bluuebunny/crossref_metadata_2025 huggingface dataset:
Population implications of the deployment of novel universal vaccines against epidemic and pandemic influenza
Authors: Arinaminpathy N. , Riley S. , Barclay W. S. , Saad-Roy C. , Grenfell B.
Published: March 2020

There is increasing interest in the development of new, ‘universal’ influenza vaccines (UIVs) that––unlike current vaccines––are effective against a broad range of seasonal influenza strains, as well as against novel pandemic viruses. While the existing literature discusses the potential epidemiological benefits of UIVs, it is also important to anticipate their potential unintended population consequences. Using mathematical modelling, we illustrate two such types of adverse consequences. First, by reducing the amount of infection-induced immunity in a population without fully replacing it, a seasonal UIV programme may permit larger pandemics than in the absence of vaccination. Second, the more successful a future UIV programme is in reducing transmission of seasonal influenza, the more vulnerable the population could become to the emergence of a vaccine escape variant. These risks could be mitigated by optimal deployment of any future UIV vaccine: namely, the use of a combined vaccine formulation (incorporating conventional as well as multiple universal antigenic targets) and achieving sufficient population coverage to compensate for any reductions in infection-induced immunity. In the absence of large-scale trials of UIVs, disease-dynamic models can provide helpful, early insights into their potential impact. In future, data from continuing vaccine development will be invaluable in developing robustly predictive modelling approaches.
Denitrification performance of
Pseudomonas fluorescens
Z03 immobilized by graphene oxide-modified polyvinyl-alcohol and sodium alginate gel beads at low temperature
Authors: Tang Meizhen , Jiang Jie , Lv Qilin , Yang Bin , Zheng Mingna , Gao Xin , Han Jindi , Zhang Yingjie , Yang Yuewei
Published: March 2020

Improving the effect of microbial denitrification under low-temperature conditions has been a popular focus of research in recent years. In this study, graphene oxide (GO)-modified polyvinyl-alcohol (PVA) and sodium alginate (SA) (GO/PVA–SA) gel beads were used as a heterotrophic nitrification–aerobic denitrification (HN–AD) bacteria (
Pseudomonas fluorescens
Z03) carrier to enhance nitrogen removal efficiency levels at low temperatures (6–8°C). The removal efficiency of

N

H
4

 
 
+

-N

and

N

O
3

 
 
 
−

-N

and the variations in concentrations of extracellular polymeric substances (EPS) under different GO doses (0.03–0.15 g l
−1
) were studied. The results indicated that the addition of GO can improve the efficiency of nitrogen removal, and the highest removal efficiency level and highest carbohydrate, protein, and total EPS content levels (50.28 mg, 132.78 mg and 183.06 mg (g GO/PVA–SA gel)
−1
, respectively) were obtained with 0.15 g l
−1
GO. The simplified Monod model accurately predicted the nitrogen removal efficiency level. These findings suggested that the application of GO serves as an effective means to enhance nitrogen removal by stimulating the activity of HN–AD bacteria.
Forest habitat parameters influence abundance and diversity of cadaver-visiting dung beetles in Central Europe
Authors: von Hoermann Christian , Weithmann Sandra , Deißler Markus , Ayasse Manfred , Steiger Sandra
Published: March 2020

Dung beetles provide crucial ecosystem services and serve as model organisms for various behavioural, ecological and evolutionary studies. However, dung beetles have received little attention as consumers of large cadavers. In this study, we trapped copronecrophagous dung beetles on above-ground exposed piglet cadavers in 61 forest plots distributed over three geographically distinct regions in Germany, Central Europe. We examined the effects of land use intensity, forest stand, soil characteristics, vascular plant diversity and climatic conditions on dung beetle abundance, species richness and diversity. In all three regions, dung beetles, represented mainly by the geotrupid speciesAnoplotrupes stercorosusandTrypocopris vernalis, were attracted to the cadavers. High beetle abundance was associated with higher mean ambient temperature. Furthermore,A. stercorosusandT. vernaliswere more abundant in areas where soil contained higher proportions of fine sand. Additionally, an increased proportion of forest understorey vegetation and vascular plant diversity positively affected the species richness and diversity of dung beetles. Thus, even in warm dry monocultured forest stands exploited for timber, we found thriving dung beetle populations when a diverse understorey was present. Therefore, forestry practices that preserve the understorey can sustain stable dung beetle populations and ensure their important contribution to nutrient cycles.
Local species diversity, β-diversity and climate influence the regional stability of bird biomass across North America
Authors: Catano Christopher P. , Fristoe Trevor S. , LaManna Joseph A. , Myers Jonathan A.
Published: March 2020

Biodiversity often stabilizes aggregate ecosystem properties (e.g. biomass) at small spatial scales. However, the importance of species diversity within communities and variation in species composition among communities (β-diversity) for stability at larger scales remains unclear. Using a continental-scale analysis of 1657 North American breeding-bird communities spanning 20-years and 35 ecoregions, we show local species diversity and β-diversity influence two components of regional stability: local stability (stability of bird biomass within sites) and spatial asynchrony (asynchronous fluctuations in biomass among sites). We found spatial asynchrony explained three times more variation in regional stability of bird biomass than did local stability. This result contrasts with studies at smaller spatial scales—typically plant metacommunities under 1 ha—that find local stability to be more important than spatial asynchrony. Moreover, spatial asynchrony of bird biomass increased with bird β-diversity and climate heterogeneity (temperature and precipitation), while local stability increased with species diversity. Our study reveals new insights into the scale-dependent processes regulating ecosystem stability, providing evidence that both local biodiversity loss and homogenization can destabilize ecosystem processes at biogeographic scales.
Within-host priority effects and epidemic timing determine outbreak severity in co-infected populations
Authors: Clay Patrick A. , Duffy Meghan A. , Rudolf Volker H. W.
Published: March 2020

Co-infections of hosts by multiple pathogen species are ubiquitous, but predicting their impact on disease remains challenging. Interactions between co-infecting pathogens within hosts can alter pathogen transmission, with the impact on transmission typically dependent on the relative arrival order of pathogens within hosts (within-host priority effects). However, it is unclear how these within-host priority effects influence multi-pathogen epidemics, particularly when the arrival order of pathogens at the host-population scale varies. Here, we combined models and experiments with zooplankton and their naturally co-occurring fungal and bacterial pathogens to examine how within-host priority effects influence multi-pathogen epidemics. Epidemiological models parametrized with within-host priority effects measured at the single-host scale predicted that advancing the start date of bacterial epidemics relative to fungal epidemics would decrease the mean bacterial prevalence in a multi-pathogen setting, while models without within-host priority effects predicted the opposite effect. We tested these predictions with experimental multi-pathogen epidemics. Empirical dynamics matched predictions from the model including within-host priority effects, providing evidence that within-host priority effects influenced epidemic dynamics. Overall, within-host priority effects may be a key element of predicting multi-pathogen epidemic dynamics in the future, particularly as shifting disease phenology alters the order of infection within hosts.
pAgo-induced DNA interference protects bacteria from invader DNA
Authors: Kuzmenko Anton , Oguienko Anastasiya , Esyunina Daria , Yudin Denis , Petrova Mayya , Kudinova Alina , Maslova Olga , Ninova Maria , Ryazansky Sergei , Leach David , Aravin Alexei A. , Kulbachinskiy Andrey
Published: March 2020

Members of the conserved Argonaute protein family use small RNA guides to find their mRNA targets to regulate gene expression and suppress mobile genetic elements in eukaryotes. Argonautes are also present in many bacterial and archaeal species1–3. Unlike eukaryotic proteins, several studied prokaryotic Argonautes use small DNA guides to cleave DNA, a process dubbed DNA interference4–8. However, the natural functions and targets of DNA interference are poorly understood and the mechanisms of DNA guide generation and target discrimination remain unknown. Here, we studied thein vivoactivities of a bacterial Argonaute nuclease CbAgo and demonstrated that it induces cleavage of multicopy genetic elements, including plasmids, transposons and repetitive chromosomal loci. Generation of small DNA guides employed by CbAgo requires cooperation between its intrinsic endonuclease activity and the cellular double-strand break repair machinery. The mechanism of guide generation ensures that small DNA guides are enriched in sequences that target foreign DNA and endows CbAgo with capacity to eliminate plasmids and fight phage infection. Similar principles may underlie the specificity of self-nonself discrimination by diverse defense systems in prokaryotes.
Modeling an Integrated HIV Prevention and Care Continuum to Achieve the Ending the HIV Epidemic Goals
Authors: Jenness Samuel M. , Johnson Jordan A. , Hoover Karen W. , Smith Dawn K. , Delaney Kevin P.
Published: March 2020

Objective

We sought to evaluate which combinations of HIV prevention and care activities would have the greatest impact towards reaching the US Ending the HIV Epidemic (EHE) plan goals of reducing HIV incidence at least 75% by 2025 and 90% by 2030.

Design

A stochastic HIV transmission model for men who have sex with men (MSM), calibrated to local surveillance estimates in the Atlanta area, a focal EHE target jurisdiction.

Methods

Model scenarios varied HIV screening rates relative to current levels, under different assumptions of how HIV-negative MSM would be linked to PrEP initiation, and also considered improvements to HIV care linkage and retention for those screening positive.

Results

A 10-fold relative increase in HIV screening rates (to approximately biannual screening for black and Hispanic MSM and quarterly for white MSM) would lead to 43% of infections averted if integrated with PrEP initiation. Improvements to HIV care retention would avert 41% of infections if retention rates were improved 10-fold. If both screening and retention were jointly improved 10-fold, up to 74% of cumulative infections would be averted. Under this scenario, it would take 4 years to meet the 75% EHE goal and 12 years to meet the 90% goal for MSM in Atlanta.

Conclusions

Interventions to improve HIV screening linked with PrEP for those screening negative, and HIV care retention would have a substantial impact on HIV prevention. However, additional interventions may be necessary to reach the EHE goal of a 90% reduction in incidence for Atlanta MSM by 2030.
Description and Validation of the Colorectal Cancer and Adenoma Incidence & Mortality (CRC-AIM) Microsimulation Model
Authors: Piscitello Andrew , Saoud Leila , Matney Michael , Borah Bijan J , Fendrick A Mark , Lich Kristen Hassmiller , Rinde Harald , Limburg Paul J
Published: March 2020

Background

Microsimulation models of colorectal cancer (CRC) have helped inform national screening guidelines and health policy decision-making. However, detailed descriptions of particular underlying assumptions are not published, limiting access to robust platforms for exploratory analyses. We describe the development and validation of the Colorectal Cancer and Adenoma Incidence and Mortality (CRC-AIM) microsimulation model, a robust model built to facilitate collaborative simulation studies on disease progression and early detection through screening interventions.

Design

We used the Cancer Intervention and Surveillance Modeling Network (CISNET) CRC models, specifically CRC-SPIN, as a foundation for CRC-AIM’s formulas and parameters. In addition, we developed novel submodels and recalibrated various parameters to address gaps and discrepancies in publicly available information. Along with evaluating the natural history and screening detection outcomes from CRC-AIM, we determined the impact of using different life tables (cohort versus period) on natural history outcomes.

Results

CRC-AIM demonstrated substantial cross-model validity when comparing multiple natural history and screening outputs and probability curves to those from CISNET models, particularly CRC-SPIN. Additionally, using period life tables, CRC-AIM’s cumulative probability of developing CRC from ages 40 to 100 (7.1%) lies within the range of the CISNET models (6.7% to 7.2%). Using cohort tables, that probability increases to 8.0%. One notable difference is that, regardless of life table used, the cumulative probability of dying from CRC (3.2% for period; 3.8% for cohort) is slightly higher in CRC-AIM than the CISNET models (2.7% to 2.8%), due to CRC-AIM’s different methodology for determining survival. Additionally, there is substantial overlap (e.g. 94-95% overall agreement for strategies on and off the efficient frontier for stool-based strategies) across multiple screening overlay outputs between CRC-AIM and the CISNET models, especially CRC-SPIN.

Conclusions

We developed and validated a robust CRC microsimulation model, CRC-AIM, and demonstrate the influence of life table choice on downstream outputs. We further describe CRC-AIM’s parameters and include complete component tables to enhance transparency and encourage collaboration.
Cetaceans of the Black Sea: where did they survive glacial?
Authors: Dekanoidze Davit , Kopaliani Natia , Gurielidze Zurab , Ninua Levan , Devidze Nana , Tarkhnishvili David
Published: March 2020

Three species of cetaceans,Phocoena phocoena,Delphinus delphisandTursiops truncatus ponticusare found in the Black Sea. The Black Sea populations of all three species show morpho-ecological peculiarities that leaded to their subspecific status:P. p. relicta(PPR),D. d. ponticus(DDP), andT. t. ponticus(TTP). It is not clear how long-lasting was their isolation from the core conspecific populations that ensured the development of adaptive features of PPR, DDP, and TTP. The analysis of mitochondrial haplotypes of PPR suggests that the split time of the at least maternal lineage of the Black Sea population of harbour porpoise lasted for over 100 ky (i.e. they should survive at least the latest glacial maximum within the Black Sea). However, the analysis of multiple microsatellite genotypes leaded some authors to suggest that the isolation is much less long, since middle Holocene. We re-analysed published mitochondrial sequences of all three Black Sea cetaceans along with several tens of sequences obtained from the stranded cetaceans. Our analyses suggest that Black Sea populations of all three cetacean species have an important input of populations that survived the last (and maybe earlier) glacial maxima within the Black Sea, most likely in its south-eastern fragment, which did not freeze in winter time even during the glacial peaks. This analysis is supported by both molecular clock approach and simple population modelling based on the assumption on the effective population size range. Different from the PPR, whose Black Sea population is currently fully isolated, there is a limited migration between the Black Sea and Atlantic populations ofT. truncatusandD. delphis, through the Mediterranean “bridge” population. However, the migration rates are not sufficient to overweight differential selection between the Black Sea and Mediterranean populations, and the local morpho-ecological specifics is successfully maintained.
p38δ genetic ablation protects female mice from anthracycline cardiotoxicity
Authors: George Sharon A , Kiss Alexi , Obaid Sofian N , Venegas Aileen , Talapatra Trisha , Wei Chapman , Efimova Tatiana , Efimov Igor R
Published: March 2020

BACKGROUND

The efficacy of an anthracycline antibiotic doxorubicin (DOX) as a chemotherapeutic agent is limited by dose-dependent cardiotoxicity. DOX is associated with activation of intracellular stress signaling pathways including p38 MAPKs. While previous studies have implicated p38 MAPK signaling in DOX-induced cardiac injury, the roles of the individual p38 isoforms, specifically, of the alternative isoforms p38γ and p38δ, remain uncharacterized.

OBJECTIVES

To determine the potential cardioprotective effects of p38γ and p38δ genetic deletion in mice subjected to acute DOX treatment.

METHODS

Male and female wild-type (WT), p38γ-/-, p38δ-/-and p38γ-/-δ-/-mice were injected with 30 mg/kg DOX and their survival was tracked for ten days. During this period cardiac function was assessed by echocardiography and electrocardiography and fibrosis by PicroSirius Red staining. Immunoblotting was performed to assess the expression of signaling proteins and markers linked to autophagy.

RESULTS

Significantly improved survival was observed in p38δ-/-female mice post-DOX relative to WT females, but not in p38γ-/-or p38γ-/-δ-/-male or female mice. The improved survival in DOX-treated p38δ-/-females was associated with decreased fibrosis, increased cardiac output and LV diameter relative to DOX-treated WT females, and similar to saline-treated controls. Structural and echocardiographic parameters were either unchanged or worsened in all other groups. Increased autophagy, as evidenced by increased LC3-II level, and decreased mTOR activation was also observed in DOX-treated p38δ-/-females.

CONCLUSIONS

p38δ plays a crucial role in promoting DOX-induced cardiotoxicity in female mice by inhibiting autophagy. Therefore, p38δ targeting could be a potential cardioprotective strategy in anthracycline chemotherapy.

NEW AND NOTEWORTHY

This study for the first time identifies the roles of the alternative p38γ and p38δ MAPK isoforms in promoting DOX-cardiotoxicity in a sex-specific manner. While p38γ systemic deletion did not affect DOX-cardiotoxicity, p38δ systemic deletion was cardioprotective in female but not in male mice. Cardiac structure and function were preserved in DOX-treated p38δ-/- females and autophagy was increased.
Identification of determinants of differential chromatin accessibility through a massively parallel genome-integrated reporter assay
Authors: Hammelman Jennifer , Krismer Konstantin , Banerjee Budhaditya , Gifford David K , Sherwood Richard
Published: March 2020

A key mechanism in cellular regulation is the ability of the transcriptional machinery to physically access DNA. Pioneer transcription factors interact with DNA to open chromatin, which subsequently enables changes to gene expression during development, disease, or as a response to environmental stimuli. However, the regulation of DNA accessibility via the recruitment of transcription factors is difficult to understand in the context of the native genome because every genomic site is distinct in multiple ways. Here we introduce the Multiplexed Integrated Accessibility Assay (MIAA), a multiplexed parallel reporter assay which measures changes to genome accessibility as a result of the integration of synthetic oligonucleotide phrase libraries into a controlled, natively inaccessible genomic context. We apply MIAA to measure the effects of sequence motifs on cell type-specific DNA accessibility between mouse embryonic stem cells and embryonic stem cell-derived definitive endoderm cells, screening a total of 7,905 distinct phrases. MIAA is able to recapitulate differential accessibility patterns of 100-nt sequences derived from natively differential genomic regions, identifying the presence of E-box motifs common to epithelial-mesenchymal transition driver transcription factors in stem cell-specific accessible regions that become repressed during differentiation to endoderm. We further present causal evidence that a single binding motif for a key regulatory transcription factor is sufficient to open chromatin, and classify sets of stem cell-specific, endoderm-specific, and shared pioneer factor motifs. We also demonstrate that over-expression of two definitive endoderm transcription factors, Brachyury and FoxA2, results in changes to accessibility in phrases containing their respective DNA-binding motifs. Finally, we use MIAA results to explore the order of motif interactions and identify preferential motif ordering arrangements that appear to have an effect on accessibility.
Synonymous Dinucleotide Usage: A Codon-Aware Metric for Quantifying Dinucleotide Representation in Viruses
Authors: Lytras Spyros , Hughes Joseph
Published: March 2020

Distinct patterns of dinucleotide representation, such as CpG and UpA suppression, are characteristic of certain viral genomes. Recent research has uncovered vertebrate immune mechanisms that select against specific dinucleotides in targeted viruses. This evidence highlights the importance of systematically examining the dinucleotide composition of viral genomes. We have developed a novel metric, called Synonymous Dinucleotide Usage (SDU), for quantifying dinucleotide representation in coding sequences. Our method compares the abundance of a given dinucleotide to the null hypothesis of equal synonymous codon usage in the sequence. We present a Python3 package,DinuQ, for calculating SDU and other relevant metrics. We have applied this method on two sets of invertebrate- and vertebrate-specific flaviviruses and rhabdoviruses. The SDU shows that the vertebrate viruses exhibit consistently greater under-representation of CpG dinucleotides in all three codon positions in both datasets. In comparison to existing metrics for dinucleotide quantification, the SDU allows for a statistical interpretation of its values by comparing it to a null expectation based on the codon table. Here we apply the method to viruses, but coding sequences of other living organisms can be analysed in the same way.
Architectural Mediator subunits are differentially essential for global transcription in yeast
Authors: Tourigny Jason P. , Schumacher Kenny , Devys Didier , Zentner Gabriel E.
Published: March 2020

The modular Mediator complex is a coactivator of RNA polymerase II transcription. We show that depletion of the main complex scaffold Med14 or the head module scaffold Med17 is lethal and results in global transcriptional downregulation in yeast, though Med17 removal has a markedly greater negative effect. Depletion of Med14 or Med17 impairs pre-initiation complex (PIC) assembly similarly, suggesting that the differential transcriptional effects observed are not due to differing extents of defective PIC formation. Co-depletion of Med14 and Med17 reduced transcription and TFIIB promoter occupancy similarly to Med17 ablation alone, suggesting that the independent head module can weakly stimulate transcriptionin vivo, though not to a level that maintains viability. We suggest that, while the structural integrity of complete Mediator and the head module are both important for PIC assembly, the head module additionally promotes optimal PIC function and is thus the key functional module of Mediator in this regard.
Designing and Comparing Optimised Pseudo-Continuous Arterial Spin Labelling Protocols for Measurement of Cerebral Blood Flow
Authors: Woods Joseph G. , Chappell Michael A. , Okell Thomas W.
Published: March 2020

1.

Arterial Spin Labelling (ASL) is a non-invasive, non-contrast, perfusion imaging technique which is inherently SNR limited. It is, therefore, important to carefully design scan protocols to ensure accurate measurements. Many pseudo-continuous ASL (PCASL) protocol designs have been proposed for measuring cerebral blood flow (CBF), but it has not yet been demonstrated which design offers the most accurate and repeatable CBF measurements. In this work, a wide range of literature PCASL protocols, including single-delay, sequential and time-encoded multi-timepoint protocols, and several novel protocol designs, which are hybrids of time-encoded and sequential multi-timepoint protocols, were first optimised using a Cramér-Rao Lower Bound framework and then compared for CBF accuracy and repeatability using Monte Carlo simulations and in vivo experiments. It was found that several multi-timepoint protocols produced more confident, accurate, and repeatable CBF estimates than the single-delay protocol, while also generating maps of arterial transit time. One of the novel hybrid protocols, HybridT1-adj, was found to produce the most confident, accurate and repeatable CBF estimates of all protocols tested in both simulations and in vivo (24%, 47%, and 28% more confident, accurate, and repeatable than single-PLD in vivo). The HybridT1-adjprotocol makes use of the best aspects of both time-encoded and sequential multi-timepoint protocols and should be a useful tool for accurately and efficiently measuring CBF.
The INO80 ATP-dependent chromatin remodelling complex alleviates stalled Polymerase II to promote non-coding RNA transcription termination
Authors: Luzzi Sara , Szachnowski Ugo , Greener Sarah , Schumacher Kenny , Fulton Stuart , Walton Chloe , Gautier Camille , Han Kang Hoo , Darke Jack , Piccinno Rossana , Lafon Anne , Pugh B. Franklin , Devys Didier , Tora Laszlo , Morillon Antonin , Papamichos-Chronakis Manolis
Published: March 2020

Co-transcriptional RNA quality control is essential for gene expression. However, its regulation remains poorly understood. Here, we report that the evolutionarily conserved ATP-dependent chromatin remodelling INO80 complex promotes transcription termination by the non-coding RNA quality control pathway inS. cerevisiae. Loss of INO80 leads to accumulation of stalled RNA Polymerase II preferentially at promoter-proximal pausing sites, compromising Pol II processivity and hindering transcription elongation. We reveal that binding of RNA surveillance and non-coding transcription termination factors to promoter-proximal mRNA regions is associated with increased promoter-proximal pausing. INO80 counteracts promoter-proximal stalling of genes attenuated by the Nrd1-Nab3-Sen1 (NNS) non-coding transcription termination complex, promoting their expression. We show that INO80 interacts with Nrd1 and the Nab2 RNA surveillance factorin vivo. Absence of INO80 leads to defective transcription termination by the Nrd1-Nab3-Sen1 (NNS) complex. We demonstrate that INO80 facilitates the recruitment of Nab2 at non-coding transcription termination sites and its association with promoter-proximally terminated mRNA transcripts. Finally, we provide evidence that INO80 promotes the release of stalled RNA Polymerase II from a non-coding transcription termination site. Collectively, our work suggests that the INO80 complex regulates transcription by removal of stalled Polymerase, implicating a chromatin-based mechanism for non-coding and premature transcription termination in gene expression.
A Microfluidic Platform for Functional Testing of Cancer Drugs on Intact Tumor Slices
Authors: Rodriguez A.D , Horowitz L.F , Castro K. , Kenerson H. , Bhattacharjee N. , Gandhe G. , Raman A. , Monnat R. J. , Yeung R. , Rostomily R.C. , Folch A.
Published: March 2020

Present approaches to assess cancer treatments are often inaccurate, costly, and/or cumbersome. Functional testing platforms that use live tumor cells are a promising tool both for drug development and for identifying the optimal therapy for a given patient, i.e. precision oncology. However, current methods that utilize patient-derived cells from dissociated tissue typically lack the microenvironment of the tumor tissue and/or cannot inform on a timescale rapid enough to guide decisions for patient-specific therapy. We have developed a microfluidic platform that allows for multiplexed drug testing of intact tumor slices cultured on a porous membrane. The device is digitally-manufactured in a biocompatible thermoplastic by laser-cutting and solvent bonding. Here we describe the fabrication process in detail, we characterize the fluidic performance of the device, and demonstrate on-device drug-response testing with tumor slices from xenografts and from a patient colorectal tumor.
A computational framework to explore cellular response mechanisms from multi-omics datasets
Authors: Pino James C. , Lubbock Alexander L. R. , Harris Leonard A. , Gutierrez Danielle B. , Farrow Melissa A. , Muszynski Nicole , Tsui Tina , Norris Jeremy L. , Caprioli Richard M. , Wikswo John P. , Lopez Carlos F.
Published: March 2020

Recent technological advances have made it feasible to collect multi-condition transcriptome and proteome time-courses of cellular response to perturbation. The increasing size and complexity of these datasets impedes mechanism of action discovery due to challenges in data management, analysis, visualization, and interpretation. Here, we introduce MAGINE, a software framework to explore complex time-course multi-omics datasets and build mechanistic hypotheses of dynamic cellular response. MAGINE combines data management, enrichment, and network analysis and visualization within an interactive, Jupyter notebook-based environment to enable human-in-the-loop inquiry of complex datasets. We demonstrate how measurements from HL-60 cellular response to bendamustine treatment can be used to build a mechanistic, multi-resolution description of cellular commitment to fate. We present a systems-level description of signal execution from cellular DNA-damage response, to cell cycle arrest, and eventual commitment to apoptosis, mediated by over 2000 biochemical species. We further show that MAGINE can reveal unexpected, non-canonical effects of bendamustine treatment, including disruption of cellular pathways relevant to HIV infection response. MAGINE is available fromhttps://github.com/lolab-vu/magine.
Limited Environmental Serine Confers Sensitivity to PHGDH Inhibition in Brain Metastasis
Authors: Ngo Bryan , Kim Eugenie , Osorio-Vasquez Victoria , Doll Sophia , Bustraan Sophia , Luengo Alba , Davidson Shawn M. , Ali Ahmed , Ferraro Gino D. , Kang Diane , Ni Jing , Liang Roger , Plasger Ariana , Kastenhuber Edward R. , Eskandari Roozbeh , Bacha Sarah , Siriam Roshan K. , Bakhoum Samuel F. , Mullarky Edouard , Snuderl Matija , Cotzia Paolo , Mainolfi Nello , Suri Vipin , Friedman Adam , Manfredi Mark , Sabatini David M. , Jones Drew , Yu Min , Zhao Jean J. , Jain Rakesh K. , Vander Heiden Matthew G. , Hernando Eva , Mann Matthias , Cantley Lewis C. , Pacold Michael E.
Published: March 2020

A hallmark of metastasis is the adaptation of tumor cells to new environments. Although it is well established that the metabolic milieu of the brain is severely deprived of nutrients, particularly the amino acids serine and its catabolite glycine, how brain metastases rewire their metabolism to survive in the nutrient-limited environment of the brain is poorly understood. Here we demonstrate that cell-intrinsicde novoserine synthesis is a major determinant of brain metastasis. Whole proteome comparison of triple-negative breast cancer (TNBC) cells that differ in their capacity to colonize the brain reveals that 3-phosphoglycerate dehydrogenase (PHGDH), which catalyzes the rate-limiting step of glucose-derived serine synthesis, is the most significantly upregulated protein in cells that efficiently metastasize to the brain. Genetic silencing or pharmacological inhibition of PHGDH attenuated brain metastasis and improved overall survival in mice, whereas expression of catalytically active PHGDH in a non-brain trophic cell line promoted brain metastasis. Collectively, these findings indicate that nutrient availability determines serine synthesis pathway dependence in brain metastasis, and suggest that PHGDH inhibitors may be useful in the treatment of patients with cancers that have spread to the brain.

Statement of Significance

Our study highlights how limited serine and glycine availability within the brain microenvironment potentiates tumor cell sensitivity to serine synthesis inhibition. This finding underscores the importance of studying cancer metabolism in physiologically-relevant contexts, and provides a rationale for using PHGDH inhibitors to treat brain metastasis.
Analysis of reliability and its characteristics of a k-out-of-n network incorporating copula
Authors: Nautiyal Nisha , Singh S.B. , Bisht Soni
Published: March 2020

Purpose

The present paper focuses on the evaluation of reliability and its characteristics (Mean time to failure and Sensitivity) of a k-out-of-n network.

Design/methodology/approach

The minimal cuts of the network have been evaluated for different nodes in this paper, using an algorithm. With the help of these cuts, reliability and its characteristics are obtained using Gumbel–Hougaard family of the copula.

Findings

The present paper proposes to compute the reliability and its measures of the k-out-of-n network using the minimal cuts and copula methodology. The completely failed nodes of the network have been repaired using Gumbel–Hougaard family of the copula.

Originality/value

In this paper, the reliability of a k-out-of-n network has been evaluated by first calculating k-out-of-n minimal cuts, and the failed nodes have also been repaired using Gumbel–Hougaard family of the copula, unlike as done in the past.
To lead or not to lead: that is the (courageous) question
Authors: Bajer Javier
Published: March 2020

Purpose

The purpose of this paper is to challenge the constructs regularly used by organisations around the world for the development of leadership.

Design/methodology/approach

This is an opinion piece based on direct observation of hundreds of organisations over the years.

Findings

The regular approaches used for the development of leadership skills in organisations have consistently failed to deliver against its promise. Moreover, it is often the case that organisations pursue new “solutions” to bridge the leadership gap, often to discover that their new approach not only failed to develop the skills needed but also had the side effect of distracting vast amounts of attention. This paper describes what, if not the various taxonomies that describe, “good leadership” looks like really and how it delivers sustainable and effective leadership transformation.

Originality/value

This piece challenges the status quo, offering a more powerful way of connecting people with the purpose of their work, increasing the impact that individual leadership could have in the creation of value for all stakeholders, including themselves.
Attitudes toward organic products: a cross-national comparison and scale validation
Authors: Sarabia-Andreu Francisco , Sarabia-Sanchez Francisco J. , Parra-Meroño María Concepción , Moreno-Albaladejo Pablo
Published: March 2020

Purpose

This study aims to examine the formal and metric properties of Gil et al.’s (2000) scale of attitudes toward organic products, which is the most popular scale to measure these attitudes.

Design/methodology/approach

The sample consisted of 4,992 household shoppers living in Hong Kong, Germany, Norway, Spain and the UK. The questionnaire was distributed using a third-party consumer panel, and the fieldwork was conducted using computer-assisted Web interviewing. The approach was based on confirmatory factor analysis and measurement of invariance, as well as format analysis using a wording-syntactic and semantic descriptive method.

Findings

The scale reflects an attitude-toward-object model approach. Its use has been heavily varied (in terms of wording, item semantics and the attributes to be measured). A two-factor structure that meets the metric conditions (reliability and validity) is found. However, the analysis of invariance shows that the scale behaves differently in different countries.

Research limitations/implications

This scale offers a good starting point for measuring attitudes toward organic products. However, it requires refinement to adapt to consumer evolution and improve its metric validity. Verification of its applicability in cross-national studies is recommended.

Originality/value

To the best of the authors’ knowledge, this is the first study that assesses the format and quantitative characteristics of this scale on a cross-national level. For scholars and companies with international interests, preventing the use of scales with poor properties at the transnational level can improve the design of future studies and save money through a more informed choice of attitudinal scale.
Safety evaluation of four entomopathogenic nematode species against two silkworm species
Authors: Dong Hui , Bi Yu , Wang Jia‐Lin , Liu Yan‐Qun , Wang Huan
Published: March 2020

Chinese oak silkworm (Antheraea pernyi) and mulberry silkworm (Bombyx mori) are economically important insects used for silk production and food resource. Entomopathogenic nematodes (EPNs) from the families of Steinernematidae and Heterorhabditidae are beneficial organisms currently considered in biological control. In this paper, we evaluated survival of two silkworm species exposed to fourSteinernemaspecies which are widely applied in pest control. The results showed that among fourSteinernemaspecies,S. bicornutumandS. feltiaedid not have an effect on the larval survival to the two silkworm species, whereasS. carpocapsaeandS. glaseridid have an effect. EachSteinernemaspecies poses no threat to hatchability of eggs, pupation rate, larval durations and cocoon shell ratio.
Colorectal peritoneal metastases: pathogenesis, diagnosis and treatment options – an evidence‐based update
Authors: Narasimhan Vignesh , Ooi Geraldine , Michael Michael , Ramsay Robert , Lynch Craig , Heriot Alexander
Published: March 2020

Peritoneal metastases confer the worst survival among all sites in patients with metastatic colorectal cancer. They develop largely through transcoelomic spread, with a sequence of events that allow cells to first detach from primary tumours, survive in the peritoneal environment, attach to the peritoneal surface of organs and migrate into the submesothelial space to create a microenvironment conducive to metastatic growth. Diagnostic challenges have previously hindered early identification of peritoneal metastases. While advances in diagnostic modalities have improved our ability to identify peritoneal metastases, lesions under 0.5 cm remain challenging to detect. The advent of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC) can offer selected patients with colorectal peritoneal metastases a favourable long‐term survival. Recent trials, however, have cast doubts on the efficacy of HIPEC, with the recent PRODIGE 7 trial showing no benefit from oxaliplatin based HIPEC in addition to good quality cytoreductive surgery in resectable disease. While peritoneal recurrence can be reliably predicted from high‐risk features in primary tumours such as a perforated cancer, ovarian metastases or T4a cancers, the use of prophylactic second look surgery with HIPEC or adjuvant HIPEC failed to demonstrate any survival benefit in high‐risk cases in recent clinical trials, raising further questions about the efficacy of HIPEC. With high failure rates from systemic chemotherapy in unresectable disease, novel surgical techniques such as pressurized intraperitoneal aerolized chemotherapy are being investigated in clinical trials worldwide. Further collaborative research is needed to explore newer avenues of treatment for this poor prognostic cohort.
The effects of acute and sustained cannabidiol dosing for seven days on the haemodynamics in healthy men: A randomised controlled trial
Authors: Sultan Salahaden R. , O'Sullivan Saoirse E. , England Timothy J.
Published: March 2020

Background

In vivo studies show that cannabidiol (CBD) acutely reduces blood pressure (BP) in men. The aim of this study was to assess the effects of repeated CBD dosing on haemodynamics.

Methods

Twenty‐six healthy males were given CBD (600 mg) or placebo orally for seven days in a randomised, placebo‐controlled, double‐blind, parallel study (n = 13/group). Cardiovascular parameters were assessed at rest and in response to isometric exercise after acute and repeated dosing using Finometer®, Vicorder® and Duplex ultrasound.

Results

Compared to placebo, CBD significantly reduced resting mean arterial pressure (P = .04, two‐way ANOVA, mean difference (MD) –2 mmHg, 95% CI ‐3.6 to −0.3) after acute dosing, but not after repeated dosing. In response to stress, volunteers who had taken CBD had lower systolic BP after acute (P = .001, two‐way ANOVA, MD −6 mmHg, 95% CI –10 to −1) and repeated (P = .02, two‐way ANOVA, MD −5.7 mmHg, 95% CI –10 to −1) dosing. Seven days of CBD increased internal carotid artery diameter (MD +0.55 mm, P = .01). Within the CBD group, repeated dosing reduced arterial stiffness by day 7 (pulse wave velocity; MD −0.44 m/s, P = .05) and improved endothelial function (flow mediation dilatation, MD +3.5%, P = .02, n = 6 per group), compared to day 1.

Conclusion

CBD reduces BP at rest after a single dose but the effect is lost after seven days of treatment (tolerance); however, BP reduction during stress persists. The reduction in arterial stiffness and improvements in endothelial function after repeated CBD dosing are findings that warrant further investigation in populations with vascular diseases.
The changing sociocultural context of wildlife conservation
Authors: Manfredo Michael J. , Teel Tara L. , Don Carlos Andrew W. , Sullivan Leeann , Bright Alan D. , Dietsch Alia M. , Bruskotter Jeremy , Fulton David
Published: March 2020

We introduced a multilevel model of value shift to describe the changing social context of wildlife conservation. Our model depicts how cultural‐level processes driven by modernization (e.g., increased wealth, education, and urbanization) affect changes in individual‐level cognition that prompt a shift from domination to mutualism wildlife values. Domination values promote beliefs that wildlife should be used primarily to benefit humans, whereas mutualism values adopt a view that wildlife are part of one's social network and worthy of care and compassion. Such shifts create emergent effects (e.g., new interest groups) and challenges to wildlife management organizations (e.g., increased conflict) and dramatically alter the sociopolitical context of conservation decisions. Although this model is likely applicable to many modernized countries, we tested it with data from a 2017–2018 nationwide survey (mail and email panel) of 43,949 residents in the United States. We conducted hierarchical linear modeling and correlational analysis to examine relationships. Modernization variables had strong state‐level effects on domination and mutualism. Higher levels of education, income, and urbanization were associated with higher percentages of mutualists and lower percentages of traditionalists, who have strong domination values. Values affected attitudes toward wildlife management challenges; for example, states with higher proportions of mutualists were less supportive of lethal control of wolves (Canis lupus) and had lower percentages of active hunters, who represent the traditional clientele of state wildlife agencies in the United States. We contend that agencies will need to embrace new strategies to engage and represent a growing segment of the public with mutualism values. Our model merits testing for application in other countries.
Sex‐related difference in the prognostic value of syncope for 30‐day mortality among hospitalized pulmonary embolism patients
Authors: Dzudovic Boris , Subotic Bojana , Novicic Natasa , Matijasevic Jovan , Trobok Jadranka , Miric Milica , Salinger‐Martinovic Sonja , Stanojevic Dragana , Nikolic Maja , Miloradovic Vladimir , Markovic Nikolic Natasa , Dekleva Milica , Lepojevic Stefanovic Danijela , Kos Ljiljana , Kovacevic Preradovic Tamara , Obradovic Slobodan
Published: March 2020

Introduction

Recent studies report that syncope is not a significant predictor of 30‐day mortality in pulmonary embolism (PE) patients, yet some data suggest sex‐related differences may be relevant.

Objectives

To evaluate sex‐specific prediction significance of syncope for 30‐day mortality in PE patients.

Methods

A multicentric, retrospective, observational, registry‐based study on consecutive PE patients was undertaken. Patients were allocated into either a men or a women group before comparisons were made between patients with syncope and those without syncope. A sex‐related prediction of the significance of syncope for 30‐day mortality was evaluated.

Results

Overall 588 patients [294 (50%) men and 294 (50%) women] were included within the study. Among men, patients with syncope were older and had significantly higher parameters of increased 30‐day mortality then patients without syncope. Within the same group, however, difference in the 30‐day mortality rate was not significant (log rank P = .942). In contrast to the men, fewer differences in admission characteristics were noticed among women, but those with syncope had significantly increased signs of the right ventricular dysfunction and increased 30‐day mortality rate, as compared with those without syncope (log rank P = .025). After adjustment for age in a Cox regression analysis, syncope was a significant predictor of 30‐day mortality in women (HR = 2.01, 95%CI 1.02‐3.95).

Conclusion

Although syncope is associated with other predictors of higher early mortality in both male and female PE patients, only in women it is a significant predictor of 30‐day mortality.
Validation of the Australian Treatment Outcomes Profile for use in clients with cannabis dependence
Authors: Mills Llewellyn , Lintzeris Nicholas , Bruno Raimondo , Montebello Mark , Dunlop Adrian , Deacon Rachel M. , Copeland Jan , Jefferies Meryem , Rivas Consuelo , Mammen Kristie
Published: March 2020

Introduction and Aims

The Australian Treatment Outcomes Profile (ATOP) was developed as a clinical tool for monitoring the substance use, health and wellbeing of clients in alcohol and other drug treatment. This is the first psychometric validation of the ATOP in a cannabis‐dependent treatment population.

Design and Methods

A total of 128 individuals with cannabis dependence enrolled in an outpatient randomised controlled trial were administered the ATOP and gold‐standard health and wellbeing questionnaires once by clinicians and once by researchers at baseline. Concurrent validity was assessed by testing ATOP Psychological Health, Physical Health and Quality of Life questions against concurrently administered gold‐standard questionnaires: the Short Form 36 Health Survey (SF‐36), the 21‐item Depression, Anxiety and Stress Scale (DASS‐21) and the Sheehan Disability Scale (SDS). Interrater reliability was tested by comparing clinician‐administered ATOP items at the medical screening interview to the same ATOP items administered by researchers at baseline.

Results

ATOP Psychological Health showed moderate to strong correlations with SF‐36 Mental Components, SF‐36 Mental Health and DASS‐21 scores (r= 0.40–0.52) and ATOP Physical Health with SF‐36 Physical Components and SF‐36 General Health scores (r= 0.36–0.67). The ATOP Quality of Life scale showed moderate agreement with the SDS and six‐dimensional health state short form scales (r= 0.38–0.40). ATOP substance use, employment, education and child care items showed good to excellent interrater reliability (Krippendorff'sα= 0.62–0.81), and tobacco use, Psychological Health, Physical Health and Quality of Life showed fair to moderate interrater reliability (Krippendorff'sα= 0.42–0.53).

Discussion and Conclusions

The ATOP appears to be valid and reliable when tested in a population with cannabis‐dependence, justifying its widespread use in clinical settings.