bluuebunny/crossref_metadata_2025 huggingface dataset:
Brunner syndrome associated MAOA dysfunction in human dopaminergic neurons results in NMDAR hyperfunction and increased network activity
Authors: Shi Yan , van Rhijn Jon-Ruben , Bormann Maren , Mossink Britt , Frega Monica , Recaioglu Hatice , Hakobjan Marina , Gunnewiek Teun Klein , Schoenmaker Chantal , Palmer Elizabeth , Faivre Laurence , Kittel-Schneider Sarah , Schubert Dirk , Brunner Han , Franke Barbara , Kasri Nael Nadif
Published: October 2020

Background

Monoamine neurotransmitter abundance affects motor control, emotion, and cognitive function and is regulated by monoamine oxidases. Amongst these, monoamine oxidase A (MAOA) catalyzes the degradation of dopamine, norepinephrine, and serotonin into their inactive metabolites. Loss-of-function mutations in the X-linkedMAOAgene cause Brunner syndrome, which is characterized by various forms of impulsivity, maladaptive externalizing behavior, and mild intellectual disability. Impaired MAOA activity in individuals with Brunner syndrome results in bioamine aberration, but it is currently unknown how this affects neuronal function.

Methods

We generated human induced pluripotent stem cell (hiPSC)-derived dopaminergic (DA) neurons from three individuals with Brunner syndrome carrying different mutations, and used CRISPR/Cas9 mediated homologous recombination to rescue MAOA function. We used these lines to characterize morphological and functional properties of DA neuronal cultures at the single cell and neuronal network levelin vitro.

Results

Brunner syndrome DA neurons showed reduced synaptic density but hyperactive network activity. Intrinsic functional properties and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated synaptic transmission were not affected by MAOA dysfunction. Instead, we show that the neuronal network hyperactivity is mediated by upregulation of theGRIN2AandGRIN2Bsubunits of the N-methyl-D-aspartate receptor (NMDAR), and rescue ofMAOAresults in normalization of NMDAR function as well as restoration of network activity.

Conclusions

Our data suggest that MAOA dysfunction in Brunner syndrome increases activity of dopaminergic neurons through upregulation of NMDAR function, which may contribute to Brunner syndrome associated phenotypes.
APOEε3/ε4andAPOEε4/ε4genotypes drive unique gene signatures in the cortex of young mice
Authors: Foley Kate E. , Garceau Dylan T. , Kotredes Kevin P. , Carter Gregory W. , Sasner Michael , Howell Gareth R.
Published: October 2020

Background

Restrictions on mouse models have significantly impacted research towards understanding the most common genotype contributing to dementia in the human population –APOEε3/ε4. To address this, as part of MODEL-AD, we created new versions of humanizedAPOEε4andAPOEε3mice on a C57BL/6J background that allow for unrestricted distribution and breeding.

Methods

To determine similarities and differences betweenAPOEε3/ε4andAPOEε4/ε4risk genotypes, we analyzed peripheral lipid concentrations as well as performed unbiased transcriptional profiling of the cortex at two and four months of age, comparingAPOEε3/ε4andAPOEε4/ε4to the referenceAPOEε3/ε3. To further compare APOE genotypes, cohorts ofAPOEε3/ε3,APOEε3/ε4, andAPOEε4/ε4mice were exercised by voluntary running from 1 month to 4 months of age.

Results

Cholesterol composition was significantly influenced by APOE genotype as early as 2 months, while triglycerides were affected by APOE genotype at 4 months. Importantly, RNA-sequencing of the cortex followed by linear modeling or weighted gene co-expression network analysis (WGCNA) revealed that theAPOEε3/ε4genotype showed unique transcriptomic signatures to that ofAPOEε4/ε4. Functional enrichment of theAPOEε3/ε4, but notAPOEε3/ε4genotype, revealed sulfur and heparin binding as significant terms at 2 months, and extracellular matrix and blood coagulation at 4 months. Further, cell specific contributions of significant genes identified endothelial cells as overrepresented in theAPOEε3/ε4but notAPOEε4/ε4genotype. WGCNA analysis confirmed findings from linear modeling but also predicted that running at a young age affects myelination and gliogenesis across APOE genotypes.

Conclusions

In summary,APOEε3/ε4genotype-specific effects were observed in cortical transcriptional profiles, suggesting therapies aimed at modifying APOE biology to treat dementias may need to be targeted to specificAPOEgenotypes.
Mechanisms of protein kinase C epsilon down-regulation by transforming growth factor-beta in lung cancer cells
Authors: Casado-Medrano Victoria , Baker Martin J. , Cooke Mariana , Kazanietz Marcelo G.
Published: October 2020

Protein kinase C epsilon (PKCε), a diacylglycerol (DAG)/phorbol ester-regulated PKC isoform, has been widely linked to oncogenesis and metastasis. PKCε plays important roles in the regulation of motility and invasiveness in non-small cell lung cancer (NSCLC). We previously reported that this kinase becomes prominently down-regulated upon TGF-β-induced epithelial-to-mesenchymal transition (EMT), which leads to prominent phenotypic changes. While the phorbol ester PMA causes down-regulation of PKCα, δ and ε within hours, TGF-β requires at least 4 days to reduce the expression levels of PKCε without affecting the expression of other PKCs, an effect that parallels the acquisition of a mesenchymal phenotype. Despite the prominent transcriptional component involved in EMT, we found that PKCε down-regulation does not involve changes in PKCε mRNA levels and was entirely independent of transcriptional activation of thePRKCEgene. Further mechanistic analysis revealed that the reduction in PKCε expression is dependent on proteasomal and endolysosomal pathways, but independent of autophagy processing mechanisms. Site-directed mutagenesis of Lys312 and Lys321 in PKCε prevented its down-regulation in response to either TGF-β or the phorbol ester PMA. The shift in PKCε isozyme levels depending on cell plasticity underscores relevant functional consequences by modulating the expression of this oncogenic/metastatic kinase and highlights key roles of protein stability mechanisms in the control of PKCε phenotypic outcomes.
Neural basis of opioid-induced respiratory depression and its rescue
Authors: Liu Shijia , Kim Dongil , Oh Tae Gyu , Pao Gerald , Kim Jonghyun , Palmiter Richard D. , Banghart Matthew R. , Lee Kuo-Fen , Evans Ronald M. , Han Sung
Published: October 2020

Opioid-induced respiratory depression (OIRD) causes death following an opioid overdose, yet the neurobiological mechanisms of this process are not well understood. Here, we show that neurons within the lateral parabrachial nucleus that express the μ-opioid receptor (PBLOprm1neurons) are involved in OIRD pathogenesis. PBLOprm1neuronal activity is tightly correlated with respiratory rate, and this correlation is abolished following morphine injection. Chemogenetic inactivation of PBLOprm1neurons mimics OIRD in mice, whereas their chemogenetic activation following morphine injection rescues respiratory rhythms to baseline levels. We identified several excitatory G-protein coupled receptors expressed by PBLOprm1neurons and show that agonists for these receptors restore breathing rates in mice experiencing OIRD. Thus, PBLOprm1neurons are critical for OIRD pathogenesis, providing a promising therapeutic target for treating OIRD in patients.
Normalization by distributional resampling of high throughput single-cell RNA-sequencing data
Authors: Brown Jared , Ni Zijian , Mohanty Chitrasen , Bacher Rhonda , Kendziorski Christina
Published: October 2020

Motivation

Normalization to remove technical or experimental artifacts is critical in the analysis of single-cell RNA-sequencing experiments, even those for which unique molecular identifiers (UMIs) are available. The majority of methods for normalizing single-cell RNA-sequencing data adjust average expression in sequencing depth, but allow the variance and other properties of the gene-specific expression distribution to be non-constant in depth, which often results in reduced power and increased false discoveries in downstream analyses. This problem is exacerbated by the high proportion of zeros present in most datasets.

Results

To address this, we present Dino, a normalization method based on a flexible negative-binomial mixture model of gene expression. As demonstrated in both simulated and case study datasets, by normalizing the entire gene expression distribution, Dino is robust to shallow sequencing depth, sample heterogeneity, and varying zero proportions, leading to improved performance in downstream analyses in a number of settings.

Availability and implementation

The R package, Dino, is available on GitHub athttps://github.com/JBrownBiostat/Dino.

Contact

brownj@biostat.wisc.edu,kendzior@biostat.wisc.edu
A phylogenomic perspective on gene tree conflict and character evolution in Caprifoliaceae using target enrichment data, with Zabelioideae recognized as a new subfamily
Authors: Wang Hong-Xin , Morales-Briones Diego F. , Moore Michael J. , Wen Jun , Wang Hua-Feng
Published: October 2020

The use of diverse datasets in phylogenetic studies aiming for understanding evolutionary histories of species can yield conflicting inference. Phylogenetic conflicts observed in animal and plant systems have often been explained by hybridization, incomplete lineage sorting (ILS), or horizontal gene transfer. Here, we employed target enrichment data, species tree and species network approaches to infer the backbone phylogeny of the family Caprifoliaceae, while distinguishing among sources of incongruence. We used 713 nuclear loci and 46 complete plastome sequence data from 43 samples representing 38 species from all major clades to reconstruct the phylogeny of the family using concatenation and coalescence approaches. We found significant nuclear gene tree conflict as well as cytonuclear discordance. Additionally, coalescent simulations and phylogenetic species network analyses suggested putative ancient hybridization among subfamilies of Caprifoliaceae, which seems to be the main source of phylogenetic discordance. Ancestral state reconstruction of six morphological characters revealed some homoplasy for each character examined. By dating the branching events, we inferred the origin of Caprifoliaceae at approximately 66.65 Ma in the late Cretaceous. By integrating evidence from molecular phylogeny, divergence times, and morphology, we herein recognize Zabelioideae as a new subfamily in Caprifoliaceae. This work shows the necessity of using a combination of multiple approaches to identify the sources of gene tree discordance. Our study also highlights the importance of using data from both nuclear and chloroplast genomes to reconstruct deep and shallow phylogenies of plants.
Towards end-to-end disease prediction from raw metagenomic data
Authors: Queyrel Maxence , Prifti Edi , Templier Alexandre , Zucker Jean-Daniel
Published: October 2020

Analysis of the human microbiome using metagenomic sequencing data has demonstrated high ability in discriminating various human diseases. Raw metagenomic sequencing data require multiple complex and computationally heavy bioinformatics steps prior to data analysis. Such data contain millions of short sequences read from the fragmented DNA sequences and are stored as fastq files. Conventional processing pipelines consist in multiple steps including quality control, filtering, alignment of sequences against genomic catalogs (genes, species, taxonomic levels, functional pathways, etc.). These pipelines are complex to use, time consuming and rely on a large number of parameters that often provide variability and impact the estimation of the microbiome elements.

Training Deep Neural Networks directly from raw sequencing data is a promising approach to bypass some of the challenges associated with mainstream bioinformatics pipelines. Most of these methods use the concept of word and sentence embeddings that create a meaningful and numerical representation of DNA sequences, while extracting features and reducing the dimensionality of the data. In this paper we present an end-to-end approach that classifies patients into disease groups directly from raw metagenomic reads:metagenome2vec. This approach is composed of four steps (i) generating a vocabulary of k-mers and learning their numerical embeddings; (ii) learning DNA sequence (read) embeddings; (iii) identifying the genome from which the sequence is most likely to come and (iv) training a multiple instance learning classifier which predicts the phenotype based on the vector representation of the raw data. An attention mechanism is applied in the network so that the model can be interpreted, assigning a weight to the influence of the prediction for each genome. Using two public real-life data-sets as well a simulated one, we demonstrated that this original approach reaches high performance, comparable with the state-of-the-art methods applied directly on processed data though mainstream bioinformatics workflows. These results are encouraging for this proof of concept work. We believe that with further dedication, the DNN models have the potential to surpass mainstream bioinformatics workflows in disease classification tasks.
Gene Drives Across Engineered Fitness Valleys: Modeling a Design to Prevent Drive Spillover
Authors: de Haas Frederik J.H. , Otto Sarah P.
Published: October 2020

1

Engineered gene drive techniques for population replacement and/or suppression have potential for tackling complex challenges, including reducing the spread of diseases and invasive species. Unfortunately, the self-propelled behavior of drives can lead to the spread of transgenic elements beyond the target population, which is concerning. Gene drive systems with a low threshold frequency for invasion, such as homing-based gene drive systems, require initially few transgenic individuals to spread and are therefore easy to implement. However their ease of spread presents a double-edged sword; their low threshold makes these drives much more susceptible to spread outside of the target population (spillover). We model a proposed drive system that transitions in time from a low threshold drive system (homing-based gene drive) to a high threshold drive system (underdominance) using daisy chain technology. This combination leads to a spatially restricted drive strategy, while maintaining an attainable release threshold. We develop and analyze a discrete-time model as proof of concept and find that this technique effectively generates stable local population suppression, while preventing the spread of transgenic elements beyond the target population under biologically realistic parameters.
Indexing of diffraction patterns for determination of crystal orientations
Authors: Morawiec Adam
Published: October 2020

The task of determining the orientations of crystals is usually performed by indexing reflections detected on diffraction patterns. The well known underlying principle of indexing methods is universal: they are based on matching experimental scattering vectors to some vectors of the reciprocal lattice. Despite this, the standard attitude has been to devise algorithms applicable to patterns of a particular type. This paper provides a broader perspective. A general approach to indexing of diffraction patterns of various types is presented. References are made to formally similar problems in other research fields, e.g. in computational geometry, computer science, computer vision or star identification. Besides a general description of available methods, concrete algorithms are presented in detail and their applicability to patterns of various types is demonstrated; a program based on these algorithms is shown to index Kikuchi patterns, Kossel patterns and Laue patterns, among others.
Isogonal non-crystallographic periodic graphs based on knotted sodalite cages
Authors: Delgado-Friedrichs Olaf , O'Keeffe Michael , Treacy Michael M. J.
Published: October 2020

This work considers non-crystallographic periodic nets obtained from multiple identical copies of an underlying crystallographic net by adding or flipping edges so that the result is connected. Such a structure is called a `ladder' net here because the 1-periodic net shaped like an ordinary (infinite) ladder is a particularly simple example. It is shown how ladder nets with no added edges between layers can be generated from tangled polyhedra. These are simply related to the zeolite nets SOD, LTA and FAU. They are analyzed using new extensions of algorithms in the program Systre that allow unambiguous identification of locally stable ladder nets.
Segmentation of wine consumers based on level of involvement: a case of Lebanon
Authors: Koksal Mehmet Haluk
Published: October 2020

Purpose

The purpose of this study is to segment Lebanese wine customers based on their level of involvement with wine. It also profiles them on the basis of wine drinking motivations, wine attributes and information sources, wine consumption and purchasing behaviour and socio-demographic characteristics.

Design/methodology/approach

The data in the study was collected from the main supermarkets, hypermarkets and special liquor outlets as well as upscale restaurants serving alcohol in the Lebanese capital, Beirut, through a structured questionnaire. Out of 700 people approached, only 498 surveys were collected. After splitting consumers into three different segments: high, moderate and low involvement, the study clearly profiles the groups by employing principal component analysis, ANOVA and chi-square analysis.

Findings

After splitting consumers into three different groups based on involvement with wine; high, moderate and low, the study clearly identified the differences between groups regarding wine attributes, information sources, purchasing and consumption and socio-demographic characteristics.

Originality/value

Although there are plenty of studies on the examination of wine consumers in the literature from diverse countries, this is the first study investigating wine consumers based on wine involvement in a Middle Eastern country, Lebanon.
Workplace incivility: the impact on the Malaysian public service department
Authors: Alias Mazni , Ojo Adedapo Oluwaseyi , Ameruddin Nur Farhana Lyana
Published: October 2020

Purpose

This study aims to investigate the implication of workplace incivility among employees in the public service department in Putrajaya involving job satisfaction, work stress, psychological contract, knowledge sharing and work engagement.

Design/methodology/approach

This cross-sectional study examines the implication of workplace incivility among 180 employees in the Malaysian public service organization. Purposive sampling was used in this study. Partial least square was used to examine the measurement and the structural model of this study.

Findings

The result demonstrated that workplace incivility was associated with the psychological contract, job satisfaction, work stress and work engagement. The study also found that workplace incivility does not impact knowledge sharing in the public service organization department.

Practical implications

Future research could provide a more broadened scope to ensure the generalization of the results for the overall public service in Malaysia. Human resource development researchers could look into experimental studies to raise the awareness of workplace incivility that may lead to the decline of workplace incivility.

Originality/value

The research could trigger more empirical research toward understanding the phenomenon and implication of workplace incivility in the perspective of Malaysian public service organizations specifically in Asian countries, which are currently limited.
The nexus between economic institutions and unemployment: evidence from sub-Saharan Africa
Authors: Kilishi Abdullahi Abdulhakeem , Adebowale Hammed Adesola , Oladipupo Sodiq Abiodun
Published: October 2020

Purpose

This paper aims to investigate the nexus between economic institutions (EI) and unemployment in sub-Saharan African (SSA) countries. Specifically, the paper examines the impact of aggregate EI and ten different components of institutions on total, male and female unemployment in SSA.

Design/methodology/approach

The paper used unbalanced panel data of 37 SSA countries covering the period between 1995 and 2018. A dynamic heterogenous panel data model is specified for the study. Two alternative estimation techniques of dynamic fixed effect and pool mean group methods were used to estimate the models. The choice of appropriate method is based on Hausman specification test.

Findings

The findings reveal that aggregate EI and institutions related to the monetary system, trade flows, government spending and fiscal process significantly lead to less unemployment in the long-run. However, there is no evidence of a significant relationship between EI and unemployment in the short-run. These findings are consistent for total, male and female unemployment, respectively.

Practical implications

To reduce unemployment significantly in the long run, policymakers in SSA need to build more market-friendly institutions that will incentivize private investment, allow free movement of labour and goods, as well as guarantee a stable macroeconomic environment and efficient fiscal system.

Originality/value

Most of the existing studies focused on the influence of labour market institutions on unemployment ignoring the effects of other forms of institutions. While available studies on the link between institutions and unemployment used either OECD or other developed countries sample, with scanty evidence from Africa. However, the effects of EI could vary across regions. Thus, generalizing the findings from developed countries for SSA countries and other developing countries may be misleading. Hence, this paper contributes to the existing literature by examining the nexus between different types of EI and unemployment using the SSA sample.
India’s new-found love for wine tourism: a decanter of expectations and change
Authors: Singh Swati , Wagner Ralf , Raab Katharina
Published: October 2020

Purpose

This study aims to investigate driving factors for wine tourists to revisit Indian vineyards. It explores the motivation for Indians engaged in wine tourism and specific behaviors related thereto. Framed in the theory of planned behavior, this paper proposes a conceptual model of revisit intentions for wine tourism. This model covers environmental concerns, escapism, countryside lifestyle, entertainment and spillovers of international traveling as direct antecedents for the revisit intentions.

Design/methodology/approach

A quantitative approach was adopted for this research. Data was gathered through a standardized questionnaire from 141 vineyard tourists in Nashik, India and evaluated by fitting a structural equation model.

Findings

Important drivers for wine tourists revisit intentions are countryside lifestyle and spillovers of international travel. Notably, entertainment does not have a significant direct effect, but a substantial impact moderated by escapism. Environmental concerns have a negative impact. The escapism component is the most influential motivation for revisiting the Indian vineyards.

Research limitations/implications

The attractiveness of vineyards visits in contrast to nearby tourist attractions needs to be clarified, e.g. by calibrating gravitation models.

Practical implications

Escapism is a substantial antecedent for the revisit intention of the vineyards while environmental concerns are its major barrier.

Social implications

Countryside lifestyle contributes to overcoming the disadvantage of the contemporary hectic society of the Indian middle class and preserving Indian roots along with modernizing lifestyles.

Originality/value

The first evidence of Indian wine tourists revisits intentions. The current research fills a research gap by examining India’s wine tourism phenomenon.
Optimal path strategy for the web computing under deep reinforcement learning
Authors: Shengdong Mu , Fengyu Wang , Zhengxian Xiong , Xiao Zhuang , Lunfeng Zhang
Published: October 2020

Purpose

With the advent of the web computing era, the transmission mode of the Internet of Everything has caused an explosion in data volume, which has brought severe challenges to traditional routing protocols. The limitations of the existing routing protocols under the condition of rapid data growth are elaborated, and the routing problem is remodeled as a Markov decision process. this paper aims to solve the problem of high blocking probability due to the increase in data volume by combining deep reinforcement learning. Finally, the correctness of the proposed algorithm in this paper is verified by simulation.

Design/methodology/approach

The limitations of the existing routing protocols under the condition of rapid data growth are elaborated and the routing problem is remodeled as a Markov decision process. Based on this, a deep reinforcement learning method is used to select the next-hop router for each data transmission task, thereby minimizing the length of the data transmission path while avoiding data congestion.

Findings

Simulation results show that the proposed method can significantly reduce the probability of data congestion and increase network throughput.

Originality/value

This paper proposes an intelligent routing algorithm for the network congestion caused by the explosive growth of data volume in the future of the big data era. With the help of deep reinforcement learning, it is possible to dynamically select the transmission jump router according to the current network state, thereby reducing the probability of congestion and improving network throughput.
Cross-country income variations and inclusive financing
Authors: Safdar Muhammad Nabeel , Lin Tian , Amin Saba
Published: October 2020

Purpose

This study, a symposium, aims to explore the determinants of financial inclusion, impact of cross-country income-variations on financial inclusion, do high-income countries really uplift the financial inclusion and does the higher financial inclusion index indicate the larger economy?

Design/methodology/approach

This study adopts the panel data model to investigate the impact of high-income countries and low- and middle-income countries on financial inclusion. However, this study further adopts the principal component analysis rather than Sarma’s approach to calculate the financial inclusion index.

Findings

Based on the Data of World Bank, United Nations, International Monetary Fund, World Development Indicators, this study concludes that there is no nexus between income variations and financial inclusion, as the study reveals that some low- and middle-income countries have greater financial inclusion index such as Thailand (2.8538FII), Brazil (1.9526FII) and Turkey (0.8582FII). In low- and middle-income countries, the gross domestic product per capita, information technology and communication, the rule of law, age dependency ratio and urbanization have a noteworthy impact on financial inclusion that accumulatively describe the 83% of the model. Whereas, in high-income countries, merely, information technology and urbanization have a substantial influence on the growth of financial revolution and financial inclusion that describes the 70% of the total.

Research limitations/implications

The biggest limitation is the availability of data from different countries.

Originality/value

The originality of this paper is its technique, which is used in this paper to calculate the financial inclusion index. Furthermore, this study contributes to 40 different countries based on income, which could help to boost financial inclusion, and ultimately, it leads them toward economic growth.
The performance of consumers' cooperatives in America
Authors: Pencavel John
Published: October 2020

Purpose

The purpose is to evaluate the performance of consumers' cooperatives in the United States over the last 100 years. This evaluation is based on an overlooked series of surveys undertaken by the U.S. Bureau of Labor Statistics between 1920 and 1950. Where possible, the series are brought up to date.

Design/methodology/approach

The surveys did not follow a single consistent organization. Therefore, the observations require rearrangement so that a single meaningful design is achieved.

Findings

In a number of instances, consumers' cooperatives have not merely survived but thrived. Indeed, some of their original and continuing methods of operation have been copied and adopted by firms that are not cooperatives.

Originality/value

The series constructed are original and singular. The author knows of no such comparable data.
Are biotech and big pharma the perfect match?
Authors: Salle Margaux Bruneau de la , Thomas Mark
Published: October 2020

Purpose

The biotechnology (biotech) and pharmaceutical (pharma) industries have a lot of similarities, particularly regarding their mission to provide lifesaving and life-improving drugs. However, there are some key distinctions between the two industries. It is these differences, however, that make that ideal partners and have resulted in a wave of mergers and acquisitions between the two industries.

Design/methodology/approach

This research paper offers an insider-outsider approach to the biotechnology and pharmaceutical industries. Based on an extensive review of the industries it offers key insights into the reasons for the multiple partnerships that have developed.

Findings

The findings demonstrate that the different stages of maturity of the business models of biotech and big pharma make them ideal partners. Both rely on the advantages of the other in their development, hence the wave on M&As between the two industries.

Originality/value

This article clearly shows how two firms or industries at different stages of maturity can be mutually beneficial. This has led to many acquisitions and mergers.
Long‐term effects of antibiotic treatments on honeybee colony fitness: A modelling approach
Authors: Bulson Laura , Becher Matthias A. , McKinley Trevelyan J. , Wilfert Lena
Published: October 2020

Gut microbiome disequilibrium is increasingly implicated in host fitness reductions, including for the economically important and disease‐challenged western honey bee Apis mellifera. In laboratory experiments, the antibiotic tetracycline, which is used to prevent American Foulbrood Disease in countries including the US, elevates honey bee mortality by disturbing the microbiome. It is unclear, however, how elevated individual mortality affects colony‐level fitness.

We used an agent‐based model (BEEHAVE) and empirical data to assess colony‐level effects of antibiotic‐induced worker bee mortality, by measuring colony size. We investigated the relationship between the duration that the antibiotic‐induced mortality probability is imposed for and colony size.

We found that when simulating antibiotic‐induced mortality of worker bees from just 60 days per year, up to a permanent effect, the colony is reduced such that tetracycline treatment would not meet the European Food Safety Authority's (EFSA) honey bee protection goals. When antibiotic mortality was imposed for the hypothetical minimal exposure time, which assumes that antibiotics only impact the bee's fitness during the recommended treatment period of 15 days in both spring and autumn, the colony fitness reduction was only marginally under the EFSA's threshold.

Synthesis and Applications. Modelling colony‐level impacts of antibiotic treatment shows that individual honey bee worker mortality can lead to colony mortality. To assess the full impact, the persistence of antibiotic‐induced mortality in honey bees must be determined experimentally, in vivo. We caution that as the domestication of new insect species increases, maintaining healthy gut microbiomes is of paramount importance to insect health and commercial productivity. The recommendation from this work is to limit prophylactic use of antibiotics and to not exceed recommended treatment strategies for domesticated insects. This is especially important for highly social insects as excess antibiotic use will likely decrease colony growth and an increase in colony mortality.
Beyond the Home: Space and Agency in the Experiences of Female Service in Early Modern England
Authors: Mansell Charmian
Published: October 2020

This article reconfigures our understanding of female service in early modern England by examining the roles and spaces female servants occupied not only within their employers homes but outside and within the wider community. Using both quantitative and qualitative approaches to categorise and analyse the spaces in which female servants were recorded in church court depositions from the dioceses of Exeter, Gloucester and Winchester between 1550 and 1650, it argues that female servants were not confined to the domestic sphere either in their work or their social interactions. And further, it shows that female servants' links to the wider community gave them power and agency – limited perhaps, but significant nonetheless ‐ in their dealings with their employers.
Behavioral health home impact on transitional care and readmissions among adults with serious mental illness
Authors: Kennedy‐Hendricks Alene , Bandara Sachini , Daumit Gail L. , Busch Alisa B. , Stone Elizabeth M. , Stuart Elizabeth A. , Murphy Karly A. , McGinty Emma E.
Published: October 2020

Objective

To evaluate the impact of Maryland's behavioral health homes (BHHs) on receipt of follow‐up care and readmissions following hospitalization among Medicaid enrollees with serious mental illness (SMI).

Data Sources

Maryland Medicaid administrative claims for 12 232 individuals.

Study Design

Weighted marginal structural models were estimated to account for time‐varying exposure to BHH enrollment and time‐varying confounders. These models compared changes over time in outcomes among BHH and comparison participants. Outcome measures included readmissions and follow‐up care within 7 and 30 days following hospitalization.

Data Collection/Extraction Methods

Eligibility criteria included continuous enrollment in Medicaid for the first two years of the study period; 21‐64 years; and use of psychiatric rehabilitation services.

Principal Findings

Over three years, BHH enrollment was associated with 3.8 percentage point (95% CI: 1.5, 6.1) increased probability of having a mental health follow‐up service within 7 days of discharge from a mental illness–related hospitalization and 1.9 percentage point (95% CI: 0.0, 3.9) increased probability of having a general medical follow‐up within 7 days of discharge from a somatic hospitalization. BHHs had no effect on probability of readmission.

Conclusions

BHHs may improve follow‐up care for Medicaid enrollees with SMI, but effects do not translate into reduced risk of readmission.
Decompositions of house price distributions over time: The rise and fall of Tokyo house prices
Authors: McMillen Daniel , Shimizu Chihiro
Published: October 2020

We use recentered influence function regressions to decompose the differences in the distribution of sales prices across five stages of the business cycle in Tokyo for 1986–2016. Tokyo's housing market went through a period of rapid appreciation in prices during this time, followed by a long period of decline and a more recent increase. We find that a substantial portion of the change in the distribution of condominium prices across time periods is due to the natural aging of the housing stock, but also due to the location of the sales and the tendency for units to get larger over time.
In search of ‘low‐hanging fruits’ or ‘ideal’ candidates? Understanding headhunters' candidate search activities
Authors: Peltokorpi Vesa
Published: October 2020

Drawing on theory and research on labour market intermediaries, we interviewed 51 contingency headhunters specialised in foreign subsidiaries in Japan to explore how they search host country national candidates and what factors influence their search activities. The findings suggest that headhunters search candidates through cold calls, personal and shared databases, online job boards and social network sites, and referrals. The findings also suggest that how headhunters search candidates are congruent with the perceived importance of client organisations, search firm size and headhunters' experience. The findings contribute to human resource management research by providing evidence of a complex cost‐benefit and experience‐related candidate search activities.
A Systematic Review of Interventions to Improve Mental Health and Substance Use Outcomes for Individuals with Prenatal Alcohol Exposure and Fetal Alcohol Spectrum Disorder
Authors: Flannigan Katherine , Coons‐Harding Kelly D. , Anderson Tara , Wolfson Lindsay , Campbell Alanna , Mela Mansfield , Pei Jacqueline
Published: October 2020

Individuals with fetal alcohol spectrum disorder (FASD) experience remarkably high rates of mental health and substance use challenges, beginning early in life and extending throughout adulthood. Proactive intervention can help to mitigate some of these negative experiences. Although the literature on FASD intervention is growing, there is currently a lack of consolidated evidence on interventions that may improve mental health and substance use outcomes in this population. Informed by a life course perspective, we undertook a systematic review of the literature to identify interventions that improve mental wellness through all developmental stages for people with prenatal alcohol exposure (PAE) and FASD. A total of 33 articles were identified, most of which were focused on building skills or strategies that underlie the well‐being of children with PAE and FASD and their families. Other interventions were geared toward supporting child and family wellness and responding to risk or reducing harm. There was a notable lack of interventions that directly targeted mental health and substance use challenges, and a major gap was also noted in terms of interventions for adolescents and adults. Combined, these studies provide preliminary and emerging evidence for a range of intervention approaches that may support positive outcomes for individuals with FASD across the life course.
A micro‐computed tomographic evaluation of retreatability of BioRoot RCS in comparison with AH Plus
Authors: Alsubait Sara , Alhathlol Nuha , Alqedairi Abdullah , Alfawaz Hussam
Published: October 2020

This study compared the retreatability of filling material from canals filled with BioRoot RCS (Septodont, Saint‐Maur‐des‐Fosses, France) and AH Plus (Dentsply DeTrey, Konstanz, Germany) combined with gutta‐percha using micro‐computed tomography for evaluation. Thirty‐four mandibular premolars were divided into two groups according to the sealer used. Thirty days after obturation, canals were retreated with a ProTaper Universal retreatment system (Dentsply Maillefer, Ballaigues, Switzerland) followed by passive ultrasonic irrigation (PUI). The time taken for retreatment was recorded. The roots were scanned after obturation, after retreatment and after PUI. Data were analysed using the Mann–Whitney and Wilcoxon tests. Canals filled with BioRoot RCS exhibited significantly less remaining filling material than canals filled with AH Plus (P < 0.05). The addition of PUI resulted in a significant decrease in the residual material in both groups (P < 0.05). A significantly shorter retreatment time was reported for the AH Plus group than the BioRoot RCS group (P < 0.05).
Hospitalisations due to respiratory syncytial virus infection in children with Down syndrome before and after palivizumab recommendation in Japan
Authors: Okamoto Keisuke , Morio Tomohiro , Nakamura Yoshikazu , Hataya Hiroshi , Mizuta Koichi , Mori Masaaki
Published: October 2020

Aim

Down syndrome has been considered an independent risk factor for respiratory syncytial virus (RSV) infection. Palivizumab, an anti‐RSV humanised monoclonal antibody, was currently approved for all children with Down syndrome in Japan. To investigate the change in RSV‐associated hospitalisation (RSVH) rates before and after the universal approval of palivizumab in Japan in 2013, we conducted a nationwide retrospective survey.

Methods

We conducted a nationwide, retrospective, questionnaire survey across paediatric institutions in Japan. The recruited children with Down syndrome were divided into two groups: those born April 2010 to March 2013 (2010–2012 cohort) and those born April 2013 to March 2016 (2013–2015 cohort).

Results

Of the 664 institutions, 321 (48.3%) replied, and a total of 3929 children with Down syndrome were registered. The percentage of children who received palivizumab increased from 49.2% to 82.2%. The cumulative RSVH rate showed a decreased trend in the 2013–2015 cohort (OR, 0.83; 95%CI, 0.63–1.10), while the rate of these children (without CHD and born at a gestational age ≥ 36 weeks) was significantly decreased in the 2013–2015 cohort (OR, 0.56; 95%CI, 0.34–0.92).

Conclusion

The cumulative RSVH rate tended to be decreased after approval for all children with Down syndrome although the result was not significant.
Population pharmacokinetics of gabapentin in patients with neuropathic pain: Lack of effect of diabetes or glycaemic control
Authors: Costa Ana Carolina Conchon , de Lima Benzi Jhohann Richard , Yamamoto Priscila Akemi , de Freitas Maria Cristina Foss , de Paula Francisco José Albuquerque , Zanelli Cleslei Fernando , Lauretti Gabriela Rocha , de Moraes Natália Valadares
Published: October 2020

Aims

Gabapentin (GBP) is widely used to treat neuropathic pain, including diabetic neuropathic pain. Our objective was to evaluate the role of diabetes and glycaemic control on GBP population pharmacokinetics.

Methods

A clinical trial was conducted in patients with neuropathic pain (n = 29) due to type 2 diabetes (n = 19) or lumbar/cervical disc herniation (n = 10). All participants were treated with a single oral dose GBP. Blood was sampled up to 24 hours after GBP administration. Data were analysed with a population approach using the stochastic approximation expectation maximization algorithm. Weight, body mass index, sex, biomarkers of renal function and diabetes, and genotypes for the main genetic polymorphisms of SLC22A2 (rs316019) and SLC22A4 (rs1050152), the genes encoding the transporters for organic cations OCT2 and OCTN1, were tested as potential covariates.

Results

GBP drug disposition was described by a 1‐compartment model with lag‐time, first‐order absorption and linear elimination. The total clearance was dependent on estimated glomerular filtration rate. Population estimates (between‐subject variability in percentage) for lag time, first‐order absorption rate, apparent volume of distribution and total clearance were 0.316 h (10.6%), 1.12 h−1 (10.7%), 140 L (7.7%) and 14.7 L/h (6.97%), respectively. No significant association was observed with hyperglycaemia, glycated haemoglobin, diabetes diagnosis, age, sex, weight, body mass index, SLC22A2 or SLC22A4 genotypes.

Conclusion

This population pharmacokinetics model accurately estimated GBP concentrations in patients with neuropathic pain, using estimated glomerular filtrationrate as a covariate for total clearance. The distribution and excretion processes of GBP were not affected by hyperglycaemia or diabetes.
Influence of allopurinol on thiopurine associated toxicity: A retrospective population‐based cohort study
Authors: Houwen Jeroen P.A. , Egberts Antoine C.G. , de Boer Anthonius , van Maarseveen Erik M. , Houwen Roderick H.J. , Lalmohamed Arief
Published: October 2020

Aims

Thiopurines are important for treating inflammatory bowel disease, but are often discontinued due to adverse effects. Concomitant use of allopurinol might lower the risk of these unwanted effects, but large studies in the general population are lacking. The aims of this study were to evaluate rates of hepatotoxicity, myelotoxicity, pancreas toxicity and therapy persistence in adult thiopurine users with or without allopurinol.

Methods

A retrospective population‐based cohort study was conducted within current thiopurine users (Clinical Practice Research Datalink). Among these patients, co‐use of allopurinol was compared to non‐use. Hazard ratios (HRs) for hepatotoxicity, myelotoxicity and pancreatitis were derived using time‐dependent Cox proportional hazards models, and were adjusted for potential confounders. Persistence of thiopurine use was evaluated using Log‐rank statistics.

Results

Patients using thiopurines (n = 37 360) were identified of which 1077 were concomitantly taking allopurinol. A 58% decreased risk of hepatotoxicity was observed in those concomitantly taking allopurinol (HR 0.42; 95% CI 0.30–0.60; NNT 46). Rate of myelotoxicity (HR 0.96; 95% CI 0.89–1.03) was not influenced. Risk of pancreatitis was increased (HR 3.00; 95% CI 1.01–8.93; NNH 337), but was only seen in those with active gout (suggesting confounding by indication). Finally, allopurinol co‐users were able to maintain thiopurine therapy over twice as long as those not on allopurinol (3.9 years vs. 1.8 years, P < 0.0001).

Conclusion

In thiopurine users, allopurinol is associated with a 58% reduced risk of hepatotoxicity. In addition, thiopurine persistence was prolonged by 2.1 years in allopurinol users. These data support the use of allopurinol in individuals requiring thiopurine therapy.
Geomorphic response to the Lateglacial–Holocene transition in high Alpine regions (Sanetsch Pass, Swiss Alps)
Authors: Serra Elena , Valla Pierre G. , Gribenski Natacha , Guedes Magrani Fabio , Carcaillet Julien , Delaloye Reynald , Grobéty Bernard , Braillard Luc
Published: October 2020

Several palaeoclimatic archives have documented the pronounced climatic and environmental change associated with the Lateglacial–Holocene transition in the European Alps. However, the geomorphic response to this major environmental transition has only been punctually investigated. In this study, we propose a detailed reconstruction of post‐Last Glacial Maximum palaeoenvironmental conditions and geomorphic connectivity in the Sanetsch Pass area (2252 m a.s.l., western Swiss Alps) based on a multi‐method approach combining geomorphological and sedimentological field investigations with quantitative sedimentology and geochronology. Samples for sediment characterization (grain size, micromorphology and X‐ray diffraction) and geochronology (optically stimulated luminescence and 10Be surface exposure dating) were collected from three representative landforms of the study area: a high‐elevation silty deposit covered by patterned ground, an alluvial fan, and a hummocky moraine covered by rockfall deposits. Our results reveal the geomorphic history of the three deposits and their connectivity through sediment cascade. These results highlight the development of rapid and most probably transient landscape changes in high Alpine regions during the Lateglacial–Holocene transition, with an increase in sediment flux and the establishment of paraglacial and periglacial geomorphic processes.