bluuebunny/crossref_metadata_2025 huggingface dataset:
Single cell multi-omics profiling reveals a hierarchical epigenetic landscape during mammalian germ layer specification
Authors: Argelaguet Ricard , Mohammed Hisham , Clark Stephen J , Stapel L Carine , Krueger Christel , Kapourani Chantriolnt-Andreas , Xiang Yunlong , Hanna Courtney , Smallwood Sebastien , Ibarra-Soria Ximena , Buettner Florian , Sanguinetti Guido , Krueger Felix , Xie Wei , Rugg-Gunn Peter , Kelsey Gavin , Dean Wendy , Nichols Jennifer , Stegle Oliver , Marioni John C , Reik Wolf
Published: January 2019

Formation of the three primary germ layers during gastrulation is an essential step in the establishment of the vertebrate body plan. Recent studies employing single cell RNA-sequencing have identified major transcriptional changes associated with germ layer specification. Global epigenetic reprogramming accompanies these changes, but the role of the epigenome in regulating early cell fate choice remains unresolved, and the coordination between different epigenetic layers is unclear. Here we describe the first single cell triple-omics map of chromatin accessibility, DNA methylation and RNA expression during the exit from pluripotency and the onset of gastrulation in mouse embryos. We find dynamic dependencies between the different molecular layers, with evidence for distinct modes of epigenetic regulation. The initial exit from pluripotency coincides with the establishment of a global repressive epigenetic landscape, followed by the emergence of local lineage-specific epigenetic patterns during gastrulation. Notably, cells committed to mesoderm and endoderm undergo widespread coordinated epigenetic rearrangements, driven by loss of methylation in enhancer marks and a concomitant increase of chromatin accessibility. In striking contrast, the epigenetic landscape of ectodermal cells is already established in the early epiblast. Hence, regulatory elements associated with each germ layer are either epigenetically primed or epigenetically remodelled prior to overt cell fate decisions during gastrulation, providing the molecular logic for a hierarchical emergence of the primary germ layers.

Highlights

First map of mouse gastrulation using comprehensive single cell triple-omic analysis.

Exit from pluripotency is associated with a global repressive epigenetic landscape, driven by a sharp gain of DNA methylation and a gradual decrease of chromatin accessibility.

DNA methylation and chromatin accessibility changes in enhancers, but not in promoters, are associated with germ layer formation.

Mesoderm and endoderm enhancers become open and demethylated upon lineage commitment.

Ectoderm enhancers are primed in the early epiblast and protected from the global repressive dynamics, supporting a default model of ectoderm commitmentin vivo.
Molecular Genetic Analysis ofRB1gene among Sudanese children with Retinoblastoma
Authors: Ibrahim Nada O. , Saleem Mahgoub , Eltayeb Entesar , Mekki Salwa , Elnaim Elteleb G. , Idris Abeer Babiker , Bashir Sanaa , Salim Mohammed A. , Hassan Mohamed A.
Published: January 2019

BACKGROUND

Retinoblastoma (RB), the commonest early childhood intraocular tumor, is most often related to mutations in theRB1gene with an incidence of 3% of all pediatric tumors. It has good prognosis if diagnosed early but it is life-threatening when diagnosed late.

OBJECTIVE

To study the Molecular Genetic Analysis of Retinoblastoma (RB) in Sudanese families.

METHODS

Thirty one (n=31) clinically and histopathologically diagnosed cases of RB attending Makkah Eye Complex (MEC) Orbit clinic (Khartoum, Sudan) were included in this Molecular Genetic RB Analysis. Fresh blood samples extracted from seven RB patients and 15 close families for DNA extraction and PCR were sent for Genetic Sequencing andIn silicoapproach for “Exon 18 mutations” which is one of the highly mutated exons worldwide.

RESULTS

The majority of patients (41.9%) were below five years old. Females were 58.1%, males were 41.9%. Leukocoria was the commonest sign at presentation (41.9%). RB Unilaterality were in (77.4%) while Bilaterality in 19.4%. Both eyes were equally affected 50% each. The age at diagnosis time ranged from 0.02 to five years. Consanguinity of parents was very high (85.7%), the 1stdegree cousins were less (28.6%) while the 2nddegree was high (57.1%). The patients’ ethnic background and geographical area were from seven different tribes; all belong to the Western Sudan. The molecular genetic study showed that exon 18 was free of mutation among the seven patients + their three relatives. The Functional Analysis and (SNPs) prediction study of exon 18 from NCBI data base showed that the various computational approaches used (SIFT, PolyPhen-2, I-mutantandProject hope) identified 16 reported mutations worldwide, three of which (rs137853292, rs375645171 and rs772068738) are major nsSNPs (non-synonymous) which might contribute to nativeRB1protein malfunction and ultimately causing carcinoma.

CONCLUSION

RB mainly affected children under five years and both sexes are equally affected. Unilaterality was predominant. Consanguinity plays a role in inheritance and the majority of patients were from Western Sudan. The most commonly detected deleterious mutations worldwide in exon 18 were not found in the Sudanese studies samples. Further screening for the highly reported mutations in exons 8, 10 and 14 or Next Generation Sequencing (NGS) are recommended.In silicotools are useful in studying the functional analysis of SNPs.
A comprehensive evaluation of long read error correction methods
Authors: Zhang Haowen , Jain Chirag , Aluru Srinivas
Published: January 2019

Background

Third-generation single molecule sequencing technologies can sequence long reads, which is advancing the frontiers of genomics research. However, their high error rates prohibit accurate and efficient downstream analysis. This difficulty has motivated the development of many long read error correction tools, which tackle this problem through sampling redundancy and/or leveraging accurate short reads of the same biological samples. Existing studies to asses these tools use simulated data sets, and are not sufficiently comprehensive in the range of software covered or diversity of evaluation measures used.

Results

In this paper, we present a categorization and review of long read error correction methods, and provide a comprehensive evaluation of the corresponding long read error correction tools. Leveraging recent real sequencing data, we establish benchmark data sets and set up evaluation criteria for a comparative assessment which includes quality of error correction as well as run-time and memory usage. We study how trimming and long read sequencing depth affect error correction in terms of length distribution and genome coverage post-correction, and the impact of error correction performance on an important application of long reads, genome assembly. We provide guidelines for practitioners for choosing among the available error correction tools and identify directions for future research.

Conclusions

Despite the high error rate of long reads, the state-of-the-art correction tools can achieve high correction quality. When short reads are available, the best hybrid methods outperform non-hybrid methods in terms of correction quality and computing resource usage. When choosing tools for use, practitioners are suggested to be careful with a few correction tools that discard reads, and check the effect of error correction tools on downstream analysis. Our evaluation code is available as open-source at https://github.com/haowenz/LRECE.
Genotype-by-environment interactions inferred from genetic effects on phenotypic variability in the UK Biobank
Authors: Wang Huanwei , Zhang Futao , Zeng Jian , Wu Yang , Kemper Kathryn E. , Xue Angli , Zhang Min , Powell Joseph E. , Goddard Michael E. , Wray Naomi R. , Visscher Peter M. , McRae Allan F. , Yang Jian
Published: January 2019

Genotype-by-environment interaction (GEI) is a fundamental component in understanding complex trait variation. However, it remains challenging to identify genetic variants with GEI effects in humans largely because of the small effect sizes and the difficulty of monitoring environmental fluctuations. Here, we demonstrate that GEI can be inferred from genetic variants associated with phenotypic variability in a large sample without the need of measuring environmental factors. We performed a genome-wide variance quantitative trait locus (vQTL) analysis of ~5.6 million variants on 348,501 unrelated individuals of European ancestry for 13 quantitative traits in the UK Biobank, and identified 75 significant vQTLs with P<2.0×10−9 for 9 traits, especially for those related to obesity. Direct GEI analysis with five environmental factors showed that the vQTLs were strongly enriched with GEI effects. Our results indicate pervasive GEI effects for obesity-related traits and demonstrate the detection of GEI without environmental data.
GWAS identifies nine nephrolithiasis susceptibility loci related with metabolic metabolic and crystallization pathways
Authors: Tanikawa Chizu , Kamatani Yoichiro , Terao Chikashi , Usami Masayuki , Takahashi Atsushi , Momozawa Yukihide , Suzuki Kichiya , Ogishima Soichi , Shimizu Atsushi , Satoh Mamoru , Matsuo Keitaro , Mikami Haruo , Naito Mariko , Wakai Kenji , Yamaji Taiki , Sawada Norie , Iwasaki Motoki , Tsugane Shoichiro , Kohri Kenjiro , Yasui Takahiro , Murakami Yoshinori , Kubo Michiaki , Matsuda Koichi
Published: January 2019

Nephrolithiasis is a common urological trait disorder with acute pain. Although previous studies have identified various genetic variations associated with nephrolithiasis, the host genetic factors remain largely unidentified. To identify novel nephrolithiasis loci in the Japanese population, we performed large-scale GWAS (Genome wide association study) using 11,130 cases and 187,639 controls, followed by a replication analysis using 2,289 cases and 3,817 controls. The analysis identified 14 significant loci, including 9 novel loci on 2p23.2-3, 6p21.2, 6p12.3, 6q23.2, 16p12.3, 16q12.2, 17q23.2, 19p13.12, and 20q13.2. Interestingly, 10 of the 14 regions showed a significant association with any of 16 quantitative traits, including metabolic, kidney-related, and electrolyte traits, suggesting a common genetic background among nephrolithiasis patients and these quantitative traits. Four novel loci are related to the metabolic pathway, while the remaining 10 loci are associated with the crystallization pathway. Our findings demonstrate the crucial roles of genetic variations in the development of nephrolithiasis.

SIGNIFICANCE STATEMENT

Nephrolithiasis is a common urothelial disorders with frequent recurrence rate, but its genetic background is largely remained unidentified. Previous GWAS identified 6 genetic factors in total. Here we performed a GWAS using more than 200,000 samples in the Japanese populations, and identified 14 significant loci and nine of them are novel. We also found that 10 of the 14 loci showed a significant association with any of 16 quantitative traits, including metabolic, kidney-related, and electrolyte traits (BMI, eGFR, UA, Ca etc). All 14 significant loci are associate with either metabolic or crystallization pathways. Thus, our findings elucidated the underlying molecular pathogenesis of nephrolithiasis.
Structural basis of HMCES interactions with DNA reveals multivalent substrate recognition
Authors: Halabelian Levon , Ravichandran Mani , Li Yanjun , Zheng Hong , Aravind L. , Rao Anjana , Arrowsmith Cheryl H
Published: January 2019

HMCES can covalently crosslink to abasic sites in single-stranded DNA at stalled replication forks to prevent genome instability. Here, we report crystal structures of the HMCES SRAP domain in complex with DNA-damage substrates, revealing interactions with both single-stranded and duplex segments of 3’ overhang DNA. HMCES may also bind gapped DNA and 5’ overhang structures to align single stranded abasic sites for crosslinking to the conserved Cys2 of its catalytic triad.
TooManyCells identifies and visualizes relationships of single-cell clades
Authors: Schwartz Gregory W. , Petrovic Jelena , Fasolino Maria , Zhou Yeqiao , Cai Stanley , Xu Lanwei , Pear Warren , Vahedi Golnaz , Faryabi Robert B.
Published: January 2019

Transcriptional programs contribute to phenotypic and functional cell states. While elucidation of cell state heterogeneity and its role in biology and pathobiology has been advanced by studying single cell level measurements, the underlying assumptions of current analytical methods limit the identification and exploration of cell clades. Unlike other methods, which produce a single uni-layer partition of cells ignoring echelons of cell states, we presentTooManyCells, a software consisting of a suite of graph-based tools for efficient, global, and unbiased identification and visualization of cell clades while maintaining and presenting the relationship between cell states.TooManyCellsprovides a set of tools based on a matrix-free efficient divisive hierarchical spectral clustering algorithm wholly different from the prevalent Louvain-based methods.BirchBeer, the visualization component ofTooManyCells, introduces a new approach for single cell analysis that is built on a concept intentionally orthogonal to the widely used dimensionality reduction methods. Together, this suite of tools provide a paradigm shift in the analysis and interpretation of single cell data by enabling simultaneous comparisons of cell states at context-and application-dependent scales. A byproduct of this shift is the immediate detection and visualization of rare populations that outperforms previous algorithms as demonstrated by applying these tools to existing single cell RNA-seq data sets from various mouse organs.
Single-Cell Transcriptomic Evidence for Dense Intracortical Neuropeptide Networks
Authors: Smith Stephen J , Sümbül Uygar , Graybuck Lucas , Collman Forrest , Seshamani Sharmishtaa , Gala Rohan , Gliko Olga , Elabbady Leila , Miller Jeremy A. , Bakken Trygve , Rossier Jean , Yao Zizhen , Lein Ed , Zeng Hongkui , Tasic Bosiljka , Hawrylycz Michael
Published: January 2019

Seeking new insights into the homeostasis, modulation and plasticity of cortical synaptic networks, we have analyzed results from a single-cell RNA-seq study of 22,439 mouse neocortical neurons. Our analysis exposes transcriptomic evidence for dozens of molecularly distinct neuropeptidergic modulatory networks that directly interconnect all cortical neurons. This evidence begins with a discovery that transcripts of one or more neuropeptide precursor (NPP) and one or more neuropeptide-selective G-protein-coupled receptor (NP-GPCR) genes are highly abundant in all, or very nearly all, cortical neurons. Individual neurons express diverse subsets of NP signaling genes from palettes encoding 18 NPPs and 29 NP-GPCRs. These 47 genes comprise 37 cognate NPP/NP-GPCR pairs, implying the likelihood of local neuropeptide signaling. Here we use neuron-type-specific patterns of NP gene expression to offer specific, testable predictions regarding 37 peptidergic neuromodulatory networks that may play prominent roles in cortical homeostasis and plasticity.

Impact

Single-cell mRNA sequencing data from mouse neocortex expose evidence for peptidergic neuromodulatory networks that locally interconnect every cortical neuron

Data Highlights

At least 97% of mouse neocortical neurons express one or more of 18 neuropeptide precursor proteins (NPP) genes at very high levels

At least 98% of cortical neurons express one or more of 29 neuropeptide-selective G-protein-coupled receptor (NP-GPCR) genes cognate to the 18 highly expressed NPP genes

Neocortical expression of these 18 NPP and 29 NP-GPCR genes is highly neuron-type-specific and their expression patterns differentiate transcriptomic neuron types with exceptional power

Neuron-type taxonomy and type-specific expression of 37 cognate NPP / NP-GPCR gene pairs generate testable predictions of at least 37 local intracortical neuromodulation networks
Molecular characterization of Chlamydomonas reinhardtii telomeres and telomerase mutants
Authors: Eberhard Stephan , Valuchova Sona , Ravat Julie , Jolivet Pascale , Bujaldon Sandrine , Lemaire Stéphane D. , Wollman Francis-André , Teixeira Maria Teresa , Riha Karel , Xu Zhou
Published: January 2019

Telomeres are repeated sequences found at the end of the linear chromosomes of most eukaryotes and are required for chromosome integrity. They shorten with each cell division because of the end-replication problem. Expression of the reverse transcriptase telomerase allows for extension of telomeric repeats to counteract telomere shortening. Although Chlamydomonas reinhardtii, a photosynthetic unicellular green alga, is widely used as a model organism in photosynthesis and flagella research, and for biotechnological applications, the biology of its telomeres has not been investigated in depth. Here, we show that the C. reinhardtii (TTTTAGGG)n telomeric repeats are mostly non-degenerate and that the telomeres form a protective structure, ending with a 3′ overhang. While telomere size and length distributions are stable under various standard growth conditions, they vary substantially between 12 genetically close reference strains. Finally, we identify CrTERT, the gene encoding the catalytic subunit of telomerase and show that mutants of this gene display an “ever shortening telomere” phenotype and eventually enter replicative senescence, demonstrating that telomerase is required for long-term maintenance of telomeres in C. reinhardtii.
Is the 2014 E-Rate reform a game changer? An empirical analysis of Pennsylvania data
Authors: Grzeslo Jenna , Bai Yang , Min Bumgi , Jayakar Krishna
Published: January 2019

Purpose

This study aims to analyze the impact of the 2014 E-Rate reforms on the pattern of distribution of funds of the program.

Design/methodology/approach

Using Pennsylvania data, the paper investigates whether a school district that successfully applied for funding received increased support post-reforms, and what socio-economic characteristics of school districts were associated with successful applications. Furthermore, it asks whether the reforms reduced the barriers that disadvantaged school districts face in obtaining support.

Findings

The finding suggests that, even after controlling for changes in the school districts’ eligibility and application skills, the amount of funding committed to the school districts was still significantly higher after the reform.

Originality/value

The analysis shows that, immediately after the reform, the non-urban school districts were committed more funding than urban school districts were; they also received more funds than they would have without the reforms. This indicates that the 2014 reform might have benefited disadvantaged applicants, especially rural school districts.
Outcomes of open government
Authors: Schmidthuber Lisa , Stütz Simone , Hilgers Dennis
Published: January 2019

Purpose

Governments all over the world have implemented citizensourcing initiatives to integrate citizens into decision-making processes. A more participative decision-making process is associated with an open government and assumed to benefit public service quality and interactive value creation. The purpose of this paper is to highlight the outcomes of open government initiatives and ask to what extent open government participation is related to perceived outcomes of open government.

Design/methodology/approach

Data conducted from a survey among users of a citizensourcing platform and platform data are used to perform non-parametric analyses and examine the relationship between platform participation and perceived outcomes of open government.

Findings

The findings of this paper suggest that active platform usage positively relates to several outcomes perceived by citizens, such as improved information flow, increased trust in and satisfaction with local government. In contrast, repetitive participation does not significantly relate to users’ outcome evaluation.

Practical implications

This study suggests public managers to provide possibilities for citizen participation and interaction with government such as citizensourcing initiatives. In particular, it recommends promoting participants’ platform activity, as proactive platform participation has positive effects on perceived outcomes of open government.

Originality/value

Previous literature discussed what it needs to realize a transparent and participatory government. First empirical studies deal with government institutions’ reasons to promote exchange with citizens, and investigate citizens’ motivation to participate in citizensourcing activities, but have disregarded the consequences of open government so far. This study thus provides first insights into the outcomes of open government, as perceived by the users.
Intra‐clade metabolomic profiling of MAR4 Streptomyces from the Macaronesia Atlantic region reveals a source of anti‐biofilm metabolites
Authors: Bauermeister Anelize , Pereira Florbela , Grilo Inês R. , Godinho Camila C. , Paulino Marisa , Almeida Vanessa , Gobbo‐Neto Leonardo , Prieto‐Davó Alejandra , Sobral Rita G. , Lopes Norberto P. , Gaudêncio Susana P.
Published: January 2019

The search for new and effective strategies to reduce bacterial biofilm formation is of utmost importance as bacterial resistance to antibiotics continues to emerge. The use of anti‐biofilm agents that can disrupt recalcitrant bacterial communities can be an advantageous alternative to antimicrobials, as their use does not lead to the development of resistance mechanisms. Six MAR4 Streptomyces strains isolated from the Madeira Archipelago, at the unexplored Macaronesia Atlantic ecoregion, were used to study the chemical diversity of produced hybrid isoprenoids. These marine actinomycetes were investigated by analysing their crude extracts using LC–MS/MS and their metabolomic profiles were compared using multivariate statistical analysis (principal component analysis), showing a separation trend closely related to their phylogeny. Molecular networking unveiled the presence of a class of metabolites not previously described from MAR4 strains and new chemical derivatives belonging to the napyradiomycin and marinone classes. Furthermore, these MAR4 strains produce metabolites that inhibit biofilm formation of Staphylococcus aureus and Marinobacter hydrocarbonoclasticus. The anti‐biofilm activity of napyradiomycin SF2415B3 (1) against S. aureus was confirmed.
Real time monitoring of Aeromonas salmonicida evolution in response to successive antibiotic therapies in a commercial fish farm
Authors: Du Xiaochen , Bayliss Sion C. , Feil Edward J. , Liu Ying , Wang Chao , Zhang Gang , Zhou Dongsheng , Wei Dawei , Tang Na , Leclercq Sébastien O. , Feng Jie
Published: January 2019

Our ability to predict evolutionary trajectories of pathogens in response to antibiotic pressure is one of the promising leverage to fight against the present antibiotic resistance worldwide crisis. Yet, few studies tackled this question in situ at the outbreak level, due to the difficulty to link a given pathogenic clone evolution with its precise antibiotic exposure over time. In this study, we monitored the real‐time evolution of an Aeromonas salmonicida clone in response to successive antibiotic and vaccine therapies in a commercial fish farm. The clone was responsible for a four‐year outbreak of furunculosis within a Recirculating Aquaculture System Salmo salar farm in China, and we reconstructed the precise tempo of mobile genetic elements (MGEs) acquisition events during this period. The resistance profile provided by the acquired MGEs closely mirrored the antibiotics used to treat the outbreak, and we evidenced that two subclonal groups developed similar resistances although unrelated MGE acquisitions. Finally, we also demonstrated the efficiency of vaccination in outbreak management and its positive effect on antibiotic resistance prevalence. Our study provides unprecedented knowledge critical to understand evolutionary trajectories of resistant pathogens outside the laboratory.
Minority species influences microbiota formation: the role of Bifidobacterium with extracellular glycosidases in bifidus flora formation in breastfed infant guts
Authors: Gotoh Aina , Ojima Miriam Nozomi , Katayama Takane
Published: January 2019

The human body houses a variety of microbial ecosystems, such as the microbiotas on the skin, in the oral cavity and in the digestive tract. The gut microbiota is one such ecosystem that contains trillions of bacteria, and it is well established that it can significantly influence host health and diseases. With the advancement in bioinformatics tools, numerous comparative studies based on 16S ribosomal RNA (rRNA) gene sequences, metabolomics, pathological and epidemical analyses have revealed the correlative relationship between the abundance of certain taxa and disease states or amount of certain causative bioactive compounds. However, the 16S rRNA‐based taxonomic analyses using next‐generation sequencing (NGS) technology essentially detect only the majority species. Although the entire gut microbiome consists of 1013 microbial cells, NGS read counts are given in multiples of 106, making it difficult to determine the diversity of the entire microbiota. Some recent studies have reported instances where certain minority species play a critical role in creating locally stable conditions for other species by stabilizing the fundamental microbiota, despite their low abundance. These minority species act as ‘keystone species’, which is a species whose effect on the community is disproportionately large compared to its relative abundance. One of the attributes of keystone species within the gut microbiota is its extensive enzymatic capacity for substrates that are rare or difficult to degrade for other species, such as dietary fibres or host‐derived complex glycans, like human milk oligosaccharides (HMOs). In this paper, we propose that more emphasis should be placed on minority taxa and their possible role as keystone species in gut microbiota studies by referring to our recent studies on HMO‐mediated microbiota formation in the infant gut.
A roadmap for high‐throughput sequencing studies of wild animal populations using noninvasive samples and hybridization capture
Authors: White Lauren C. , Fontsere Claudia , Lizano Esther , Hughes David A. , Angedakin Samuel , Arandjelovic Mimi , Granjon Anne‐Céline , Hans Jörg B. , Lester Jack D. , Rabanus‐Wallace M. Timothy , Rowney Carolyn , Städele Veronika , Marques‐Bonet Tomas , Langergraber Kevin E. , Vigilant Linda
Published: January 2019

Large‐scale genomic studies of wild animal populations are often limited by access to high‐quality DNA. Although noninvasive samples, such as faeces, can be readily collected, DNA from the sample producers is usually present in low quantities, fragmented, and contaminated by microorganism and dietary DNAs. Hybridization capture can help to overcome these impediments by increasing the proportion of subject DNA prior to high‐throughput sequencing. Here we evaluate a key design variable for hybridization capture, the number of rounds of capture, by testing whether one or two rounds are most appropriate, given varying sample quality (as measured by the ratios of subject to total DNA). We used a set of 1,780 quality‐assessed wild chimpanzee (Pan troglodytes schweinfurthii) faecal samples and chose 110 samples of varying quality for exome capture and sequencing. We used multiple regression to assess the effects of the ratio of subject to total DNA (sample quality), rounds of capture and sequencing effort on the number of unique exome reads sequenced. We not only show that one round of capture is preferable when the proportion of subject DNA in a sample is above ~2%–3%, but also explore various types of bias introduced by capture, and develop a model that predicts the sequencing effort necessary for a desired data yield from samples of a given quality. Thus, our results provide a useful guide and pave a methodological way forward for researchers wishing to plan similar hybridization capture studies.
Inclusion of Sex and Gender in Emergency Medicine Research—A 2018 Update
Authors: Safdar Basmah , Ona Ayala Kimberly E. , Ali Syed Shayan , Seifer Benjamin J. , Hong Michelle , Greenberg Marna Rayl , Choo Esther K. , McGregor Alyson J.
Published: January 2019

Objectives

The objectives were to 1) evaluate the inclusion of sex and gender in publications by emergency medicine (EM) researchers following the 2014 federal mandate and an Academic Emergency Medicine consensus conference on sex‐ and gender‐based research and 2) assess trends compared with 2011 status report that showed 29% studies used sex and gender in the study design and 2% reported it as a primary outcome.

Methods

Using MEDLINE, the term “emergency” was used to identify all English‐language studies of adult humans published between 2014 and 2017 as EM affiliated (i.e., the first, second, or last author belonged to an EM section, division, center, or institution functioning as emergency department). Four trained abstractors reviewed the data using a standardized data abstraction form.

Results

The search revealed 6,442 articles using the selected “emergency” terms, and 2,628 original studies coded as EM‐affiliated publications were reviewed, 2,340 met inclusion criteria, and 2,336 were analyzed. This compared to 750 articles reviewed in 2011 using similar search strategy. The adjusted inter‐rater reliability for data abstraction was 97% (95% confidence interval [CI] = 95.4%–98.6%]. The leading study areas contributing the most articles were cardiovascular (17.5%), administration/crowding (15.8%), infectious diseases (9.2%), trauma/injury (9.2%), emergency medical services (6.1%), and pulmonary (6.1%). Eighty‐six percent (n = 1,921) reported the sex/gender composition of the sample and 0.4% (n = 8) reported transgender identity. Thirty‐four percent used sex/gender in the study design, with 27% (n = 609) reporting it as a control variable, 24% (n = 543) as an independent variable, and 2% using sex/gender as primary outcome. Studies funded by federal sources were significantly more likely to include sex/gender in the study design than other sources of funding (odds ratio = 1.77; 95% CI = 1.4–2.2).

Conclusions

Compared to 2011, we noted an increase in the number of EM scholarship and use of sex and gender in study design, yet the proportion evaluating it as a primary outcome remained unchanged.
A EAACI drug allergy interest group survey on how European allergy specialists deal with β‐lactam allergy
Authors: Torres Maria Jose , Celik Gulfem Elif , Whitaker Paul , Atanaskovic‐Markovic Marina , Barbaud Annick , Bircher Andreas , Blanca Miguel , Brockow Knut , Caubet Jean‐Christoph , Cernadas Josefina Rodrigues , Chiriac Anca , Demoly Pascal , Garvey Lene Heise , Merk Hans F. , Mosbech Holger , Nakonechna Alla , Romano Antonino
Published: January 2019

An accurate diagnosis of β‐lactam (BL) allergy can reduce patient morbidity and mortality. Our aim was to investigate the availability of BL reagents, their use and test procedures in different parts of Europe, as well as any differences in the diagnostic workups for evaluating subjects with BL hypersensitivity. A survey was emailed to all members of the EAACI Drug Allergy Interest Group (DAIG) between February and April 2016, and the questionnaire was meant to study the management of suspected BL hypersensitivity. The questionnaire was emailed to 82 DAIG centres and answered by 57. Amoxicillin alone or combined to clavulanic acid were the most commonly involved BL except in the Danish centre, where penicillin V was the most frequently suspected BL. All centres performed an allergy workup in subjects with histories of hypersensitivity to BL: 53 centres (93%) followed DAIG guidelines, two national guidelines and two local guidelines. However, there were deviations from DAIG recommendations concerning allergy tests, especially drug provocation tests. A significant heterogeneity exists in current practice not only among countries, but also among centres within the same country. This suggests the need to re‐evaluate, update and standardize protocols on the management of patients with suspected BL allergy.
Islands of connectivity: Archipelago relationality and transport infrastructure in Venice Lagoon
Authors: Grydehøj Adam , Casagrande Marco
Published: January 2019

Researchers are increasingly turning to relational approaches to island geography, with special emphasis being placed on archipelagos and land–sea interactions. Islands nevertheless continue to be associated with isolation, peripherality and/or disconnectedness, and fixed links such as bridges and causeways continue to be regarded as factors that decrease the quality of islandness. This does not, however, take into account the diversity of island spatialities and islands’ various positions within centre–periphery relationships. This paper sheds light on the complexity of island and archipelago connectivities by considering the transport infrastructure (bridges, boats, channels, harbours, canals, roadways) and relationships between, within and among the numerous islands of Venice Lagoon, Italy. The paper argues that island communities face diverse sets of challenges, and there is no single connectivity‐enhancing solution that is applicable to all islands. It furthermore argues that instead of seeing fixed links and intense connectivity as reducing a place's islandness, we should see them as altering the way in which a place's islandness is practised.
Radiation exposure and longitudinal changes in peripheral monocytes over 50 years: the Adult Health Study of atomic‐bomb survivors
Authors: Yoshida Kengo , French Benjamin , Yoshida Noriaki , Hida Ayumi , Ohishi Waka , Kusunoki Yoichiro
Published: January 2019

Enhanced inflammatory responses have been suggested decades after radiation exposure in atomic‐bomb survivors, but cellular and molecular alterations related to prolonged inflammation remain unclear. This study, utilizing longitudinal haematological data over 50 years for 14 000 persons, investigated whether radiation exposure promoted the relative increase in peripheral myeloid cells, known as an aging‐associated indicator of low‐grade inflammation. Statistical modelling was performed with a linear mixed‐effects model for leucocyte subsets, together with a proportional hazards regression model for all‐cause mortality. We found that age trends in lymphocyte, neutrophil and monocyte percentages or counts differed before versus after age 60 years. Radiation dose was associated with monocyte percentages and counts, but not with the lymphoid‐myeloid cell ratio. Radiation effects on monocytes were stronger after versus before age 60 years. Increases in monocyte percentages and counts were associated with higher risk of all‐cause mortality. Studies of chromosomal aberrations have shown a clonal expansion of haematopoietic stem cells among atomic‐bomb survivors. Therefore, radiation exposure might accelerate aging‐associated clonal haematopoiesis, which could result in a long‐lasting elevation of circulating monocytes.
Computational insights into the different catalytic activities of CYP3A4 and CYP3A5 toward schisantherin E
Authors: Xue Yuhan , Li Junhao , Wu Zengrui , Liu Guixia , Tang Yun , Li Weihua
Published: January 2019

The cytochromes CYP3A4 and CYP3A5 share 84% sequence identity, but they exhibit different catalytic activities toward some substrates. Schisantherin E (SE) was recently identified as a selective substrate of CYP3A5, which exhibited catalytic efficiency that was more than 23 times higher than CYP3A4. At present, however, the structural determinants responsible for the different catalytic activities of the two enzymes toward SE have not been fully understood. In this study, a combination of molecular docking, molecular dynamic simulations, and binding free energy calculation was performed on the CYP3A4/CYP3A5‐SE systems to investigate the issue. The results demonstrate that Ser119 in CYP3A4 and Glu374 in CYP3A5 formed direct hydrogen bonding with SE, respectively. Additionally, one water molecule located between the B‐C loop and the I helix mediated different hydrogen‐bonding networks between CYP3A4/3A5 and SE. The residue differences (Phe/Leu108 and Leu/Phe210) triggered the distinct conformational changes of the Phe‐cluster residues, especially Phe213 and Phe215, which formed stronger hydrophobic interactions with SE in CYP3A5. The calculated binding free energies were consistent with the experimental results.
Bisubstrate inhibitors to target histone acetyltransferase 1
Authors: Ngo Liza , Brown Tyler , Zheng Yujun G.
Published: January 2019

Developing selective enzyme inhibitors allows for the expansion of molecular toolboxes to investigate functions and activities of target enzymes. The histone acetyltransferase 1 (HAT1) is among the first histone acetyltransferase (HAT) enzymes that were discovered in the mid‐1990s; however, it remains one of the poorly studied enzymes in comparison with the other HATs. Although HAT1 has been linked to various disease states, no inhibitors have been reported to target HAT1. Here, we designed a set of peptide‐CoA conjugates as bisubstrate inhibitors of HAT1 with submicromolar potency. In particular, the bisubstrate inhibitor H4K12CoA exhibited a low Ki value of 1.1 nM for HAT1. In addition, H4K12CoA was shown to be a competitive inhibitor with respect to both AcCoA and H4 peptide, suggesting a unique kinetic mechanism of HAT1 catalysis. Creating these submicromolar inhibitors offers mechanistic tools to better understand how HAT1 recognizes substrates and cofactors, as well as provides chemical leads to further develop therapeutic agents to target this important enzyme for disease therapy.
The effect of isolated nocturnal oxygen desaturations on serum hs‐CRP and IL‐6 in patients with chronic obstructive pulmonary disease
Authors: Macrea Madalina M. , Owens Robert L. , Martin Thomas , Smith Dan , Oursler Krisann K. , Malhotra Atul
Published: January 2019

Introduction

A majority of patients with chronic obstructive pulmonary disease (COPD) die of cardiovascular disease (CVD), yet the mechanisms responsible for this association are not fully understood. It remains unknown if isolated nocturnal oxygen desaturation (iNOD) could be one of the potential pathways by which the ‘inflammatory COPD’ phenotype leads to CVD.

Objectives

We aimed to evaluate if COPD patients who meet the Medicare guidelines for nocturnal oxygen therapy (iNOT+) had higher serum hs‐CRP and IL‐6 than those who did not meet the guidelines for iNOT (iNOT−).

Methods

Patients with moderate to severe COPD (ie FEV1 < 80% and FEV1/FVC < 70), who were not on oxygen, underwent nocturnal oximetry on room air. Serum IL‐6 and hs‐CRP were collected the morning after the nocturnal oximetry testing.

Results

A total of 28 patients were included in the study, 8 of whom had more than 5 minutes and 5% of their sleep time spent at oxygen saturation less than 88% and constituted the iNOT+ group. Only serum hs‐CRP was significantly higher in iNOT+ than iNOT− (P = 0.050). There was no difference in the rate of COPD exacerbations at one and three months, or five‐year survival between the groups (P > 0.3).

Conclusion

COPD patients who have more than 5 minutes and 5% of their sleep time spent at oxygen saturation less than 88% have increased hs‐CRP, which is associated with increased risk of future CVD.
Continuity, Discontinuity and Incoherence in the Bretton Woods Order: A Hirschmanian Reading
Authors: Grabel Ilene
Published: January 2019

This article examines the effects of the Asian crisis and especially the global financial crisis on developmental finance (that is, long‐term project finance and counter‐cyclical liquidity support) and the global financial architecture. In this connection three claims are advanced. The first is positive: that the crises occasioned meaningful although ad hoc, uneven discontinuities. The conjunction of discontinuities and continuities is imparting incoherence to the developmental and global financial architecture. The second claim is normative and controversial. Contrary to the common narrative, emergent incoherence is (on balance) productive of development and stability rather than debilitating. Actors in parts of the global South and East enjoy greater opportunities for institutional experimentation today in comparison with the limited space available in the coherent neoliberal era when the Bretton Woods institutions were monolithic. All of the experiments underway are not equally likely to survive, but even failures can provide lessons and networks that contribute to future successes. Emergent redundancy and new networks of institutional cooperation increase financial resilience. The article also explores the risks of incoherence and redundancy. The third claim is that productive incoherence can be understood within a ‘Hirschmanian mindset’ — an understanding of change and development informed by Albert Hirschman's theoretical and epistemic commitments.
Coordinated Credit Spaces: The Globalization of Chinese Development Finance
Authors: Chin Gregory T. , Gallagher Kevin P.
Published: January 2019

This article examines the emergence of Chinese development finance on the global stage and evaluates the extent to which it differs from, complements and/or competes with the Western‐backed development finance institutions. Whereas the new, China‐backed multilaterals are closer to the Western model, especially the Asian Infrastructure Investment Bank, this analysis finds that China's national development finance is significantly distinct along three parameters — the scale and business model of Chinese finance relative to its Western counterparts, the composition and approach of China's lending portfolio, and the governance of China's development finance institutions. These differences can be seen as complements to the Western‐backed system, given that much of Chinese development finance has flowed into countries and sectors in which Western development finance institutions have ventured to a lesser extent. However, the globalization of Chinese development finance, patterned on the international diffusion of what is coined in this article as the ‘coordinated credit space model’, contrasts with Western development finance, governance and business models, and has triggered a competitive stance from Western actors. Either contestation or convergence are possible trajectories for the future, and the outcome will be determined by whichever can produce conditions akin to the ‘politics of productivity’.
White matter hyperintensities and recurrent stroke risk in patients with stroke with small‐vessel disease
Authors: Park J.‐H. , Heo S. H. , Lee M. H. , Kwon H. S. , Kwon S. U. , Lee J. S. ,   the PICASSO investigators
Published: January 2019

Background and purpose

White matter hyperintensities (WMH) are a predictor of stroke among elderly individuals. This study aimed to evaluate the association between WMH severity and the risk of recurrent vascular events among Asian patients with ischaemic stroke with small‐vessel disease (SVD) including micro/macrobleeds and lacunes.

Methods

Data from participants (n = 1454) in the PICASSO (PreventIon of CArdiovascular Events in iSchemic Stroke Patients with High Risk of Cerebral HemOrrhage) trial were reviewed. The severity of WMH in baseline brain magnetic resonance imaging scans was assessed using the Fazekas scale. The association between WMH severity and stroke (ischaemic or hemorrhagic) and major vascular events (MVEs) (a composite of stroke/myocardial infarction/vascular death) was assessed.

Results

Study patients had a significant burden of SVD: Fazekas score 0 (n = 2), 1 (n = 426), 2 (n = 650) and 3 (n = 376) [median Fazekas score 2 (mean follow‐up, 1.9 ± 1.3 years)]. The stroke incidence rate per 100 personyears was 2.6 in the Fazekas 0–1 group, 3.6 in the Fazekas 2 group and 7.0 in the Fazekas 3 group, and the rates for MVEs were 3.3, 4.3 and 7.6, respectively. Compared with the Fazekas 0–1 group, the Fazekas 3 group was associated with a higher risk of stroke [adjusted hazard ratio (HR), 2.15; 95% confidence interval (CI), 1.19–3.88; P = 0.011], ischaemic stroke (adjusted HR, 2.11; 95% CI, 1.07–4.15; P = 0.031), hemorrhagic stroke (adjusted HR, 3.72; 95% CI, 1.09–12.70; P = 0.036) and MVEs (adjusted HR, 2.09; 95% CI, 1.20–3.66; P = 0.010).

Conclusion

Advanced WMH in Asian patients with ischaemic stroke with SVD burden was associated with an increased risk of recurrent vascular events. It may exert an effect as a prognostic indicator in high risk of recurrent vascular events.
No additive genetic variance for tolerance to ethynylestradiol exposure in natural populations of brown trout (Salmo trutta)
Authors: Marques da Cunha Lucas , Uppal Anshu , Seddon Emily , Nusbaumer David , Vermeirssen Etienne L.M. , Wedekind Claus
Published: January 2019

One of the most common and potent pollutants of freshwater habitats is 17‐alpha‐ethynylestradiol (EE2), a synthetic component of oral contraceptives that is not completely eliminated during sewage treatment and that threatens natural populations of fish. Previous studies found additive genetic variance for the tolerance against EE2 in different salmonid fishes and concluded that rapid evolution to this type of pollution seems possible. However, these previous studies were done with fishes that are lake‐dwelling and hence typically less exposed to EE2 than river‐dwelling species. Here, we test whether there is additive genetic variance for the tolerance against EE2 also in river‐dwelling salmonid populations that have been exposed to various concentrations of EE2 over the last decades. We sampled 287 adult brown trout (Salmo trutta) from seven populations that show much genetic diversity within populations, are genetically differentiated, and that vary in their exposure to sewage‐treated effluent. In order to estimate their potential to evolve tolerance to EE2, we collected their gametes to produce 730 experimental families in blockwise full‐factorial in vitro fertilizations. We then raised 7,302 embryos singly in 2‐ml containers each and either exposed them to 1 ng/L EE2 (an ecologically relevant concentration, i.e., 2 pg per embryo added in a single spike to the water) or sham‐treated them. Exposure to EE2 increased embryo mortality, delayed hatching time, and decreased hatchling length. We found no population differences and no additive genetic variance for tolerance to EE2. We conclude that EE2 has detrimental effects that may adversely affect population even at a very low concentration, but that our study populations lack the potential for rapid genetic adaptation to this type of pollution. One possible explanation for the latter is that continuous selection over the last decades has depleted genetic variance for tolerance to this synthetic stressor.
Tilapia fisheries in Guangdong Province, China: Socio‐economic benefits, and threats on native ecosystems and economics
Authors: Gu Dang En , Yu Fan Dong , Yang Ye Xin , Xu Meng , Wei Hui , Luo Du , Mu Xi Dong , Hu Yin Chang
Published: January 2019

Tilapia is one of the groups of fish species most widely cultured globally. China has been the largest producer of tilapia in the world since 1990s. Guangdong Province produces almost 40% of all tilapia in China because of its suitable geography and weather conditions, and tilapia culture has brought considerable economic benefits. Unfortunately, many of the biological traits that make tilapia popular for culture also contribute to its success as an invader. Tilapia has invaded natural waters and has become the dominant fish in many rivers of Guangdong Province, causing economic loss in capture fisheries, and affecting native fish species, biodiversity and aquatic ecosystems. Poor fishery management, water quality degradation and biodiversity loss have all facilitated the tilapia invasion. Tilapia have filled the niches left vacant by now locally extinct native species resulting from environmental changes in freshwater ecosystems of the province. The introduction of tilapia has both advantages and disadvantages, which should be managed to use effectively the various tilapia species in aquaculture while controlling their spread in natural waters.