bluuebunny/crossref_metadata_2025 huggingface dataset:
Fast and precise single-cell data analysis using hierarchical autoencoder
Authors: Tran Duc , Nguyen Hung , Tran Bang , La Vecchia Carlo , Luu Hung N. , Nguyen Tin
Published: October 2019

A primary challenge in single-cell RNA sequencing (scRNA-seq) studies comes from the massive amount of data and the excess noise level. To address this challenge, we introduce a hierarchical autoencoder that reliably extracts representative information of each cell. In an extensive analysis, we demonstrate that the approach vastly outperforms state-of-the-art techniques in many research sub-fields of scRNA-seq analysis, including cell segregation through unsupervised learning, visualization of transcriptome landscape, cell classification, and pseudo-time inference.
Genetic relatedness cannot explain social preferences in black-and-white ruffed lemurs (Varecia variegata)
Authors: Baden Andrea L , Webster Timothy H , Bradley Brenda J
Published: October 2019

Fission-fusion social dynamics are common among a number of vertebrate taxa, and yet the factors shaping these variable associations among subgroup members have not been widely addressed. Associations may occur simply because of shared habitat preferences; however, social ties may also be influenced by genetic relatedness (kinship) or social attraction. Here, we investigate the association patterns of wild black-and-white ruffed lemurs,Varecia variegata, in Ranomafana National Park, Madagascar using behavioural, spatial (home range), and genetic data from twenty-four individually identified animals. We collected 40,840 records of group composition over a 17-month period and from this calculated pairwise association indices. We also used ranging coordinates and genetic samples to estimate patterns of spatial overlap and kinship, and then related these measures to patterns of affiliation. From these analyses, we found that dyadic ruffed lemur social associations were generally sparse and weak; that home range overlap was minimal; and that average relatedness within the community was low. We found no evidence that kinship was related to patterns of either spatial overlap or social association; instead, associations were primarily driven by space use. Moreover, social preferences were unrelated to kinship. While home range overlap explained most of the variation seen in social association, some variation remains unaccounted for, suggesting that other social, ecological, and biological factors such as shared resource defense or communal breeding might also play a role in social attraction. Our results further highlight the need to consider individual space use and nuances of species behavior when investigating social preference and social association more generally.
An anti-diuretic hormone receptor in the human disease vector,Aedes aegypti: identification, expression analysis and functional deorphanization
Authors: Sajadi Farwa , Uyuklu Ali , Paputsis Christine , Lajevardi Aryan , Wahedi Azizia , Ber Lindsay Taylor , Matei Andreea , Paluzzi Jean-Paul V.
Published: October 2019

Insect CAPA neuropeptides, which are homologs of mammalian neuromedin U, have been described in various insect species and are known to influence ion and water balance by regulating the activity of the Malpighian ‘renal’ tubules (MTs). A number of diuretic hormones have been shown to increase primary fluid and ion secretion by the insect MTs and, in the adult female mosquito, a calcitonin-related peptide (DH31) also known as mosquito natriuretic peptide, increases sodium secretion at the expense of potassium to remove the excess salt load acquired upon blood-feeding. An endogenous mosquito anti-diuretic hormone was recently described, having inhibitory activity against select diuretic factors and being particularly potent against DH31-stimulated diuresis. In the present study, we have functionally deorphanized, bothin vitroandin vivo, a mosquito anti-diuretic hormone receptor (AedaeADHr). Expression analysis by quantitative PCR indicates the receptor is highly enriched in the MTs, and fluorescentin situhybridization confirms expression within principal cells. Characterization using a heterologous system demonstrated the receptor was highly sensitive to mosquito CAPA peptides. In adult females,AedaeADHr transcript knockdown using RNAi led to the abolishment of CAPA-peptide induced anti-diuretic control of DH31-stimulated MTs. The neuropeptidergic ligand is produced within a pair of neurosecretory cells in each of the six abdominal ganglia, whose axonal projections innervate the abdominal neurohaemal organs (known as the perivisceral organs), where these neurohormones are released into the open circulatory system of the insect. Furthermore, pharmacological inhibition of PKG/NOS signalling abolished the anti-diuretic activity ofAedaeCAPA-1, which collectively confirms the role of cGMP/PKG/NOS in this anti-diuretic signalling pathway.

Significance

Insects are by far the most successful and abundant group of organisms on earth. As a result of their small size, insects have a relatively large surface area to volume ratio, raising the potential for rapid gain or loss of water, ions and other molecules including toxins – a phenomenon that applies to insects living in both aquatic and terrestrial environments. In common with many other organisms, hormones are key regulators of the excretory system in insects, and numerous factors control the clearance of excess water and ions (i.e. diuretics) or retention of these elements (i.e. anti-diuretics). Here we characterized an endogenous anti-diuretic hormone receptor in the human disease vector,Aedes aegypti, demonstrating its expression is highly enriched in the Malpighian ‘renal’ tubules and is necessary for eliciting anti-diuretic control of this key component of the mosquito excretory system.
Improved prediction of MHC II antigen presentation through integration and motif deconvolution of mass spectrometry MHC eluted ligand data
Authors: Reynisson Birkir , Barra Carolina , Kaabinejadian Saghar , Hildebrand William H , Peters Bjoern , Nielsen Morten
Published: October 2019

Major Histocompatibility Complex II (MHC II) molecules play a vital role in the onset and control of cellular immunity. In a highly selective process, MHC II presents peptides derived from exogenous antigens on the surface of antigen-presenting cells for T cell scrutiny. Understanding the rules defining this presentation holds critical insights into the regulation and potential manipulation of the cellular immune system. Here, we apply the NNAlign_MA machine learning framework to analyse and integrate large-scale eluted MHC II ligand mass spectrometry (MS) data sets to advance prediction of CD4+ epitopes. NNAlign_MA allows integration of mixed data types, handling ligands with multiple potential allele annotations, encoding of ligand context, leveraging information between data sets, and has pan-specific power allowing accurate predictions outside the set of molecules included in the training data. Applying this framework, we identified accurate binding motifs of more than 50 MHC class II molecules described by MS data, particularly expanding coverage for DP and DQ beyond that obtained using current MS motif deconvolution techniques. Further, in large-scale benchmarking, the final model termed NetMHCIIpan-4.0, demonstrated improved performance beyond current state-of-the-art predictors for ligand and CD4+ T cell epitope prediction. These results suggest NNAlign_MA and NetMHCIIpan-4.0 are powerful tools for analysis of immunopeptidome MS data, prediction of T cell epitopes and development of personalized immunotherapies.
Ultrastructure of light-activated axons following optogenetic stimulation to produce late-phase long-term potentiation
Authors: Kuwajima Masaaki , Ostrovskaya Olga I. , Cao Guan , Weisberg Seth A. , Harris Kristen M. , Zemelman Boris V.
Published: October 2019

Analysis of neuronal compartments has revealed many state-dependent changes in geometry but establishing synapse-specific mechanisms at the nanoscale has proven elusive. We co-expressed channelrhodopsin2-GFP and mAPEX2 in a subset of hippocampal CA3 neurons and used trains of light to induce late-phase long-term potentiation (L-LTP) in area CA1. L-LTP was shown to be specific to the labeled axons by severing CA3 inputs, which prevented back-propagating recruitment of unlabeled axons. Membrane-associated mAPEX2 tolerated microwave-enhanced chemical fixation and drove tyramide signal amplification to deposit Alexa Fluor dyes in the light-activated axons. Subsequent post-embedding immunogold labeling resulted in outstanding ultrastructure and clear distinctions between labeled (activated), and unlabeled axons without obscuring subcellular organelles. The gold-labeled axons in potentiated slices were reconstructed through serial section electron microscopy; presynaptic vesicles and other constituents could be quantified unambiguously. The genetic specification, reliable physiology, and compatibility with established methods for ultrastructural preservation make this an ideal approach to link synapse ultrastructure and function in intact circuits.
Modeling a gene regulatory network of EMT hybrid states for mouse embryonic skin cells
Authors: Ramirez Dan , Kohar Vivek , Katebi Ataur , Lu Mingyang
Published: October 2019

Epithelial-mesenchymal transition (EMT) plays a crucial role in embryonic development and tumorigenesis. Although EMT has been extensively studied with both computational and experimental methods, the gene regulatory mechanisms governing the transition are not yet well understood. Recent investigations have begun to better characterize the complex phenotypic plasticity underlying EMT using a computational systems biology approach. Here, we analyzed recently published single-cell RNA sequencing data from E9.5 to E11.5 mouse embryonic skin cells and identified the gene expression patterns of both epithelial and mesenchymal phenotypes, as well as a clear hybrid state. By integrating the scRNA-seq data and gene regulatory interactions from the literature, we constructed a gene regulatory network model governing the decision-making of EMT in the context of the developing mouse embryo. We simulated the network using a recently developed mathematical modeling method, named RACIPE, and observed three distinct phenotypic states whose gene expression patterns can be associated with the epithelial, hybrid, and mesenchymal states in the scRNA-seq data. Additionally, the model is in agreement with published results on the composition of EMT phenotypes and regulatory networks. We identified Wnt signaling as a major pathway in inducing the EMT and its role in driving cellular state transitions during embryonic development. Our findings demonstrate a new method of identifying and incorporating tissue-specific regulatory interactions into gene regulatory network modeling.

Author Summary

Epithelial-mesenchymal transition (EMT) is a cellular process wherein cells become disconnected from their surroundings and acquire the ability to migrate through the body. EMT has been observed in biological contexts including development, wound healing, and cancer, yet the regulatory mechanisms underlying it are not well understood. Of particular interest is a purported hybrid state, in which cells can retain some adhesion to their surroundings but also show mesenchymal traits. Here, we examine the prevalence and composition of the hybrid state in the context of the embryonic mouse, integrating gene regulatory interactions from published experimental results as well as from the specific single cell RNA sequencing dataset of interest. Using mathematical modeling, we simulated a regulatory network based on these sources and aligned the simulated phenotypes with those in the data. We identified a hybrid EMT phenotype and revealed the inducing effect of Wnt signaling on EMT in this context. Our regulatory network construction process can be applied beyond EMT to illuminate the behavior of any biological phenomenon occurring in a specific context, allowing better identification of therapeutic targets and further research directions.
Predicting 3D genome folding from DNA sequence
Authors: Fudenberg Geoff , Kelley David R. , Pollard Katherine S.
Published: October 2019

In interphase, the human genome sequence folds in three dimensions into a rich variety of locus-specific contact patterns. Here we present a deep convolutional neural network, Akita, that accurately predicts genome folding from DNA sequence alone. Representations learned by Akita underscore the importance of CTCF and reveal a complex grammar underlying genome folding. Akita enables rapid in silico predictions for sequence mutagenesis, genome folding across species, and genetic variants.
A large inner membrane pore defines the ESX translocon
Authors: Poweleit Nicole , Czudnochowski Nadine , Nakagawa Rachael , Murphy Kenan , Sassetti Christopher , Rosenberg Oren S.
Published: October 2019

The ESX (or Type VII) secretion systems are protein export systems in mycobacteria and many Gram-positive bacteria that mediate a broad range of functions including virulence, conjugation, and metabolic regulation. These systems translocate folded dimers of WXG100-superfamily protein substrates across the cytoplasmic membrane; however, the architecture and mechanism of translocation has remained elusive. We report the cryo-electron microscopy structure of an ESX-3 system, purified using an epitope tag inserted with recombineering into the model organism Mycobacterium smegmatis. The structure reveals two large α-helical membrane pores of sufficient diameter to secrete folded substrates. A complex, asymmetric, multimeric cytoplasmic domain is poised to gate and regulate the pore’s function. Our study provides mechanistic insights into the ESX systems and will guide structure-based design of drugs targeting this unique bacterial translocon.

One Sentence Summary

The structure of the ESX-3 secretion system reveals a pore of sufficient size for the transit of folded substrates and a complex, cytoplasmic regulatory apparatus.
Impact of between-tissue differences on pan-cancer predictions of drug sensitivity
Authors: Lloyd John P. , Soellner Matthew , Merajver Sofia D. , Li Jun Z.
Published: October 2019

Increased availability of drug response and genomics data for many tumor cell lines has accelerated the development of pan-cancer prediction models of drug response. However, it is unclear how much between-tissue differences in drug response and molecular characteristics may contribute to pan-cancer predictions. Also unknown is whether the performance of pan-cancer models could vary by cancer type. Here, we built a series of pan-cancer models using two datasets containing 346 and 504 cell lines with MEK inhibitor (MEKi) response and RNA, SNP, and CNV data, and found that, while the tissue-level drug responses are accurately predicted (between-tissue ρ=0.88-0.98), only 5 of 10 cancer types showed successful within-tissue prediction performance (within-tissue ρ=0.11-0.64). Between-tissue differences make substantial contributions to the performance of pan-cancer MEKi response predictions, as we estimate that exclusion of between-tissue signals leads to a 22% decrease in performance metrics. In practice, joint analysis of multiple cancer types usually has a larger sample size, hence greater power, than for one cancer type; and we observe that the higher accuracy of pan-cancer prediction of MEKi response is almost entirely due to the sample size advantage. Success of pan-cancer prediction reveals how drug response in different cancers may invoke shared regulatory mechanisms despite tissue-specific routes of oncogenesis, yet predictions in different cancer types require flexible incorporation of between-cancer and within-cancer signals. As most datasets in genome sciences contain multiple levels of heterogeneity, careful parsing of group characteristics and within-group, individual variation is essential when making robust inference.
Vaccine-specific immune responses againstMycobacterium ulceransinfection in a low-dose murine challenge model
Authors: Mangas Kirstie M. , Buultjens Andrew H. , Porter Jessica L. , Baines Sarah L. , Marion Estelle , Marsollier Laurent , Tobias Nicholas J. , Pidot Sacha J. , Quinn Kylie M. , Price David J. , Kedzierska Katherine , Zeng Weiguang , Jackson David C. , Chua Brendon Y. , Stinear Timothy P.
Published: October 2019

The neglected tropical disease Buruli ulcer (BU) is an infection of subcutaneous tissue withMycobacterium ulcerans. There is no effective BU vaccine. Here, we assessed an experimental prime-boost vaccine in a low-dose murine tail infection model. We used the enoyl-reductase (ER) domain of theM. ulceransmycolactone polyketide synthases electrostatically coupled with a previously described TLR-2 agonist-based lipopeptide adjuvant, R4Pam2Cys. Mice were vaccinated and then challenged via tail inoculation with 14-20 colony forming units (CFU) of an engineered bioluminescent strain ofM. ulcerans. Mice receiving either the experimental ER vaccine orMycobacterium bovisBacille Calmette-Guérin (BCG) were equally well protected, with both groups faring significantly better than non-vaccinated animals (p<0.05). A suite of 29 immune parameters were assessed in the mice at the end of the experimental period. Multivariate statistical approaches were then used to interrogate the immune response data to develop disease-prognostic models. High levels of IL-2 and low IFN-γproduced in the spleen best predicted control of infection across all vaccine groups. Univariate logistic regression then revealed vaccine-specific profiles of protection. High titres of ER-specific IgG serum antibodies together with IL-2 and IL-4 in the draining lymph node (DLN) were associated with protection induced by the experimental ER vaccine. In contrast, high titres of IL-6, TNF-α, IFN-γand IL-10 in the DLN and low IFNγtitres in the spleen were associated with protection following BCG vaccination. This study suggests an effective BU vaccine must induce localized, tissue-specific immune profiles with controlled inflammatory responses at the site of infection.
The interaction of aging and oxidative stress contributes to pathogenesis in mouse and human Huntington disease neurons
Authors: Machiela Emily , Jeloka Ritika , Caron Nicholas S. , Mehta Shagun , Schmidt Mandi E. , Tom Colton M. , Polturi Nalini , Xie Yuanyun , Mattis Virginia B , Hayden Michael R. , Southwell Amber L.
Published: October 2019

Huntington disease (HD) is a fatal, inherited neurodegenerative disorder caused by a mutation in huntingtin (HTT). While mutant HTT is present ubiquitously throughout life, HD onset typically occurs in mid-life. Oxidative damage accumulates in the aging brain and is a feature of HD. We sought to interrogate the roles and interaction of age and oxidative stress in HD using primary Hu97/18 mouse neurons, neurons differentiated from HD patient induced pluripotent stem cells (iPSCs), and mice. We find that primary neurons must be matured in culture for canonical stress responses to occur. Furthermore, when aging is accelerated in mature HD neurons, mutant HTT accumulates and sensitivity to oxidative stress is selectively enhanced. Furthermore, we observe HD-specific phenotypes in iPSC-derived neurons and mouse brains that have undergone accelerated aging. These findings suggest a role for aging in HD pathogenesis and interaction between biological age of HD neurons and sensitivity to exogenous stress.
Poor sensing maximises microbial fitness when few out of many signals are sensed
Authors: Tjalma Age J. , Planqué Robert , Bruggeman Frank J.
Published: October 2019

An open problem in biology is to understand when particular adaptation strategies of microorganisms are selected during evolution. They range from random, bet-hedging strategies to deterministic, responsive strategies, relying on signalling circuits. We present an evolutionary model that integrates basic statistical physics of molecular circuits with fitness maximisation and information theory. This model provides an explanation for a puzzling observation on responsive strategies: the accuracy with which signalling networks track external signals seems remarkably low. Single cells often distinguish only between 2 to 4 concentration ranges, corresponding to 1 or 2 bits of mutual information between signal and response. Why did evolution lead to such low-fidelity signalling systems? Our theory offers an explanation by taking a novel perspective. It considers the fitness benefit of all signals, including those that are not sensed. We introduce a new concept, ‘latent information’, which captures the mutual information between all non-sensed signals and the optimal response. The theory predicts that it is often evolutionarily optimal to transduce sensed signals noisily when latent information is present. It indicates that fitness can indeed be maximal when the mutual information extracted from sensed signals is not maximal, but rather has a low value of about 1 or 2 bits. Cells likely do not sense all signals because of the fitness cost of expressing idle signalling systems that consume limited biosynthetic resources. Our theory illustrates that as the total available information about the optimal behaviour decreases, the cell should trust the available information less, and gamble more.

Significance Statement

Surprisingly, microorganisms appear to sense only very few environmental signals (such as nutrients and stresses) compared to the number of conditions they can encounter. Even worse, the signals they do sense are transduced at low fidelity. We study the accuracy of sensing in the situation where multiple signals determine the optimal response, but only few signals are actually sensed. We show that it is in fact to be expected that sensing in the presence of latent information should be imprecise, and that signalling circuits should underperform.
Mechanistic insights into NAD synthase NMNAT chaperoning phosphorylated Tau from pathological aggregation
Authors: Ma Xiaojuan , Lu Jinxia , Zhu Yi , Xie Jingfei , Li Chong , Shin Austin , Qiang Jiali , Liu Jiaqi , Dou Shuai , Xiao Yi , Wang Chuchu , Jia Chunyu , Long Houfang , Fang Yanshan , Jiang Lin , Zhang Yaoyang , Zhang Shengnan , Zhai R. Grace , Liu Cong , Li Dan
Published: October 2019

Tau hyper-phosphorylation and deposition into neurofibrillary tangles have been found in brains of patients with Alzheimer’s disease (AD) and other tauopathies. Molecular chaperones are involved in regulating the pathological aggregation of phosphorylated Tau (pTau) and modulating disease progression. Here, we report that nicotinamide mononucleotide adenylyltransferase (NMNAT), a well-known NAD synthase, serves as a chaperone of pTau to prevent its amyloid aggregation in vitro as well as mitigate its pathology in a fly tauopathy model. By combining NMR spectroscopy, crystallography, single-molecule and computational approaches, we revealed that NMNAT adopts its enzymatic pocket to specifically bind the phosphorylated sites of pTau, which can be competitively disrupted by the enzymatic substrates of NMNAT. Moreover, we found that NMNAT serves as a co-chaperone of Hsp90 for the specific recognition of pTau over Tau. Our work uncovers a dedicated chaperone of pTau and suggests NMNAT as a key node between NAD metabolism and Tau homeostasis in aging and neurodegeneration.
Organizational inclusion and academics’ psychological contract
Authors: Mousa Mohamed
Published: October 2019

Purpose

The purpose of this paper is to focus on three Egyptian public business schools in an attempt to explore the impact of organizational inclusion on the psychological contract with academics through the mediating the role of responsible leadership.

Design/methodology/approach

A total of 330 academics were contacted and given a set of questionnaires. After three follow-ups, a total of 240 responses were collected with a response rate of 72.73 percent. Multiple regressions were employed to indicate the level of variation in the types of psychological contract can be explained by organizational inclusion and responsible leadership.

Findings

The findings highlighted a positive impact for organizational inclusion on the psychological contract with academics through mediating responsible leadership or, in other words, the statistical analysis showed that responsible leadership has a role in mediating the relationship between the organizational inclusion of academics and their psychological contract type.

Originality/value

This paper contributes by filling a gap in HR management and higher education literature in which empirical studies on the relationship between organizational inclusion, responsible leadership and the psychological contract with academics have been limited until now. This may create better research opportunities for cross-disciplinary papers by scholars of HR, higher education and leadership.
Effectiveness of occupational therapy intervention for people with Parkinson’s disease: Systematic review
Authors: Welsby Ellana , Berrigan Sonja , Laver Kate
Published: October 2019

Introduction

Occupational therapists commonly provide intervention that promotes quality of life in people with Parkinson’s disease. Existing research supports the effects of multidisciplinary and motor intervention for people with Parkinson’s disease. However, few studies have identified the effectiveness of occupational therapy intervention alone. The aim of this review was to examine the efficacy of interventions provided by occupational therapists for people with Parkinson’s disease.

Methods

A comprehensive database search of the literature was performed using Medline, EMBASE, PsycInfo and CINAHL between 2003 and January 2018. There were no restrictions on study design and studies with or without a control group were selected for review. Studies were included if intervention consisted of at least 50% of occupational therapy intervention for Parkinson’s disease. Two independent reviewers extracted and synthesised data from relevant articles.

Results

In all, 10 studies representing data from 1343 people with Parkinson’s disease and 180 caregivers were included in this review. Occupational therapy interventions focussing on meaningful activities were shown to improve perceived occupational performance. Upper limb therapy programmes were shown to improve upper limb function in the short term though longer‐term effects are unclear.

Conclusion

Current research supports interventions which are intermittent, short term and intensive, and involve tailored therapy plans working towards an individual’s goals. Occupational therapists should implement goal‐oriented intervention programmes in conjunction with following the guidance of existing best practice guidelines.
Mismatch repair hierarchy of Pseudomonas putida revealed by mutagenic ssDNA recombineering of the pyrF gene
Authors: Aparicio Tomas , Nyerges Akos , Nagy István , Pal Csaba , Martínez‐García Esteban , de Lorenzo Víctor
Published: October 2019

The mismatch repair (MMR) system is one of the key molecular devices that prokaryotic cells have for ensuring fidelity of DNA replication. While the canonical MMR of E. coli involves 3 proteins (encoded by mutS, mutL and mutH), the soil bacterium Pseudomonads putida has only 2 bona fide homologues (mutS and mutL) and the sensitivity of this abridged system to different types of mismatches is unknown. In this background, sensitivity to MMR of this bacterium was inspected through single stranded (ss) DNA recombineering of the pyrF gene (the prokaryotic equivalent to yeast's URA3) with mutagenic oligos representative of every possible mispairing under either wild‐type conditions, permanent deletion of mutS or transient loss of mutL activity (brought about by the thermoinducible dominant negative allele mutLE36K). Analysis of single nucleotide mutations borne by clones resistant to fluoroorotic acid (5FOA, the target of wild type PyrF) pinpointed prohibited and tolerated single‐nucleotide replacements and exposed a clear grading of mismatch recognition. The resulting data unequivocally established the hierarchy A:G < C:C < G:A < C:A, A:A, G:G, T:T, T:G, A:C, C:T < G:T, T:C as the one prevalent in Pseudomonas putida. This information is vital for enabling recombineering strategies aimed at single‐nucleotide changes in this biotechnologically important species.
Two genes in a pathogenicity gene cluster encoding secreted proteins are required for appressorial penetration and infection of the maize anthracnose fungus Colletotrichum graminicola
Authors: Eisermann Iris , Weihmann Fabian , Krijger Jorrit‐Jan , Kröling Christian , Hause Gerd , Menzel Matthias , Pienkny Silke , Kiesow Andreas , Deising Holger B. , Wirsel Stefan G. R.
Published: October 2019

To avoid pathogen‐associated molecular pattern recognition, the hemibiotrophic maize pathogen Colletotrichum graminicola secretes proteins mediating the establishment of biotrophy. Targeted deletion of 26 individual candidate genes and seven gene clusters comprising 32 genes of C. graminicola identified a pathogenicity cluster (CLU5) of five co‐linear genes, all of which, with the exception of CLU5b, encode secreted proteins. Targeted deletion of all genes of CLU5 revealed that CLU5a and CLU5d are required for full appressorial penetration competence, with virulence deficiencies independent of the host genotype and organ inoculated. Cytorrhysis experiments and microscopy showed that Δclu5a mutants form pressurized appressoria, but they are hampered in forming penetration pores and fail to differentiate a penetration peg. Whereas Δclu5d mutants elicited WT‐like papillae, albeit at increased frequencies, papillae induced by Δclu5a mutants were much smaller than those elicited by the WT. Synteny of CLU5 is not only conserved in Colletotrichum spp. but also in additional species of Sordariomycetes including insect pathogens and saprophytes suggesting importance of CLU5 for fungal biology. Since CLU5a and CLU5d also occur in non‐pathogenic fungi and since they are expressed prior to plant invasion and even in vegetative hyphae, the encoded proteins probably do not act primarily as effectors.
Brexit, the Belfast Agreement and Northern Ireland: Imperilling a Fragile Political Bargain
Authors: Teague Paul
Published: October 2019

The major impact of the Belfast Agreement was to engineer a peaceful coexistence between nationalism and unionism that involved each bloc recognising it had sufficient power to thwart the political ambitions of the other side, but not enough to push through its own agenda. This paper argues that Brexit seriously damages this peaceful coexistence and could trigger what is termed an Ulster war of attrition in which Northern Ireland becomes entrapped in a political stalemate where each side strives to triumph without having sufficient power to do so. It also argues that to restore internal political stability in Northern Ireland, and to indemnify against the risk of disorderly relationships between the British and Irish governments in the future, the strategic importance of Strand 3 of the Belfast Agreement requires strengthening.
The vaccination debate in the “post‐truth” era: social media as sites of multi‐layered reflexivity
Authors: Numerato Dino , Vochocová Lenka , Štětka Václav , Macková Alena
Published: October 2019

This paper analyses the contemporary public debate about vaccination, and medical knowledge more broadly, in the context of social media. The study is focused on the massive online debate prompted by the Facebook status of the digital celebrity Mark Zuckerberg, who posted a picture of his two‐month‐old daughter, accompanied by a comment: ’Doctor's visit – time for vaccines!’ Carrying out a qualitative analysis on a sample of 650 comments and replies, selected through systematic random sampling from an initial pool of over 10,000 user contributions, and utilising open and axial coding, we empirically inform the theoretical discussion around the concept of the reflexive patient and introduce the notion of multi‐layered reflexivity. We argue that the reflexive debate surrounding this primarily medical problem is influenced by both biomedical and social scientific knowledge. Lay actors therefore discuss not only vaccination, but also its political and economic aspects as well as the post‐truth information context of the debate. We stress that the reflexivity of social actors related to the post‐truth era re‐enters and influences the debate more than ever. Furthermore, we suggest that the interconnection of different layers of reflexivity can either reinforce certainty or deepen the ambiguity and uncertainty of reflexive agents.
Making sense with numbers. Unravelling ethico‐psychological subjects in practices of self‐quantification
Authors: Pols Jeannette , Willems Dick , Aanestad Margunn
Published: October 2019

Prevention enthusiasts show great optimism about the potential of health apps to modify peoples’ lifestyles through the tracking and quantification of behaviours and bodily signs. Critical sociologists warn for the disciplining effects of self‐tracking. In this paper we use an empirical ethics approach to study the characteristics and strivings of the various types of ‘ethico‐psychological subjects’ that emerge in practices of self‐quantification by analysing how people and numbers relate in three cases of self‐quantification: in prevention discourse, in testimonies from the quantified self (QS) movement and in empirical work we did with people with Diabetes type I and with ‘every day self‐trackers’. We show that a free subject that needs support to enact its will is crucial to understand the optimism about prevention. In the QS‐movement the concern is with a lack of objective and personalised knowledge about imperceptible processes in the body. These subjects are decentered and multiplied when we trace how numbers in their turn act to make sense of people in our empirical study. We conclude that there are many different types of ethico‐psychological subjects in practices of self‐tracking that need to be explored in order to establish what good these practices of self‐quantification might do.
Is digital health care more equitable? The framing of health inequalities within England's digital health policy 2010–2017
Authors: Rich Emma , Miah Andy , Lewis Sarah
Published: October 2019

Informed by a discourse analysis, this article examines the framing of equity within the UK's digital health policies between 2010 and 2017, focusing on England's development of NHS Digital and its situation within the UK Government's wider digital strategy. Analysis of significant policy documents reveals three interrelated discourses that are engaged within England's digital health policies: equity as a neoliberal imaginary of digital efficiency and empowerment; digital health as a pathway towards democratising health care through data‐sharing, co‐creation and collaboration; and finally, digital health as a route towards extending citizen autonomy through their access to data systems. It advances knowledge of the relationship between digital health policy and health inequalities. Revealing that while inclusion remains a priority area for policymakers, equity is being constituted in ways that reflect broader discourses of neoliberalism, empowerment and the turn to the market for technological solutionism, which may potentially exacerbate health inequalities.
Subjective well‐being among rheumatoid arthritis patients
Authors: Kageyama Goichi , Onishi Akira , Ueda Yo , Naka Ikuko , Tsuda Kosaku , Okano Takaichi , Akashi Kengo , Nishimura Keisuke , Sendo Sho , Saegusa Jun , Morinobu Akio
Published: October 2019

Aim

Subjective well‐being (SWB) is a psychological construct that is synonymous with happiness. Many variables including age, sex, income, employment, and marital status are related to SWB. Health is also an important determinant of SWB that can be adversely affected in patients with chronic conditions such as rheumatoid arthritis (RA). In this study, we evaluate the SWB of RA patients and compare it with that of healthy controls.

Methods

We obtained the original dataset from the “Quality of Life Survey, 2013”, which was conducted by the Economic and Social Research Institute, Cabinet Office, Government of Japan. In this survey, SWB was determined by asking participants to rate their happiness between 0 (very unhappy) and 10 (very happy). The survey also included a 56‐point questionnaire regarding well‐being‐related variables. This questionnaire was administered to RA patients recruited from Kobe University Hospital, and clinical and treatment data were simultaneously collected.

Results

Multivariate analysis revealed that RA patients with high or moderate disease activity had SWB scores that were similar to those of controls. However, the SWB scores of RA patients in remission or with low disease activity were higher than those of controls (P = .013). SWB was associated with household income, self‐assessment of living costs, self‐assessment of health, depression/ anxiety, and social connection.

Conclusions

For RA patients, achieving the therapeutic target can result in better SWB than that of healthy controls. Financial status, self‐assessment of health, psychological stress, and social network are also important determinants for the SWB of RA patients.
How to evaluate community predictions without thresholding?
Authors: Scherrer Daniel , Mod Heidi K. , Guisan Antoine
Published: October 2019

Stacked species distribution models (S‐SDM) provide a tool to make spatial predictions about communities by first modelling individual species and then stacking the modelled predictions to form assemblages. The evaluation of the predictive performance is usually based on a comparison of the observed and predicted community properties (e.g. species richness, composition). However, the most available and widely used evaluation metrics require the thresholding of single species' predicted probabilities of occurrence to obtain binary outcomes (i.e. presence/absence). This binarization can introduce unnecessary bias and error.

Herein, we present and demonstrate the use of several groups of new or rarely used evaluation approaches and metrics for both species richness and community composition that do not require thresholding but instead directly compare the predicted probabilities of occurrences of species to the presence/absence observations in the assemblages.

Community AUC, which is based on traditional AUC, measures the ability of a model to differentiate between species presences or absences at a given site according to their predicted probabilities of occurrence. Summing the probabilities gives the expected species richness and allows the estimation of the probability that the observed species richness is not different from the expected species richness based on the species' probabilities of occurrence. The traditional Sørensen and Jaccard similarity indices (which are based on presences/absences) were adapted to maxSørensen and maxJaccard and to probSørensen and probJaccard (which use probabilities directly). A further approach (improvement over null models) compares the predictions based on S‐SDMs with the expectations from the null models to estimate the improvement in both species richness and composition predictions. Additionally, all metrics can be described against the environmental conditions of sites (e.g. elevation) to highlight the abilities of models to detect the variation in the strength of the community assembly processes in different environments.

These metrics offer an unbiased view of the performance of community predictions compared to metrics that requiring thresholding. As such, they allow more straightforward comparisons of model performance among studies (i.e. they are not influenced by any subjective thresholding decisions).
Low productivity and unsuitable management drive the decline of central European lapwing populations
Authors: Plard F. , Bruns H. A. , Cimiotti D. V. , Helmecke A. , Hötker H. , Jeromin H. , Roodbergen M. , Schekkerman H. , Teunissen W. , van der Jeugd H. , Schaub M.
Published: October 2019

Despite the protective measures that have been implemented to increase the productivity of meadow birds, populations are still declining in most breeding and wintering areas. We therefore still do not know how large the protective efforts need to be to curb the decline of the meadow bird populations. By taking advantage of monitoring data from the populations of lapwings in the Netherlands (NL) and one region in Germany [Schleswig‐Holstein (SH)], we investigated the demographic drivers responsible for the decline of the populations and evaluated the impact of protective measures. In these populations, some nests are marked with sticks such that they are not destroyed by farming activity. We analyzed the data with integrated population models and show that average demographic rates were similar in the two populations. Retrospective analyses demonstrated that variation in productivity most strongly impacted population dynamics and that its variation was influenced by the local environments. Our results confirmed that low productivity (0.55 and 0.46 fledglings per pairs in SH and NL, respectively) was the main reason for the decline of the lapwing populations. Productivity of 0.76 (SH) and 0.91 (NL) fledglings per pairs would be required to stabilize the populations. The implemented nest protection had a positive effect on nest success, but did not improve chick survival, and consequently the effect on population growth rates remained insufficient. The population growth rate in NL would increase by only 2% if all nests were protected. Our results suggest that protective measures should prioritize the reduction in predation and the improvement of chick habitat by promoting heterogeneous swards combining tall vegetation for hiding and short and open vegetation for foraging.
Testing the Alchian–Allen theorem for three goods using the pseudo Poisson model
Authors: Miljkovic Dragan , Gómez Miguel I. , Sharma Anupa , Puerto Sergio A.
Published: October 2019

We show that the Alchian–Allen theorem holds in three‐good world. We empirically test the theorem by examining the relative demand for three quality‐differentiated coffee varieties sold globally and confirm that a common per‐unit charge increases the overall quality of coffee demanded. Our empirical specification employs the Poisson pseudo maximum likelihood method, which prevents sample selection bias when zero flows between country pairs occur and estimated parameter inconsistency when the data exhibit heteroscedasticity. This is a significant improvement compared to previous practice of using the ordinary least squares to estimate the log‐log formulation, which led to both biased and inconsistent parameter estimates.
Doxorubicin‐induced skeletal muscle atrophy: Elucidating the underlying molecular pathways
Authors: Hiensch Anouk E. , Bolam Kate A. , Mijwel Sara , Jeneson Jeroen A. L. , Huitema Alwin D. R. , Kranenburg Onno , van der Wall Elsken , Rundqvist Helene , Wengstrom Yvönne , May Anne M.
Published: October 2019

Aim

Loss of skeletal muscle mass is a common clinical finding in cancer patients. The purpose of this meta‐analysis and systematic review was to quantify the effect of doxorubicin on skeletal muscle and report on the proposed molecular pathways possibly leading to doxorubicin‐induced muscle atrophy in both human and animal models.

Methods

A systematic search of the literature was conducted in PubMed, EMBASE, Web of Science and CENTRAL databases. The internal validity of included studies was assessed using SYRCLE’s risk of bias tool.

Results

Twenty eligible articles were identified. No human studies were identified as being eligible for inclusion. Doxorubicin significantly reduced skeletal muscle weight (ie EDL, TA, gastrocnemius and soleus) by 14% (95% CI: 9.9; 19.3) and muscle fibre cross‐sectional area by 17% (95% CI: 9.0; 26.0) when compared to vehicle controls. Parallel to negative changes in muscle mass, muscle strength was even more decreased in response to doxorubicin administration. This review suggests that mitochondrial dysfunction plays a central role in doxorubicin‐induced skeletal muscle atrophy. The increased production of ROS plays a key role within this process. Furthermore, doxorubicin activated all major proteolytic systems (ie calpains, the ubiquitin‐proteasome pathway and autophagy) in the skeletal muscle. Although each of these proteolytic pathways contributes to doxorubicin‐induced muscle atrophy, the activation of the ubiquitin‐proteasome pathway is hypothesized to play a key role. Finally, a limited number of studies found that doxorubicin decreases protein synthesis by a disruption in the insulin signalling pathway.

Conclusion

The results of the meta‐analysis show that doxorubicin induces skeletal muscle atrophy in preclinical models. This effect may be explained by various interacting molecular pathways. Results from preclinical studies provide a robust setting to investigate a possible dose‐response, separate the effects of doxorubicin from tumour‐induced atrophy and to examine underlying molecular pathways. More research is needed to confirm the proposed signalling pathways in humans, paving the way for potential therapeutic approaches.
Business networks, social capital and the economic performance of creative and cultural industries: The case of Indonesia
Authors: Fahmi Fikri Zul
Published: October 2019

This study examines the ways in which networking characteristics and practices influence the economic performance of creative and cultural industries. The notion of social capital is used to conceptualise the complex nature of networks, including both professional and social relationships that occur on multiple levels. This qualitative study is set in the context of Indonesia, in which two cases are examined: creative apparel entrepreneurs in Bandung and batik producers in Surakarta. The results show that regional environments provide opportunities for creative industries to find specialist suppliers, to gather market information and, importantly, to find and cross‐fertilise new ideas. Although regions provide these opportunities, the firms’ internal social capital is crucial in being able to internalise and transform the knowledge from the environment into innovative values embodied in their products.