systematic way. We provide semantics for all concepts of our data model, and generic queries for modeling event data over multiple entities that interact synchronously and asynchronously. The queries allow for efficiently converting large real-life event data sets into our data model, and we provide 5 converted data sets for further research. We show that typical and advanced queries for retrieving and aggregating such multi-dimensional event data can be formulated and executed efficiently in the existing query language Cypher, giving rise to several new research questions. Specifically, aggregation queries on our data model enable process mining over multiple inter-related entities using off-the-shelf technology.
Racial/Ethnic Disparities in Pregnancy and Prenatal Exposure to Endocrine-Disrupting Chemicals Commonly Used in Personal Care Products
Authors: Chan Marissa , Mita Carol , Bellavia Andrea , Parker Michaiah , James-Todd Tamarra
Published: May 2021

Purpose of Review

Endocrine-disrupting chemical (EDC) exposure during pregnancy is linked to adverse maternal and child health outcomes that are racially/ethnically disparate. Personal care products (PCP) are one source of EDCs where differences in racial/ethnic patterns of use exist. We assessed the literature for racial/ethnic disparities in pregnancy and prenatal PCP chemical exposures.

Recent Findings

Only 3 studies explicitly examined racial/ethnic disparities in pregnancy and prenatal exposure to PCP-associated EDCs. Fifty-three articles from 12 cohorts presented EDC concentrations stratified by race/ethnicity or among homogenous US minority populations. Studies reported on phthalates and phenols. Higher phthalate metabolites and paraben concentrations were observed for pregnant non-Hispanic Black and Hispanic women. Higher concentrations of benzophenone-3 were observed in non-Hispanic White women; results were inconsistent for triclosan.

This review highlights need for future research examining pregnancy and prenatal PCP-associated EDCs disparities to understand and reduce racial/ethnic disparities in maternal and child health.
Urinary complement proteins and risk of end-stage renal disease: quantitative urinary proteomics in patients with type 2 diabetes and biopsy-proven diabetic nephropathy
Authors: Zhao L. , Zhang Y. , Liu F. , Yang H. , Zhong Y. , Wang Y. , Li S. , Su Q. , Tang L. , Bai L. , Ren H. , Zou Y. , Wang S. , Zheng S. , Xu H. , Li L. , Zhang J. , Chai Z. , Cooper M. E. , Tong N.
Published: May 2021

Purpose

To investigate the association between urinary complement proteins and renal outcome in biopsy-proven diabetic nephropathy (DN).

Methods

Untargeted proteomic and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional analyses and targeted proteomic analysis using parallel reaction-monitoring (PRM)-mass spectrometry was performed to determine the abundance of urinary complement proteins in healthy controls, type 2 diabetes mellitus (T2DM) patients, and patients with T2DM and biopsy-proven DN. The abundance of each urinary complement protein was individually included in Cox proportional hazards models for predicting progression to end-stage renal disease (ESRD).

Results

Untargeted proteomic and functional analysis using the KEGG showed that differentially expressed urinary proteins were primarily associated with the complement and coagulation cascades. Subsequent urinary complement proteins quantification using PRM showed that urinary abundances of C3, C9, and complement factor H (CFAH) correlated negatively with annual estimated glomerular filtration rate (eGFR) decline, while urinary abundances of C5, decay-accelerating factor (DAF), and CD59 correlated positively with annual rate of eGFR decline. Furthermore, higher urinary abundance of CFAH and lower urinary abundance of DAF were independently associated with greater risk of progression to ESRD. Urinary abundance of CFAH and DAF had a larger area under the curve (AUC) than that of eGFR, proteinuria, or any pathological parameter. Moreover, the model that included CFAH or DAF had a larger AUC than that with only clinical or pathological parameters.

Conclusion

Urinary abundance of complement proteins was significantly associated with ESRD in patients with T2DM and biopsy-proven DN, indicating that therapeutically targeting the complement pathway may alleviate progression of DN.
Decision support model with Pythagorean fuzzy preference relations and its application in financial early warnings
Authors: Wu Wenying , Ni Zhiwei , Jin Feifei , Li Ying , Song Juan
Published: May 2021

Pythagorean fuzzy sets (PFSs) retain the advantages of intuitionistic fuzzy sets (IFSs), while PFSs portray 1.57 times more information than IFSs. In addition, Pythagorean fuzzy preference relations (PFPRs), as a generalization of intuitionistic fuzzy preference relations (IFPRs), are more flexible and applicable. The objective of this paper is to propose a novel decision support model for solving group decision-making problems in a Pythagorean fuzzy environment. First, we define the concepts of ordered consistency and multiplicative consistency for PFPRs. Then, aiming at the group decision-making problem of multiple PFPRs, a consistency improving model is constructed to improve the consistency of group preference relations. Later, a consensus reaching model is developed to reach the degree of group consensus. Furthermore, a decision support model with PFPRs is established to derive the normalized weights and output the final result. Holding these features, this paper builds a decision support model with PFPRs based on multiplicative consistency and consensus. Finally, the described method is validated by an example of financial risk management, and it is concluded that the solvency of a company is an important indicator that affects the financial early warning system.
Extreme Demand Avoidance in Children with Autism Spectrum Disorder: Refinement of a Caregiver-Report Measure
Authors: O’Nions Elizabeth , Happé Francesca , Viding Essi , Noens Ilse
Published: May 2021

Objectives

Extreme/“pathological” demand avoidance (PDA) describes a presentation found in some children on the autism spectrum, characterized by obsessive resistance to everyday demands and requests. Demands often trigger avoidance behavior (e.g., distraction, excuses, withdrawal into role play). Pressure to comply can lead to escalation in emotional reactivity and behavior that challenges.

Methods

Previously, the Extreme Demand Avoidance Questionnaire (EDA-Q) was developed to quantify resemblance to clinical accounts of PDA from caregiver reports. The aim of this study was to refine the EDA-Q using principal components analysis (PCA) and item response theory (IRT) analysis on parent/caregiver-report data from 334 children with ASD aged 5–17 years.

Results

PCA and IRT analyses identified eight items that are discriminating indices of EDA traits, and behave similarly with respect to quantifying EDA irrespective of child age, gender, reported academic level, or reported independence in daily living activities. The “EDA-8” showed good internal consistency (Cronbach’s alpha = .90) and convergent and divergent validity with other measures (some of which were only available for a subsample of 233 respondents). EDA-8 scores were not related to parental reports of ASD severity.

Conclusions

Inspection of the test information function suggests that the EDA-8 may be a useful tool to identify children on the autism spectrum who show an extreme response to demands, as a starting point for more in-depth assessment.
Identifying potential novel resistance to the foliar disease ‘Scald’ (Rhynchosporium commune) in a population of Scottish Bere barley landrace (Hordeum vulgare L.)
Authors: Cope Jonathan E. , Norton Gareth J. , George Timothy S. , Newton Adrian C.
Published: May 2021

Barley ‘Scald’ is an economically damaging fungal disease that is a global problem, causing significant yield and economical losses in the UK barley feed and malting industries. Presently, a limited number of Rhynchosporium resistance genes exist, but selective pressures on the fungi cause the demand for new sources of resistance. Landraces, such as the Scottish Bere barley, hold potential sources of resistance that can be utilised, with farmers providing anecdotal evidence of resistance in field populations of Bere. This study analysed 131 heritage cultivars and landrace lines, including 37 Bere lines, to screen for resistance using both detached leaf assays (DLAs) and field experiments. Results showed that Bere lines produced smaller, but more necrotic, lesions for the majority of isolates in the DLAs, as well as smaller scores when visually assessed in field conditions. Whilst the infection patterns of the lines differed between isolates and experimental conditions, three Bere lines were identified as consistently showing reduced levels of infection (45 A 23, 58 A 36 Eday, and 8-125). Using genome-wide association analysis, we were able to identify a number of genomic regions associated with reduced infection symptoms, four in regions associated with known resistance genes, but another four associated with new regions that contain promising candidate genes. Further analysis of these new regions and candidate genes should be undertaken to identify targets for future disease-resistance breeding.
Digital media and misinformation: An outlook on multidisciplinary strategies against manipulation
Authors: Caled Danielle , Silva Mário J.
Published: May 2021

This review discusses the dynamic mechanisms of misinformation creation and spreading used in social networks. It includes: (1) a conceptualization of misinformation and related terms, such as rumors and disinformation; (2) an analysis of the cognitive vulnerabilities that hinder the correction of the effects of an inaccurate narrative already assimilated; and (3) an interdisciplinary discussion on different strategies for coping with misinformation. The discussion encompasses journalistic, educational, governmental and computational viewpoints on the topic. The review also surveys how digital platforms handle misinformation and gives an outlook on opportunities to address it in light of the presented viewpoints.
Hybrid approaches coupling sol–gel and plasma for the deposition of oxide-based nanocomposite thin films: a review
Authors: Mitronika Maria , Granier Agnès , Goullet Antoine , Richard-Plouet Mireille
Published: May 2021

In view of developing new materials with enhanced properties, such as nanocomposite (NC) thin films, special interest has been given in optimizing the deposition processes themselves. The latter, if well selected, could give the freedom to control the NCs synthesis and final properties. Attempting to overcome severe challenges observed when creating NC or oxide-based NC film, hybrid approaches combining injection of colloidal solutions and plasma processes have been proposed. This review focuses on oxide-based NCs, using as an example the TiO2 NPs and SiO2 matrix as NCs, while investigating their optical and dielectric properties. Additionally, this review presents the state-of-the-art in processes for the preparation of the NCs. The major categories of hybrid approaches coupling sol–gel and plasma processes are given. Finally, a comparative study among the published works is provided, aiming in highlighting the impact that each approach has on the physical and chemical characteristics of the produced NCs.
Load monitoring of a cantilever plate by a novel multimodal fibre optic sensing configuration
Authors: Nazeer N. , Groves R. M.
Published: May 2021

Optical fibre sensors and in particular fibre Bragg gratings (FBG) have received a lot of interest for Structural Health Monitoring in different application fields, such as aerospace, pipeline and civil engineering. FBGs are conventionally used to monitor strain and sometimes temperature. In this paper, we propose a new method for load monitoring of a cantilever plate subjected to point loading. The bending of plate is complex due to the interaction between the axial and transverse bending stiffnesses of the material. We use a novel algorithm for interrogating fibre Bragg grating sensors based on both hybrid interferometry and FBG spectral sensing. The method is demonstrated in this paper using a single-mode optical fibre containing four FBG sensors to estimate both the point loading position and the loading magnitude at an arbitrary location on a 1 m$$^{2}$$2cantilever plate. The algorithm first utilizes point strain information through spectral sensing as well as strain from interferometric sensing over a long path. The gratings are interrogated using Wavelength Division Multiplexing (WDM). We calibrated the system using an experimental model. This model was then verified by using single point static loading tests and comparing the calculated sensing position with the actual position. The method achieved a good estimation of loading position achieving a measurement error of about 9% in a 2D plane. The analysis discusses the possible sources of inaccuracies. This study forms the basis of our future work involving morphing smart-wing sections for the purpose of load monitoring.

Article highlights

A new optical sensing configuration is demonstrated for load and structural health monitoring of cantilever structures.

The algorithm successfully estimates the position of an arbitrary load on a cantilever plate, with an error of 9%.

This methodology will be extended to monitor more complex structures, in- cluding morphing aircraft wing sections.
Addressing Bias in Responder Analysis of Patient-Reported Outcomes
Authors: Cappelleri Joseph C. , Chambers Richard
Published: May 2021

Introduction

Quantitative patient-reported outcome (PRO) measures ideally are analyzed on their original scales and responder analyses are used to aid the interpretation of those primary analyses. As stated in the FDA PRO Guidance for Medical Product Development (2009), one way to lend meaning and interpretation to such a PRO measure is to dichotomize between values where within-patient changes are considered clinically important and those that are not. But even a PRO scale with a cutoff score that discriminates well between responder and non-responders is fraught with some misclassification.

Methods

Using estimates of sensitivity and specificity on classification of responder status from a PRO instrument, formulas are provided to correct for such responder misclassification under the assumption of no treatment misclassification. Two case studies from sexual medicine illustrate the methodology.

Results

Adjustment formulas on cell counts for responder misclassification are a direct extension of correction formulas for misclassification on disease from a two-way cross-classification table of disease (yes, no) and exposure (yes, no). Unadjusted and adjusted estimates of treatment effect are compared in terms of odds ratio, response ratio, and response difference. In the two case studies, there was considerable underestimation of treatment effect.

Discussion and conclusions

The methodology can be applied to different therapeutic areas. Limitations of the methodology, such as when adjusted cell estimates become negative, are highlighted. The role of anchor-based methodology is discussed for obtaining estimates of sensitivity and specificity on responder classification. Correction for treatment effect bias from misclassification of responder status on PRO measures can lead to more trustworthy interpretation and effective decision-making.

Clinicaltrials.gov: NCT00343200
The Effectiveness of Triggered Email Marketing in Addressing Browse Abandonments
Authors: Goic Marcel , Rojas Andrea , Saavedra Ignacio
Published: May 2021

Triggered emails are personalized messages that are automatically sent as a response to specific actions or states of customers. Typical examples of this type of campaign include cross-selling recommendations, cart abandonment reminders, and re-engagement emails. Despite the widespread growth of these strategies, there has been no formal evaluation of their effectiveness. This paper investigates the impact of one type of triggered email campaign by using an experimental approach. We identify customers who had recently browsed the website of a multichannel retailer but had abandoned the process before making a purchase. Approximately half of the sample was randomly selected to receive automated emails with different configurations, while the other half receive no message at all. Comparison of the sales of these two groups indicates that browse abandonment emails have increase revenues in the online channel and in the triggered category. In terms of the design of the campaign, we found that the implementation of triggered emails plays an important role in their effectiveness. In this regard our result indicates that retargeting based on longer navigation histories is associated with larger conversions and that recommendations of wider assortments are associated with larger revenues.
Preparing for an Imperial Inheritance: Children, Play, and Empire in Eighteenth-Century Britain
Authors: Bickham Troy
Published: May 2021

In examining how children engaged with the British Empire, broadly defined, during the long eighteenth century, this article considers a range of materials, including museums, printed juvenile literature, and board games, that specifically attempted to attract children and their parents. Subjects that engaged with the wider world, and with it the British Empire, were typically not a significant part of formal education curricula, and so an informal marketplace of materials and experiences emerged both to satisfy and drive parental demand for supplementary education at home. Such engagements were no accident. Rather, they were a conscious effort to provide middling and elite children with what was considered useful information about the wider world and empire they would inherit, as well as opportunities to consider the moral implications and obligations of imperial rule, particularly with regard to African slavery.
THE RATES OF JURY PAY AND ASSEMBLY PAY IN FOURTH-CENTURY ATHENS
Authors: Sing Robert
Published: May 2021

During the fourth century, the amount of money Athenians got from thepolisfor volunteering to sit on a jury and for attending the assembly diverged significantly. Jury pay remained at 3 obols a day, despite inflation, while the pay given for a principal(kyria)assembly eventually rose from 1 obol to 9 obols—outpacing inflation and overcompensating most citizens for their time. What demographic reconstruction of the jury can explain why the real value of jury pay never declined to the point that too few Athenians volunteered? Self-reliant citizens (penêtes) must have dominated the jury pool, andpenêteswith young adult children would have volunteered most often. Having an additional source of household labour reduced the opportunity cost of jury service for these Athenians and made their participation more resilient in the face of the declining value of pay. Citizens who faced greater opportunity costs probably participated less over time, meaning that fourth-century juries gradually became less diverse. By contrast, the growth in assembly pay can best be understood in terms of the ‘Lycurgan’ agenda of the 330s and the 320s. Greater pay helped to ensure that the assembly's newly expanded meeting place on the Pnyx was filled to capacity with citizens from all over Attica. The result was a massive spectacle that celebrated a threatened democracy and stimulated thepoliseconomy. Since the courts lacked the same capacity for spectacle, there was no political motivation to pay jurors more.
Low Back Pain in a Nova Scotian Emergency Department: Prevalence and Patient Characteristics in the Older Adult Patient Population
Authors: Federico Lucy , Andrew Melissa K , Ogilvie Rachel , Wilson Maria , Magee Kirk , Hayden Jill A
Published: May 2021

Low back pain is a major cause of disability in older adults, and results in many emergency department visits each year. Characteristics of the older back pain population are largely unknown. We conducted a retrospective study to examine the prevalence and patient characteristics for older (≥ 65 years of age) and younger (16–64 years of age) adults presenting with back pain. Study objectives were to describe the characteristics of older adults with back pain presenting to an emergency department and to identify age-group-based differences in management. Older adults were most commonly diagnosed with non-specific low back pain (49%). For older adults with this diagnosis, the length of stay was 2.1 times longer (p < 0.001), and odds of being admitted to the hospital were 5.1 times higher (p < 0.001) than for younger adults. Patterns of management are different for younger and older adults with low back pain; this information can be used to direct future resource planning.
Household food insecurity and early childhood development in Brazil: an analysis of children under 2 years of age
Authors: de Oliveira Klébya HD , Buccini Gabriela , Hernandez Daphne C , Pérez-Escamilla Rafael , Gubert Muriel B
Published: May 2021

Objective:

To determine if household food insecurity (HFI) is associated with the risk of developmental delays.

Design:

Cross-sectional study of a representative sample of children under 2 years old. Risk of developmental delays was assessed with the Denver Developmental Screening Test II. HFI was measured with the Brazilian Food Insecurity Measurement Scale. Multivariable logistic regression was used to test the association between HFI (food secure/insecure) and risk of developmental delays, adjusting for household, maternal and child variables.

Setting:

Community Health Centers in the Federal District, Brazil.

Participants:

1004 children under 2 years old.

Results:

Among participants, 15 % were at risk of developmental delays and about 40 % of children lived in food-insecure households. HFI was associated with the risk of developmental delays (adjusted OR 2·61; 95 % CI 1·42, 4·80) compared with food-secure households after adjusting for key confounders.

Conclusions:

HFI was strongly associated with the risk of developmental delays in children under 2 years. Investments that prevent or mitigate HFI are likely to be key for improved human and national development.
Equality Bodies: advancing towards more responsive designs?
Authors: Benedi Lahuerta Sara
Published: May 2021

The EU has progressively introduced antidiscrimination enforcement measures like the duty to set up Equality Bodies (EBs) that applies to the ground of racial or ethnic origin, among others. Until recently, however, EU law only envisaged vague standards for EBs that allowed a wide range of national configurations. Building on international benchmarks, this paper draws a set of dimensions considered necessary to improve promotion-type EBs responsiveness to discrimination. These dimensions are applied to the British and Spanish EBs to illustrate how the gaps left by EU law may lead to the design of ineffective bodies. The paper argues that EBs can contribute to effectively tackling discrimination if they are designed to be responsive at individual and systemic levels. The 2018 EU Recommendation on Standards for EBs makes a step forward in that direction, but its practical relevance may be limited by its non-binding nature.
Dependence of Parallel Electrical Conductivity in the Topside Ionosphere on Solar and Geomagnetic Activity
Authors: Giannattasio F. , Pignalberi A. , De Michelis P. , Coco I. , Consolini G. , Pezzopane M. , Tozzi R.
Published: May 2021

The spatial and temporal dynamics of ionospheric currents are among the most evident manifestations of the interaction between the magnetized plasma of solar origin and the magnetosphere‐ionosphere system. In this context, a special role is played by field‐aligned currents (FACs), which drive energy and momentum exchanges between the magnetosphere and the ionosphere, deeply affecting the energy balance of the latter. One of the most relevant physical quantities that may help to fully characterize FACs is the ionospheric electrical conductivity. Understanding the features associated with this quantity may contribute to the advancement of knowledge on the mechanisms of solar wind‐magnetosphere‐ionosphere interaction as well as energy storage and dissipation involved in the space weather phenomena. By extending a previous study, we investigate the dependence of the electrical conductivity parallel to the geomagnetic field on solar and geomagnetic activity. To this aim, we considered a six‐year long data set of in‐situ electron density and temperature values recorded by the Langmuir probes on board the Swarm satellites in the topside ionosphere. With this large data set, we computed global maps of the parallel electron conductivity under both quiet and disturbed conditions, and for different solar activity levels. In both cases, the International Reference Ionosphere (IRI) model allowed estimating the contribution of particle precipitation to electrical conductivity.
Actuation enhances patterning in human neural tube organoids
Authors: Abdel Fattah Abdel Rahman , Daza Brian , Rustandi Gregorius , Berrocal-Rubio Miguel Ángel , Gorissen Benjamin , Poovathingal Suresh , Davie Kristofer , Barrasa-Fano Jorge , Cóndor Mar , Cao Xuanye , Rosenzweig Derek Hadar , Lei Yunping , Finnell Richard , Verfaillie Catherine , Sampaolesi Maurilio , Dedecker Peter , Van Oosterwyck Hans , Aerts Stein , Ranga Adrian
Published: May 2021

Tissues achieve their complex spatial organization through an interplay between gene regulatory networks, cell-cell communication, and physical interactions mediated by mechanical forces. Current strategies to generate in-vitro tissues have largely failed to implement such active, dynamically coordinated mechanical manipulations, relying instead on extracellular matrices which respond to, rather than impose mechanical forces. Here, we develop devices that enable the actuation of organoids. We show that active mechanical forces increase growth and lead to enhanced patterning in an organoid model of the neural tube derived from single human pluripotent stem cells (hPSC). Using a combination of single-cell transcriptomics and immunohistochemistry, we demonstrate that organoid mechanoregulation due to actuation operates in a temporally restricted competence window, and that organoid response to stretch is mediated extracellularly by matrix stiffness and intracellularly by cytoskeleton contractility and planar cell polarity. Exerting active mechanical forces on organoids using the approaches developed here is widely applicable and should enable the generation of more reproducible, programmable organoid shape, identity and patterns, opening avenues for the use of these tools in regenerative medicine and disease modelling applications.
Non-Abelian three-loop braiding statistics for 3D fermionic topological phases
Authors: Zhou Jing-Ren , Wang Qing-Rui , Wang Chenjie , Gu Zheng-Cheng
Published: May 2021

Fractional statistics is one of the most intriguing features of topological phases in 2D. In particular, the so-called non-Abelian statistics plays a crucial role towards realizing topological quantum computation. Recently, the study of topological phases has been extended to 3D and it has been proposed that loop-like extensive objects can also carry fractional statistics. In this work, we systematically study the so-called three-loop braiding statistics for 3D interacting fermion systems. Most surprisingly, we discover new types of non-Abelian three-loop braiding statistics that can only be realized in fermionic systems (or equivalently bosonic systems with emergent fermionic particles). On the other hand, due to the correspondence between gauge theories with fermionic particles and classifying fermionic symmetry-protected topological (FSPT) phases with unitary symmetries, our study also gives rise to an alternative way to classify FSPT phases. We further compare the classification results for FSPT phases with arbitrary Abelian unitary total symmetry Gf and find systematical agreement with previous studies.
Cell-free DNA captures tumor heterogeneity and driver alterations in rapid autopsies with pre-treated metastatic cancer
Authors: Pereira Bernard , Chen Christopher T. , Goyal Lipika , Walmsley Charlotte , Pinto Christopher J. , Baiev Islam , Allen Read , Henderson Laura , Saha Supriya , Reyes Stephanie , Taylor Martin S. , Fitzgerald Donna M. , Broudo Maida Williams , Sahu Avinash , Gao Xin , Winckler Wendy , Brannon A. Rose , Engelman Jeffrey A. , Leary Rebecca , Stone James R. , Campbell Catarina D. , Juric Dejan
Published: May 2021

In patients with metastatic cancer, spatial heterogeneity of somatic alterations may lead to incomplete assessment of a cancer’s mutational profile when analyzing a single tumor biopsy. In this study, we perform sequencing of cell-free DNA (cfDNA) and distinct metastatic tissue samples from ten rapid autopsy cases with pre-treated metastatic cancer. We show that levels of heterogeneity in genetic biomarkers vary between patients but that gene expression signatures representative of the tumor microenvironment are more consistent. Across nine patients with plasma samples available, we are able to detect 62/62 truncal and 47/121 non-truncal point mutations in cfDNA. We observe that mutation clonality in cfDNA is correlated with the number of metastatic lesions in which the mutation is detected and use this result to derive a clonality threshold to classify truncal and non-truncal driver alterations with reasonable specificity. In contrast, mutation truncality is more often incorrectly assigned when studying single tissue samples. Our results demonstrate the utility of a single cfDNA sample relative to that of single tissue samples when treating patients with metastatic cancer.
Targeting Gα13-integrin interaction ameliorates systemic inflammation
Authors: Cheng Ni , Zhang Yaping , Delaney M. Keegan , Wang Can , Bai Yanyan , Skidgel Randal A. , Du Xiaoping
Published: May 2021

Systemic inflammation as manifested in sepsis is an excessive, life-threatening inflammatory response to severe bacterial or viral infection or extensive injury. It is also a thrombo-inflammatory condition associated with vascular leakage/hemorrhage and thrombosis that is not effectively treated by current anti-inflammatory or anti-thrombotic drugs. Here, we show that MB2mP6 peptide nanoparticles, targeting the Gα13-mediated integrin “outside-in” signaling in leukocytes and platelets, inhibited both inflammation and thrombosis without causing hemorrhage/vascular leakage. MB2mP6 improved mouse survival when infused immediately or hours after onset of severe sepsis. Furthermore, platelet Gα13 knockout inhibited septic thrombosis whereas leukocyte Gα13 knockout diminished septic inflammation, each moderately improving survival. Dual platelet/leukocyte Gα13 knockout inhibited septic thrombosis and inflammation, further improving survival similar to MB2mP6. These results demonstrate that inflammation and thrombosis independently contribute to poor outcomes and exacerbate each other in systemic inflammation, and reveal a concept of dual anti-inflammatory/anti-thrombotic therapy without exacerbating vascular leakage.
Non-associative phase separation in an evaporating droplet as a model for prebiotic compartmentalization
Authors: Guo Wei , Kinghorn Andrew B. , Zhang Yage , Li Qingchuan , Poonam Aditi Dey , Tanner Julian A. , Shum Ho Cheung
Published: May 2021

The synthetic pathways of life’s building blocks are envisaged to be through a series of complex prebiotic reactions and processes. However, the strategy to compartmentalize and concentrate biopolymers under prebiotic conditions remains elusive. Liquid-liquid phase separation is a mechanism by which membraneless organelles form inside cells, and has been hypothesized as a potential mechanism for prebiotic compartmentalization. Associative phase separation of oppositely charged species has been shown to partition RNA, but the strongly negative charge exhibited by RNA suggests that RNA-polycation interactions could inhibit RNA folding and its functioning inside the coacervates. Here, we present a prebiotically plausible pathway for non-associative phase separation within an evaporating all-aqueous sessile droplet. We quantitatively investigate the kinetic pathway of phase separation triggered by the non-uniform evaporation rate, together with the Marangoni flow-driven hydrodynamics inside the sessile droplet. With the ability to undergo liquid-liquid phase separation, the drying droplets provide a robust mechanism for formation of prebiotic membraneless compartments, as demonstrated by localization and storage of nucleic acids, in vitro transcription, as well as a three-fold enhancement of ribozyme activity. The compartmentalization mechanism illustrated in this model system is feasible on wet organophilic silica-rich surfaces during early molecular evolution.
Compensatory evolution of Pseudomonas aeruginosa’s slow growth phenotype suggests mechanisms of adaptation in cystic fibrosis
Authors: La Rosa Ruggero , Rossi Elio , Feist Adam M. , Johansen Helle Krogh , Molin Søren
Published: May 2021

Long-term infection of the airways of cystic fibrosis patients with Pseudomonas aeruginosa is often accompanied by a reduction in bacterial growth rate. This reduction has been hypothesised to increase within-patient fitness and overall persistence of the pathogen. Here, we apply adaptive laboratory evolution to revert the slow growth phenotype of P. aeruginosa clinical strains back to a high growth rate. We identify several evolutionary trajectories and mechanisms leading to fast growth caused by transcriptional and mutational changes, which depend on the stage of adaptation of the strain. Return to high growth rate increases antibiotic susceptibility, which is only partially dependent on reversion of mutations or changes in the transcriptional profile of genes known to be linked to antibiotic resistance. We propose that similar mechanisms and evolutionary trajectories, in reverse direction, may be involved in pathogen adaptation and the establishment of chronic infections in the antibiotic-treated airways of cystic fibrosis patients.
Neurovascular coupling and oxygenation are decreased in hippocampus compared to neocortex because of microvascular differences
Authors: Shaw K. , Bell L. , Boyd K. , Grijseels D. M. , Clarke D. , Bonnar O. , Crombag H. S. , Hall C. N.
Published: May 2021

The hippocampus is essential for spatial and episodic memory but is damaged early in Alzheimer’s disease and is very sensitive to hypoxia. Understanding how it regulates its oxygen supply is therefore key for designing interventions to preserve its function. However, studies of neurovascular function in the hippocampus in vivo have been limited by its relative inaccessibility. Here we compared hippocampal and visual cortical neurovascular function in awake mice, using two photon imaging of individual neurons and vessels and measures of regional blood flow and haemoglobin oxygenation. We show that blood flow, blood oxygenation and neurovascular coupling were decreased in the hippocampus compared to neocortex, because of differences in both the vascular network and pericyte and endothelial cell function. Modelling oxygen diffusion indicates that these features of the hippocampal vasculature may restrict oxygen availability and could explain its sensitivity to damage during neurological conditions, including Alzheimer’s disease, where the brain’s energy supply is decreased.
Rupture stress of liquid metal nanoparticles and their applications in stretchable conductors and dielectrics
Authors: Liu Yang , Ji Xinyi , Liang Jiajie
Published: May 2021

Few works had systematically investigated the relationship between the rupture stress of the oxide shell and the diameter of liquid metal nanoparticles (LMNPs). Here, we fabricated a series of elastomer/LMNPs composites, which were based on various polyurethanes with different shore hardness and LMNPs with different diameters, to systematically study the rupture stress of LMNPs. We established a reliable and guidable relationship between the stress–strain curves of elastomers with different shore hardness and rupture stress of LMNPs with various diameters by both experiments and numerical calculations. Based on this guidance, we can facilely prepare stretchable conductors with remarkable stretchability and conductivity (i.e., 24,130 S · cm−1 at 500% strain) and stretchable dielectrics with excellent stretchability and permittivity (i.e., dielectric constant of 76.8 with 580% strain) through controlling the shore hardness of elastomers and diameter of LMNPs. This work will facilitate the systematic study of LMNPs and expand their use in stretchable electronics.
Giant linear magnetoresistance in half-metallic Sr2CrMoO6 thin films
Authors: Wang Zhao-Cai , Chen Lei , Li Shuang-Shuang , Ying Jing-Shi , Tang F. , Gao Guan-Yin , Fang Y. , Zhao Weiyao , Cortie David , Wang Xiaolin , Zheng Ren-Kui
Published: May 2021

Linear magnetoresistance (LMR) is a special case of a magnetic-field induced resistivity response, which has been reported in highly disordered semiconductor systems and in topological materials. In this work, we observe LMR effect in half-metallic perovskite Sr2CrMoO6 thin films, of which the maximum MR value exceeds +1600% at 2 K and 14 T. It is an unusual behavior in ferrimagnetic double perovskite material like Sr2CrMoO6, which are known for intrinsic tunneling-type negative magnetoresistance. In the thin films, the high carriers’ density (~1022 cm−3) and ultrahigh mobility (~104 cm2 V−1 s−1) provide a low-resistivity (~10 nΩ·cm) platform for spin-polarized current. Our DFT calculations and magnetic measurements further support the half-metal band structure. The LMR effect in Sr2CrMoO6 could possibly originate from transport behavior that is governed by the guiding center motion of cyclotron orbitals, where the magnetic domain structure possibly provides disordered potential. The ultrahigh mobility and LMR in this system could broaden the applications of perovskites, and introduce more research on metallic oxide ferri-/ferro-magnetic materials.
Multilayer modelling of the human transcriptome and biological mechanisms of complex diseases and traits
Authors: Azevedo Tiago , Dimitri Giovanna Maria , Lió Pietro , Gamazon Eric R.
Published: May 2021

Here, we performed a comprehensive intra-tissue and inter-tissue multilayer network analysis of the human transcriptome. We generated an atlas of communities in gene co-expression networks in 49 tissues (GTEx v8), evaluated their tissue specificity, and investigated their methodological implications. UMAP embeddings of gene expression from the communities (representing nearly 18% of all genes) robustly identified biologically-meaningful clusters. Notably, new gene expression data can be embedded into our algorithmically derived models to accelerate discoveries in high-dimensional molecular datasets and downstream diagnostic or prognostic applications. We demonstrate the generalisability of our approach through systematic testing in external genomic and transcriptomic datasets. Methodologically, prioritisation of the communities in a transcriptome-wide association study of the biomarker C-reactive protein (CRP) in 361,194 individuals in the UK Biobank identified genetically-determined expression changes associated with CRP and led to considerably improved performance. Furthermore, a deep learning framework applied to the communities in nearly 11,000 tumors profiled by The Cancer Genome Atlas across 33 different cancer types learned biologically-meaningful latent spaces, representing metastasis (p < 2.2 × 10−16) and stemness (p < 2.2 × 10−16). Our study provides a rich genomic resource to catalyse research into inter-tissue regulatory mechanisms, and their downstream consequences on human disease.
In silico analysis of BRCA1 and BRCA2 missense variants and the relevance in molecular genetic testing
Authors: Poon Kok-Siong
Published: May 2021

Over the years since the genetic testing of BRCA1 and BRCA2 has been conducted for research and later introduced into clinical practice, a high number of missense variants have been reported in the literature and deposited in public databases. Polymorphism Phenotyping v2 (PolyPhen-2) and Sorting Intolerant from Tolerant (SIFT) are two widely applied bioinformatics tools used to assess the functional impacts of missense variants. A total of 2605 BRCA1 and 4763 BRCA2 variants from the ClinVar database were analysed with PolyPhen2 and SIFT. When SIFT was evaluated alongside PolyPhen-2 HumDiv and HumVar, it had shown top performance in terms of negative predictive value (NPV) (100%) and sensitivity (100%) for ClinVar classified benign and pathogenic BRCA1 variants. Both SIFT and PolyPhen-2 HumDiv achieved 100% NPV and 100% sensitivity in prediction of pathogenicity of the BRCA2 variants. Agreement was achieved in prediction outcomes from the three tested approaches in 55.04% and 68.97% of the variants of unknown significance (VUS) for BRCA1 and BRCA2, respectively. The performances of PolyPhen-2 and SIFT in predicting functional impacts varied across the two genes. Due to lack of high concordance in prediction outcomes among the two tested algorithms, their usefulness in classifying the pathogenicity of VUS identified through molecular testing of BRCA1 and BRCA2 is hence limited in the clinical setting.
Glycoproteomic analysis of the changes in protein N-glycosylation during neuronal differentiation in human-induced pluripotent stem cells and derived neuronal cells
Authors: Kimura Kazumasa , Koizumi Takumi , Urasawa Takaya , Ohta Yuki , Takakura Daisuke , Kawasaki Nana
Published: May 2021

N-glycosylation of glycoproteins, a major post-translational modification, plays a crucial role in various biological phenomena. In central nervous systems, N-glycosylation is thought to be associated with differentiation and regeneration; however, the state and role of N-glycosylation in neuronal differentiation remain unclear. Here, we conducted sequential LC/MS/MS analyses of tryptic digest, enriched glycopeptides, and deglycosylated peptides of proteins derived from human-induced pluripotent stem cells (iPSCs) and iPSC-derived neuronal cells, which were used as a model of neuronal differentiation. We demonstrate that the production profiles of many glycoproteins and their glycoforms were altered during neuronal differentiation. Particularly, the levels of glycoproteins modified with an N-glycan, consisting of five N-acetylhexosamines, three hexoses, and a fucose (HN5H3F), increased in dopaminergic neuron-rich cells (DAs). The N-glycan was deduced to be a fucosylated and bisected biantennary glycan based on product ion spectra. Interestingly, the HN5H3F-modified proteins were predicted to be functionally involved in neural cell adhesion, axon guidance, and the semaphorin-plexin signaling pathway, and protein modifications were site-selective and DA-selective regardless of protein production levels. Our integrated method for glycoproteome analysis and resultant profiles of glycoproteins and their glycoforms provide valuable information for further understanding the role of N-glycosylation in neuronal differentiation and neural regeneration.
Tipping points induced by parameter drift in an excitable ocean model
Authors: Pierini Stefano , Ghil Michael
Published: May 2021

Numerous systems in the climate sciences and elsewhere are excitable, exhibiting coexistence of and transitions between a basic and an excited state. We examine the role of tipping between two such states in an excitable low-order ocean model. Ensemble simulations are used to obtain the model’s pullback attractor (PBA) and its properties, as a function of a forcing parameter $$\gamma$$
γ
and of the steepness $$\delta$$
δ
of a climatological drift in the forcing. The tipping time $$t_{\mathrm{{tp}}}$$

t
tp

is defined as the time at which the transition to relaxation oscillations (ROs) arises: at constant forcing this occurs at $$\gamma =\gamma _{\mathrm{c}}$$

γ
=

γ
c

. As the steepness $$\delta$$
δ
decreases, $$t_{\mathrm{{tp}}}$$

t
tp

is delayed and the corresponding forcing amplitude decreases, while remaining always above $$\gamma _{\mathrm{c}}$$

γ
c

. With periodic perturbations, that amplitude depends solely on $$\delta$$
δ
over a significant range of parameters: this provides an example of rate-induced tipping in an excitable system. Nonlinear resonance occurs for periods comparable to the RO time scale. Coexisting PBAs and total independence from initial states are found for subsets of parameter space. In the broader context of climate dynamics, the parameter drift herein stands for the role of anthropogenic forcing.
Type and magnitude of non-compliance and adulteration in neroli, mandarin and bergamot essential oils purchased on-line: potential consumer vulnerability
Authors: Pierson Marissa , Fernandez Xavier , Antoniotti Sylvain
Published: May 2021

Thirty-one samples of essential oils used both in perfumery and aromatherapy were purchased to business-to-consumers suppliers and submitted to standard gas chromatography-based analysis of their chemical composition. Their compliance with ISO AFNOR standards was checked and revealed, although ISO AFNOR ranges are relatively loose, that more than 45% of the samples analyzed failed to pass the test and more than 19% were diluted with solvents such as propylene and dipropylene glycol, triethyl citrate, or vegetal oil. Cases of non-compliance could be due to substitution or dilution with a cheaper essential oil, such as sweet orange oil, blending with selected compounds (linalool and linalyl acetate, maybe of synthetic origin), or issues of aging, harvest, or manufacturing that should be either deliberate or accidental. In some cases, natural variability could be invoked. These products are made available to the market without control and liability by resellers and could expose the public to safety issues, in addition to commercial prejudice, in sharp contrast with the ever-increasing regulations applying to the sector and the high demand of consumers for safe, controlled and traceable products in fragrances and cosmetic products.