bluuebunny/crossref_metadata_2025 huggingface dataset:
Mid-life and late life activities and their relationship with MRI measures of brain structure and functional connectivity in the UK Biobank cohort
Authors: Anatürk Melis , Suri Sana , Smith Stephen M. , Ebmeier Klaus P. , Sexton Claire E.
Published: April 2020

INTRODUCTION

This study aimed to evaluate whether mid-life and late life participation in leisure activities is linked to measures of brain structure, functional connectivity and cognition in early old age.

METHODS

We examined data collected from 7,152 participants of the UK Biobank study. Weekly participation in six leisure activities was assessed twice. A cognitive battery and 3T MRI brain scan were administered at the second visit.

RESULTS

Weekly computer use at mid-life associated with larger volumes of the left putamen and higher scores for fluid intelligence, alphanumeric and numeric trail making tasks and prospective memory. Frequent attendance at a sports club or gym at mid-life was associated with stronger connectivity of the sensorimotor network with the lateral visual and cerebellar networks. No other associations were significant.

DISCUSSION

This study demonstrates that not all leisure activities contribute to cognitive health equally, nor is there one unifying neural signature across leisure activities.
Oxygen dependent mitochondrial formate production and the reverse Pasteur effect
Authors: Meiser Johannes , Vazquez Alexei
Published: April 2020

The Pasteur effect dictates that oxygen induces respiration and represses fermentation. However, we have shown that oxygen stimulates mitochondrial formate production and excess formate production induces glycolysis in mammalian cells. Our observations suggest the hypothesis that increased respiration induces an increase, rather than a decrease, of fermentation, the reverse Pasteur effect. Using a mathematical model we show that, in the absence of mitochondrial formate production, we should always observe the Pasteur effect, a reduction in fermentation with increasing respiration. However, in cells with active mitochondrial formate production, the rate of fermentation first increases with increasing the rate of respiration, indicating a metabolic sweet spot at moderate oxygen availability that is within the range of tissue oxygen tensions. We provide experimental evidence for the manifestation of the reverse Pasteur effect at such oxygen tension.
Discovery and characterisation of novel circular bacteriocin plantacyclin B21AG fromLactobacillus plantarumB21
Authors: Golneshin Aida , Gor Mian Chee , Vezina Ben , Williamson Nicholas , Van Thi Thu Hao , May Bee K. , Smith Andrew T
Published: April 2020

Lactobacillus plantarumB21 isolated from Vietnamese sausage (nem chua) has previously displayed broad antimicrobial activity against gram positive bacteria including foodborne pathogensListeria monocytogenesandClostridium perfringens. This study successfully identified the antimicrobial agent as plantacyclin B21AG, a 5668 Da circular bacteriocin demonstrating high thermostability, resistance to a wide range of pH, proteolytic resistance and temporal stability. We report a reverse genetics approach used to identify and characterise plantacyclin B21AG. The bacteriocin was purified from culture supernatant by a short process consisting of concentration, n-butanol extraction and cation exchange chromatography. Ade novopeptide sequencing using LC-MS/MS techniques identified two putative peptide fragments which were mapped to the genome ofLactobacillus plantarumB21. This revealed an ORF corresponding to a putative circular bacteriocin with a 33-amino acid leader peptide and 58-amino acid mature peptide found on native plasmid pB21AG01. The corresponding gene cluster, consisted of seven genes associated with post-translational circularisation, immunity and secretion. The robust nature of plantacyclin B21AG, its antimicrobial activity and associated machinery for cyclisation make it an interesting biotechnological target for further development, and application as a food-safe antimicrobial.
Combinatorial analysis of gene regulatory network reveals the causal genetic basis of breast cancer and gene-specific personalized drug treatments
Authors: Sharif Siam Mohammad Kawsar , Sharif Shohan Mohammad Umer , Syed Easin Uddin
Published: April 2020

Cancer is the major burden of diseases around the world. The incidence and mortality rate of cancers is mounting up with the passage of days. Breast cancer is the most demoralizing cause of death, where both diseases interlocked with each other due to some genetic, biological and behavioral motives. The molecular mechanism of breast cancer through which they crop up and manifest together remains questionable. The genetic basis of protein-protein interactions and gene networks has elucidated a group of gene regulatory systems in Breast cancer. Thus, the extraction of all genomic and proteomic data has enabled unprecedented views of gene-protein co-expression, co-regulation, and interactions in the biological system. This study explored the biological system to develop a gene-disease interaction model by implementing the extracted genomic and proteomic data of Breast cancer. The disease-specific and correlated genes were pulled out and their cabling studied by PPI, disease pathway and drug-disease interaction data to articulate their role in disease development. By analyzing mined genes that are related to breast cancer, a network model is also proposed. Exploration of all the correlated genes, Hub and common genes have given some promising pieces of evidence surrounding the genetic networking models. The result of this prospective study disclosed breast cancer mediated crosslinking or possible metastatic relation on a genetic basis. Moreover, other diseases like prostate, colorectal and ovarian cancers are at the same risk and might count into consideration. The finding provides a narrative broad approach for understanding the genetic basis of these fatal diseases by the pathway analysis with gene regulatory network evaluation.
Putative condition-dependent viability selection in wild type stocks ofDrosophila pseudoobscura
Authors: Altindag Ulku H. , Taylor Hannah N. , Shoben Chelsea , Pownall Keeley A. , Stevison Laurie S
Published: April 2020

Meiotic recombination rates vary in response to intrinsic and extrinsic factors. Recently, heat stress has been shown to reveal plasticity in recombination rates inDrosophila pseudoobscura. Here, a combination of molecular genotyping and X-linked recessive phenotypic markers were used to investigate differences in recombination rates due to either heat stress or advanced maternal age. However, haplotype frequencies deviated from equal proportions for crosses using phenotypic markers, indicating viability selection. Interestingly, skews in haplotype frequency were condition-dependent, consistent with the fixation of alleles in the wild type stocks used that are unfit at high temperature. Evidence of viability selection due to heat stress in the wild type haplotypes was most apparent on days 7-9 when more mutant non-crossover haplotypes were recovered in comparison to wild type (p=2.2e-4). Despite the condition-dependent mutational load in both wild type and mutant stocks, an analysis of recombination rate plasticity revealed days 7-9 (p=0.0085) and day 9 (p=0.037) to be significantly higher due to heat stress and days 1-3 as significantly higher due to maternal age (p=0.025). Still, to confirm these findings, SNP genotyping markers were used to further investigate recombination rate. This analysis supported days 9-10 as significantly different due to heat stress in two pairs of consecutive SNP markers (p=0.018; p=0.015), suggesting this time period as when recombination rate is most sensitive to heat stress. This peak timing for recombination plasticity is consistent withD. melanogasterbased on comparison of similarly timed key meiotic events, enabling future mechanistic work of temperature stress on recombination rate.
Conditionally essential genes for survival during starvation inEnterococcus faeciumE745
Authors: de Maat Vincent , Arredondo-Alonso Sergio , Willems Rob J.L. , van Schaik Willem
Published: April 2020

The nosocomial pathogenEnterococcus faeciumcan survive for prolonged periods of time on surfaces in the absence of nutrients. This trait is thought to contribute to the ability ofE. faeciumto spread among patients in hospitals. Because there is currently a lack of data on the mechanisms that are responsible for the ability ofE. faeciumto survive in the absence of nutrients, we performed a high-throughput transposon mutant library screening (Tn-seq) to identify genes that have a role in long-term survival during incubation in phosphate-buffered saline (PBS) at 20°C. A total of 18 genes were identified by Tn-seq to contribute to survival in PBS, with functions associated with the general stress response, DNA repair, metabolism, and membrane homeostasis. The gene which was quantitatively most important for survival in PBS wasusp(locus tag: EfmE745_02439), which is predicted to encode a 17.4 kDa universal stress protein. After generating a targeted deletion mutant inusp, we were able to confirm thatuspsignificantly contributes to survival in PBS and this defect was restored byin transcomplementation. Asuspis present in 99% of 1644E. faeciumgenomes that span the diversity of the species, we postulate that this gene is a key determinant for the remarkable environmental robustness ofE. faecium. Further mechanistic studies intouspand other genes identified in this study may shed further light on the mechanisms by whichE. faeciumcan survive in the absence of nutrients for prolonged periods of time.
Impaired HSF1 transactivation drives proteostasis collapse and senescent phenotype of IPF lung fibroblast
Authors: Cuevas-Mora Karina , Roque Willy , Sales Dominic , Ritzenthaler Jeffrey D. , Torres-Gonzales Edilson , Halayko Andrew J , Rosas Ivan O. , Roman Jesse , Romero Freddy
Published: April 2020

Loss of proteostasis and cellular senescence are key hallmarks of aging. Recent studies suggest that lung fibroblasts from idiopathic pulmonary fibrosis (IPF) show features of cellular senescence, decline in heat shock proteins (HSPs) expression and impaired protein homeostasis (proteostasis). However, direct cause-effect relationships are still mostly unknown. In this study, we sought to investigate whether the heat shock factor 1 (HSF1), a major transcription factor that regulates the cellular HSPs network and cytoplasmic proteostasis, contributes to cellular senescence in lung fibroblasts. We found that IPF lung fibroblasts showed an upregulation in the expression of various cellular senescence markers, including β-galactosidase activity (SA-β-gal) staining, the DNA damage marker γH2Ax, the cell cycle inhibitor protein p21, and multiple senescence-associated secretory proteins (SASP), as well as upregulation of collagen 1a1, fibronectin and alpha-smooth muscle actin (α-SMA) gene expression compared with age-matched controls. These changes were associated with impaired proteostasis, as judged by an increase in levels of p-HSF1ser307and HSF1K298 sumo, downregulation of HSPs expression, and increased cellular protein aggregation. Similarly, lung fibroblasts isolated from a mouse model of bleomycin-induced lung fibrosis and mouse lung fibroblast chronically treated with H2O2showed downregulation in HSPs and increased in cellular senescence and SASP markers. Moreover, sustained pharmacologic activation of HSF1 increased the expression of HSPs, reduced cellular senescence markers and effectively reduced the expression of pro-fibrotic genes in IPF fibroblast. Our data provide evidence that the HSF1-mediated proteostasis is important for driving lung fibroblasts toward cellular senescence and a myofibroblast phenotype. We postulate that enhancing HSF1 activity could be effective in the treatment of lung fibrosis.
The RecQ DNA helicase Rqh1 promotes Rad3ATRkinase signaling in the DNA replication checkpoint pathway of fission yeast
Authors: Ahamad Nafees , Khan Saman , Xu Yong-jie
Published: April 2020

Rad3 is the orthologue of ATR and the sensor kinase of the DNA replication checkpoint inSchizosaccharomyces pombe. Under replication stress, it initiates checkpoint signaling at the forks necessary for maintaining genome stability and cell survival. To better understand the checkpoint initiation process, we have carried out a genetic screen in fission yeast by random mutation of the genome looking for mutants with defects in Rad3 kinase signaling. In addition to the previously reportedtel2-C307Ymutant (1), this screen has identified six mutations inrqh1encoding a RecQ DNA helicase. Surprisingly, theserqh1mutations except a start codon mutation are all in the helicase domain, indicating that the helicase activity of Rqh1 plays an important role in the replication checkpoint. In support of this notion, integration of two helicase-inactive mutations or deletion ofrqh1generated a similar Rad3 signaling defect and heterologous expression of human RECQ1, BLM and RECQ4 restored the Rad3 signaling and partially rescued arqh1helicase mutant. Therefore, the replication checkpoint function of Rqh1 is highly conserved and mutations in the helicase domain of these human enzymes may cause the checkpoint defect and contribute to the cancer predisposition syndromes.
DDR2 induces linear invadosome to promote angiogenesis in a fibrillar type I collagen context
Authors: Hammoud Aya Abou , Marais Sébastien , Allain Nathalie , Ezzoukhry Zakaria , Moreau Violaine , Saltel Frédéric
Published: April 2020

To generate new vessels, endothelial cells (ECs) form invadosomes, which are actin-based microdomains with a proteolytic activity that degrade the basement membrane. We previously demonstrated that ECs form linear invadosomes in fibrillar type I collagen context. In this study, we aim to investigate the molecular mechanisms by which ECs guides angiogenesis in a fibrillar type I collagen context. We found that Discoidin Domain Receptor 2 (DDR2) is the collagen receptor tyrosine kinase required to form linear invadosomes in ECs. We further demonstrated that it acts in synergy with VEGF to promote extracellular matrix degradation. We highlighted the involvement of an interaction between DDR2 and the matrix metalloproteinase MMP14 in this process. Finally, using in vitro andex-vivoangiogenesis assays, we demonstrated a pro-angiogenic function of DDR2 in a collagen-rich microenvironment. This study allows us to propose DDR2-dependent linear invadosomes as targets to modulate angiogenesis.
Higher-order assumed strain plane element immune to mesh distortion
Authors: Rezaiee-Pajand Mohammad , Gharaei-Moghaddam Nima , Ramezani Mohammadreza
Published: April 2020

Purpose

This paper aims to propose a new robust membrane finite element for the analysis of plane problems. The suggested element has triangular geometry. Four nodes and 11 degrees of freedom (DOF) are considered for the element. Each of the three vertex nodes has three DOF, two displacements and one drilling. The fourth node that is located inside the element has only two translational DOF.

Design/methodology/approach

The suggested formulation is based on the assumed strain method and satisfies both compatibility and equilibrium conditions within each element. This establishment results in higher insensitivity to the mesh distortion. Enforcement of the equilibrium condition to the assumed strain field leads to considerably high accuracy of the developed formulation.

Findings

To show the merits of the suggested plane element, its different properties, including insensitivity to mesh distortion, particularly under transverse shear forces, immunities to the various locking phenomena and convergence of the element are studied. The obtained results demonstrate the superiority of the suggested element compared with many of the available robust membrane elements.

Originality/value

According to the attained results, the proposed element performs better than the well-known displacement-based elements such as linear strain triangular element, Q4 and Q8 and even is comparable with robust modified membrane elements.
The relationship between perceived dissimilarity and feedback avoidance behaviour
Authors: Song Meng , Gok Kubilay , Moss Sherry , Borkowski Nancy
Published: April 2020

Purpose

The purpose of this study is to understand the conditions in which subordinates, after making a mistake, are more likely to engage in feedback avoidance behaviour (FAB), a set of behaviours that could ultimately jeopardise patient safety in a health care context.

Design/methodology/approach

This study used a sample of 183 independent leader-subordinate dyads in the health care service sector. For this study, a multiple mediator model in which three types of conflict (task conflict, relationship conflict and process conflict) were tested and acted as mediating mechanisms that transmitted the effects of perceived dissimilarity to FAB.

Findings

The results supported the mediating role of two of the three forms of conflict and highlighted the consequences of dissimilarity between supervisors and subordinates in the healthcare setting.

Research limitations/implications

One of the noteworthy limitations of this study was that this study used cross-sectional time-lagged data. Future research should use a more rigorous longitudinal approach such as a cross-lagged design (Whitmanet al., 2012) to explore the dynamic nature of dyadic relationships over time.

Practical implications

An important implication of our study results suggests that health care leadership development training should provide opportunities to increase awareness of the tendency of leaders to treat subordinates perceived as dissimilar more negatively.

Originality/value

These results contribute to our understanding of the interpersonal processes between subordinates and their supervisors, which could have a significant impact on organisational outcomes in the health care setting.
Exploring the spectrum of fashion rental
Authors: Mukendi Amira , Henninger Claudia Elisabeth
Published: April 2020

Purpose

Currently, fashion rental is suggested as being a way to bring about sustainability in the fashion industry. Although there has been some success for brands in this space, as of yet fashion rental remains a niche form of consumption. This study aims to uncover consumer perspectives of fashion rental to identify opportunities for developing a fashion rental business that meets the needs of current consumers.

Design/methodology/approach

This is a qualitative study utilising semi-structured interviews combined with brainstorming and drawing exercises. Interviews were conducted with 17 women and three men.

Findings

Findings indicate that considerations around fashion rentals are utilitarian in nature focussing on functional benefits rather than more hedonistic ones. A spectrum of products that people would be most interested in renting is given.

Research limitations/implications

Although the study invited male and female participants, the sample is more female-heavy, which may reflect the fact that women tend to be more open to alternative modes of consumption.

Practical implications

An important implication is that asking consumers to rent clothing requires a significant change in mindset. Brands need to ensure that their services “make sense” for the consumer to consider it as a viable alternative to purchasing new clothing.

Originality/value

This paper proposes a spectrum of fashion items that consumers may be interested in renting; this aims to help brands develop services that meet consumer needs.
Challenges in economic evaluations in obstetric care: a scoping review and expert opinion
Authors: Hulst SM , Brouwer WBF , Mol BW , van den Akker‐van Marle ME
Published: April 2020

Objective

The aim of this study is to identify items of economic evaluation guidelines that are frequently not complied within obstetric economic evaluations and to search for reasons for non‐adherence.

Design

Scoping review and qualitative study.

Setting

Literature on economic evaluations in obstetric care and interviews with experts.

Population or sample

The sample included 229 scientific articles and five experts.

Methods

A systematic literature search was performed. All types of literature about economic evaluations in obstetric care were included. The adherence to guidelines was assessed and articles were qualitatively analysed on additional information about reasons for non‐adherence. Issues that arose from the scoping review were discussed with experts.

Main outcome measures

Adherence to guideline items of the included economic evaluations studies. Analytical themes describing reasons for non‐adherence, resulting from qualitative analysis of articles and interviews with experts.

Results

A total of 184 economic evaluations and 45 other type of articles were included. Guideline items frequently not complied with were time horizon, type of economic evaluation and effect measure. Reasons for non‐adherence had to do with paucity of long‐term health data and assessing and combining outcomes for mother and child resulting from obstetric interventions.

Conclusions

This study identified items of guidelines that are frequently not complied with and the reasons behind this. The results are a starting point for a broad consensus building on how to deal with these challenges that can result in special guidance for the conduct of economic evaluations in obstetric care.

Tweetable abstract

Non‐adherence to guidelines in obstetric economic evaluation studies: the difficulties in detail.
Methionine as a methyl donor regulates caste differentiation in the European honey bee (Apis mellifera)
Authors: Chen Wen‐Feng , Wang Ying , Zhang Wei‐Xing , Liu Zhen‐Guo , Xu Bao‐Hua , Wang Hong‐Fang
Published: April 2020

Nutrition contributes to honey bee caste differentiation, but the role of individual nutrients is still unclear. Most essential amino acid contents, except that of methionine (Met), are greater in royal jelly than worker jelly. After ∼3.5 d, the Met content in the latter was slightly greater than in the former. Met is the major raw material used in the synthesis of S‐adenosyl‐L‐methionine, an active methyl donor for DNA methylation, which is an epigenetic driver of caste differentiation. Here, we tested whether Met regulates caste differentiation in honey bees by determining its effects on the caste development of bees receiving four diets: the basic, basic + 0.2% Met, basic + 0.2% Met + 20 mg/kg 5‐azacytidine, and basic + 20 mg/kg 5‐azacytidine. The presence of Met decreased the adult bee body length and the numbers of ovarioles, indicating that Met may direct the development of female larvae toward worker bees. The upregulated expression of SAMS, Dnmt1, and Dnmt3 caused by Met exposure in 4‐d‐old larvae indicated that the worker‐inductive effects of Met may occur through the promotion of DNA methylation. We investigated the co‐effects of Met and glucose on bee development, and found that the effects of an increased glucose level on the number of ovarioles and body length did not strengthen the worker‐inductive effects caused by Met. Our results contribute to caste development theory and suggest that Met—as a methyl donor—plays a regulatory, but not decisive, role in caste differentiation.
An optimized method for the extraction of ancient eukaryote DNA from marine sediments
Authors: Armbrecht Linda , Herrando‐Pérez Salvador , Eisenhofer Raphael , Hallegraeff Gustaaf M. , Bolch Christopher J. S. , Cooper Alan
Published: April 2020

Marine sedimentary ancient DNA (sedaDNA) provides a powerful means to reconstruct marine palaeo‐communities across the food web. However, currently there are few optimized sedaDNA extraction protocols available to maximize the yield of small DNA fragments typical of ancient DNA (aDNA) across a broad diversity of eukaryotes. We compared seven combinations of sedaDNA extraction treatments and sequencing library preparations using marine sediments collected at a water depth of 104 m off Maria Island, Tasmania, in 2018. These seven methods contrasted frozen versus refrigerated sediment, bead‐beating induced cell lysis versus ethylenediaminetetraacetic acid (EDTA) incubation, DNA binding in silica spin columns versus in silica‐solution, diluted versus undiluted DNA in shotgun library preparations to test potential inhibition issues during amplification steps, and size‐selection of low molecular‐weight (LMW) DNA to increase the extraction efficiency of sedaDNA. Maximum efficiency was obtained from frozen sediments subjected to a combination of EDTA incubation and bead‐beating, DNA binding in silica‐solution, and undiluted DNA in shotgun libraries, across 45 marine eukaryotic taxa. We present an optimized extraction protocol integrating these steps, with an optional post‐library LMW size‐selection step to retain DNA fragments of ≤500 base pairs. We also describe a stringent bioinformatic filtering approach for metagenomic data and provide a comprehensive list of contaminants as a reference for future sedaDNA studies. The new extraction and data‐processing protocol should improve quantitative paleo‐monitoring of eukaryotes from marine sediments, as well as other studies relying on the detection of highly fragmented and degraded eukaryote DNA in sediments.
Changes in marginal tax rates over the past three decades in the United States
Authors: Chen Xikai , Lu Meiting , Shan Yaowen
Published: April 2020

This paper investigates changes in corporate marginal tax rates (MTRs) in the United States over the past three decades. Similar to effective tax rate, MTR exhibits a significant but much more modest decline over time, even after accounting for tax‐related firm characteristics and industry variations. In contrast to Dyreng et al., we find that MTR declines more rapidly for purely domestic firms than for multinationals. Our findings highlight the puzzling evidence in Dyreng et al. and call for future research to study possible drivers that explain the sustained and differential decline in corporate tax rate over time between domestic and multinational firms.
Inhibition of uric acid or IL‐1β ameliorates respiratory syncytial virus immunopathology and development of asthma
Authors: Schuler Charles F. , Malinczak Carrie‐Anne , Best Shannon K. K. , Morris Susan B. , Rasky Andrew J. , Ptaschinski Catherine , Lukacs Nicholas W. , Fonseca Wendy
Published: April 2020

Background

Respiratory syncytial virus (RSV) affects most infants early in life and is associated with increased asthma risk. The specific mechanism remains unknown.

Objective

To investigate the role of uric acid (UA) and IL‐1β in RSV immunopathology and asthma predisposition.

Methods

Tracheal aspirates from human infants with and without RSV were collected and analyzed for pro‐IL‐1β mRNA and protein to establish a correlation in human disease. Neonatal mouse models of RSV were employed, wherein mice infected at 6‐7 days of life were analyzed at 8 days postinfection, 5 weeks postinfection, or after a chronic cockroach allergen asthma model. A xanthine oxidase inhibitor or IL‐1 receptor antagonist was administered during RSV infection.

Results

Human tracheal aspirates from RSV‐infected infants showed elevated pro‐IL‐1β mRNA and protein. Inhibition of UA or IL‐1β during neonatal murine RSV infection decreased mucus production, reduced cellular infiltrates to the lung (especially ILC2s), and decreased type 2 immune responses. Inhibition of either UA or IL‐1β during RSV infection led to chronic reductions in pulmonary immune cell composition and reduced type 2 immune responses and reduced similar responses after challenge with cockroach antigen.

Conclusions

Inhibiting UA and IL‐1β during RSV infection ameliorates RSV immunopathology, reduces the consequences of allergen‐induced asthma, and presents new therapeutic targets to reduce early‐life viral‐induced asthma development.
A novel whole blood gene expression signature for asthma, dermatitis, and rhinitis multimorbidity in children and adolescents
Authors: Lemonnier Nathanaël , Melén Erik , Jiang Yale , Joly Stéphane , Ménard Camille , Aguilar Daniel , Acosta‐Perez Edna , Bergström Anna , Boutaoui Nadia , Bustamante Mariona , Canino Glorisa , Forno Erick , Ramon González Juan , Garcia‐Aymerich Judith , Gruzieva Olena , Guerra Stefano , Heinrich Joachim , Kull Inger , Ibarluzea Maurolagoitia Jesús , Santa‐Marina Rodriguez Loreto , Thiering Elisabeth , Wickman Magnus , Akdis Cezmi , Akdis Mübeccel , Chen Wei , Keil Thomas , Koppelman Gerard H. , Siroux Valérie , Xu Cheng‐Jian , Hainaut Pierre , Standl Marie , Sunyer Jordi , Celedón Juan C. , Maria Antó Josep , Bousquet Jean
Published: April 2020

Background

Allergic diseases often occur in combination (multimorbidity). Human blood transcriptome studies have not addressed multimorbidity. Large‐scale gene expression data were combined to retrieve biomarkers and signaling pathways to disentangle allergic multimorbidity phenotypes.

Methods

Integrated transcriptomic analysis was conducted in 1233 participants with a discovery phase using gene expression data (Human Transcriptome Array 2.0) from whole blood of 786 children from three European birth cohorts (MeDALL), and a replication phase using RNA Sequencing data from an independent cohort (EVA‐PR, n = 447). Allergic diseases (asthma, atopic dermatitis, rhinitis) were considered as single disease or multimorbidity (at least two diseases), and compared with no disease.

Results

Fifty genes were differentially expressed in allergic diseases. Thirty‐two were not previously described in allergy. Eight genes were consistently overexpressed in all types of multimorbidity for asthma, dermatitis, and rhinitis (CLC,EMR4P, IL5RA, FRRS1, HRH4, SLC29A1,SIGLEC8, IL1RL1). All genes were replicated the in EVA‐PR cohort. RT‐qPCR validated the overexpression of selected genes. In MeDALL, 27 genes were differentially expressed in rhinitis alone, but none was significant for asthma or dermatitis alone. The multimorbidity signature was enriched in eosinophil‐associated immune response and signal transduction. Protein‐protein interaction network analysis identified IL5/JAK/STAT and IL33/ST2/IRAK/TRAF as key signaling pathways in multimorbid diseases. Synergistic effect of multimorbidity on gene expression levels was found.

Conclusion

A signature of eight genes identifies multimorbidity for asthma, rhinitis, and dermatitis. Our results have clinical and mechanistic implications, and suggest that multimorbidity should be considered differently than allergic diseases occurring alone.
Two cases of successful recanalization for acute cerebral artery embolism during perioperative period of radiofrequency ablation for atrial fibrillation
Authors: Xu Jin , Li Yana , Pu Jun
Published: April 2020

To explore the strategy of acute cerebral artery embolism after radiofrequency catheter ablation (RFA) for atrial fibrillation (AF). Reporting two cases with acute cerebral infarction after RFA for AF. Two patients were both with AF, and intracardiac thrombus was excluded through transesophageal echocardiogram (TEE) before procedure. Approach of ablation: circumferential pulmonary vein ablation in left atrium to isolate pulmonary vein plus linear ablation in the top and bottom of left atrium (BOX procedure). They both received Dabigatran Etexilate 110 mg twice daily, starting 6 hr after ablation. Symptoms of major stroke appeared 30 hr after ablation in Case 1. Occlusion was detected in M1 segment of the left middle cerebral artery by MRI 2 hr after symptoms onset. Intravenous thrombolysis was given immediately. In Case 2, the patient presented symptoms of major stroke 34 hr after ablation and occlusion in the basilar artery was confirmed by MRI 4.5 hr after symptoms onset. Although it was beyond the thrombolysis time window, mechanical thrombectomy was taken 7 hr after the symptoms onset. The culprit artery was successfully revascularized in both cases. In Case 1, NIHSS score was reduced from 8 (before thrombolysis) to 0 (24 hr after thrombolysis). In Case 2, NIHSS score decreased from 18 (before embolectomy) to 3 (24 hr after embolectomy). Both of the patients live a normal life without brain function impairment and hemorrhage until the last follow‐up. Timely recanalization could attained a good cure effect when acute stoke was happened after RFA for AF.
Eradication of biofilms on tympanostomy tubes with acetic acid treatment: an in vitro study
Authors: Kjeldsen Mathilde , Homøe Preben , Kirstine Nielsen Anne , Crone Stephanie , Nørskov Kragh Kasper , Bjarnsholt Thomas
Published: April 2020

The purpose was to evaluate the eradicative effect of acetic acid on bacterial biofilm grown on tympanostomy tubes by an in vitro experiment. Biofilms of Pseudomonas aeruginosa and Staphylococcus aureus were grown on sterile tympanostomy tubes for 24 h. The tubes were treated with acetic acid solutions at various concentrations for 24 h. Main outcome was viability of bacteria after treatment. The presence of consistently attached biofilm was examined on selected tympanostomy tubes with confocal laser scanning microscopy. Both pH‐adjusted and non‐pH‐adjusted media solutions were applied as control groups. Results showed complete eradication of P. aeruginosa biofilm with 0.50% v/v acetic acid. Biofilm of S. aureus was eradicated with 1.25% v/v acetic acid. Low pH value alone led to decreased growth of already established biofilm, but not eradication. In conlusion, acetic acid showed an eradicating effect on biofilm established on sterile tympanostomy tubes in vitro.
Evaluating alluvial stratigraphic response to cyclic and non‐cyclic upstream forcing through process‐based alluvial architecture modelling
Authors: Wang Youwei , Storms Joep E. A. , Martinius Allard W. , Karssenberg Derek , Abels Hemmo A.
Published: April 2020

Formation of alluvial stratigraphy is controlled by autogenic processes that mix their imprints with allogenic forcing. In some alluvial successions, sedimentary cycles have been linked to astronomically‐driven, cyclic climate changes. However, it remains challenging to define how such cyclic allogenic forcing leads to sedimentary cycles when it continuously occurs in concert with autogenic forcing. Accordingly, we evaluate the impact of cyclic and non‐cyclic upstream forcing on alluvial stratigraphy through a process‐based alluvial architecture model, the Karssenberg and Bridge (2008) model (KB08). The KB08 model depicts diffusion‐based sediment transport, erosion and deposition within a network of channel belts and associated floodplains, with river avulsion dependent on lateral floodplain gradient, flood magnitude and frequency, and stochastic components. We find cyclic alluvial stratigraphic patterns to occur when there is cyclicity in the ratio of sediment supply over water discharge (Qs/Qw ratio), in the precondition that the allogenic forcing has sufficiently large amplitudes and long, but not very long, wavelengths, depending on inherent properties of the modelled basin (e.g. basin subsidence, size, and slope). Each alluvial stratigraphic cycle consists of two phases: an aggradation phase characterized by rapid sedimentation due to frequent channel shifting and a non‐deposition phase characterized by channel belt stability and, depending on Qs/Qw amplitudes, incision. Larger Qs/Qw ratio amplitudes contribute to weaker downstream signal shredding by stochastic components in the model. Floodplain topographic differences are found to be compensated by autogenic dynamics at certain compensational timescales in fully autogenic runs, while the presence of allogenic forcing clearly impacts the compensational stacking patterns.
Five‐year safety and efficacy data from a phase Ib study of nivolumab and chemotherapy in advanced non‐small‐cell lung cancer
Authors: Kanda Shintaro , Ohe Yuichiro , Goto Yasushi , Horinouchi Hidehito , Fujiwara Yutaka , Nokihara Hiroshi , Yamamoto Noboru , Yamamoto Takanori , Tamura Tomohide
Published: April 2020

Combination antiprogrammed death 1/programmed death‐ligand 1 Ab and platinum‐based chemotherapy is standard first‐line treatment for advanced non‐small‐cell lung cancer without targetable oncogene alterations. We describe the long‐term safety and efficacy data from a previously reported phase Ib study of nivolumab and chemotherapy. Japanese patients with non‐small‐cell lung cancer were assigned to a treatment arm based on histology and treatment history. Nivolumab (10 mg/kg, i.v.) and chemotherapy (4 arms) were given every 3 weeks: arm A, 4 cycles of cisplatin and gemcitabine (first‐line); arm B, 4 cycles of cisplatin and pemetrexed followed by pemetrexed maintenance therapy (first‐line); arm C, 4‐6 cycles of carboplatin, paclitaxel, and bevacizumab followed by bevacizumab (first‐line); and arm D, docetaxel (second‐ or third‐line). Study treatments were continued every 3 weeks as maintenance therapy until disease progression. Minimum follow‐up period was 57.9 months. Median progression‐free survival (median [range, plus sign indicates censored data]) was 6.3 (0.7+‐47.8), 11.8 (1.4‐65.1+), 40.7 (5.3‐60.8+), and 3.2 (1.9‐10.9) months, and 5‐year progression‐free survival was observed in 0/6, 1/6, 1/6, and 0/6 patients in arms A, B, C, and D, respectively. Median overall survival was 13.2 (11.0‐55.4), 28.5 (14.6‐66.2+), not reached (24.2‐67.4+), and 12.5 (9.8‐16.9) months; the number of patients surviving 5 years were 0/6, 1/6, 4/6, and 0/6 in arms A, B, C, and D, respectively. No unexpected severe adverse events or treatment‐related deaths occurred. Nivolumab and platinum‐based chemotherapy combinations showed long‐term tolerability. A moderate proportion of patients in arm C showed 5‐year progression‐free and overall survival.
Monocyte-derived dendritic cells display a highly activated phenotype and altered function in patients with familial Mediterranean fever
Authors: Funk T , Fuchs A R , Altdörfer V S , Klein R , Autenrieth S E , Müller M R , Salih H R , Henes J , Grünebach F , Dörfel D
Published: April 2020

Dendritic cells (DCs) are sentinels of the immune system that bridge innate and adaptive immunity. By capturing antigens in peripheral tissue, processing and presenting them with concurrent expression of co-stimulatory molecules and cytokine secretion they control and modulate immune reactions. Through pattern recognition receptors, DCs sense molecules that are associated with infection or tissue damage, frequently resulting in the formation of inflammasomes upon intracellular stimulation. The inherited autoinflammatory familial Mediterranean fever (FMF) is associated with deregulated activity of the pyrin inflammasome leading to acute inflammatory episodes. However, differentiation and function of DCs in this disease are as yet unclear. Therefore, we first determined DC subpopulation frequency in peripheral blood of a cohort of FMF patients. Joint evaluation without classification according to specific patient characteristics, such as mutational status, did not disclose significant differences compared to healthy controls. For the further examination of phenotype and function, we used immature and mature monocyte-derived DCs (imMo-DCs, mMo-DCs) that were generated in vitro from FMF patients. Immunophenotypical analysis of imMo-DCs revealed a significantly elevated expression of CD83, CD86 and human leukocyte antigen D-related (HLA-DR) as well as a significant down-regulation of CD206, CD209 and glycoprotein NMB (GPNMB) in our FMF patient group. Furthermore, FMF imMo-DCs presented a significantly higher capacity to migrate and to stimulate the proliferation of unmatched allogeneic T cells. Finally, the transition towards a more mature, and therefore activated, phenotype was additionally reinforced by the fact that peripheral blood DC populations in FMF patients exhibited significantly increased expression of the co-stimulatory molecule CD86.
Diagnostic revisions in multiple sclerosis
Authors: de Seabra Mafalda M. L. , Abreu Pedro M. P. , Mendonça Maria T. S. , Reis Joaquim J. C. S. , Sá Maria J. P. M. , Guimarães Ferreira Almeida Joana C.
Published: April 2020

Objectives

The diagnostic criteria for inflammatory demyelinating diseases of the central nervous system have evolved over the past years. Close follow up and accurate multiple sclerosis (MS) diagnosis are key to optimal treatment. We retrospectively reviewed the patients who had a diagnostic revision.

Methods

The medical records of patients referred to our MS clinic (Centro Hospitalar Universitário de São João, Porto, Portugal) (n = 635) between 2009 and 2016 were reviewed. A total of 62 patients were identified, 44 were misdiagnosed with MS; 18 had another diagnosis, later redefined as MS. A total of 44 controls (with MS diagnosis) were matched to the 44 misdiagnosed cases, and a statistical analysis was carried out to determine the predictors of misdiagnosis.

Results

The mean age of our population (n = 44) was 51 ± 11 years; 77% were women. The mean duration of misdiagnosis was 13 years. Optic neuritis was the most frequent presenting symptom (25%), followed by spinal cord syndrome and non‐specific neurological symptoms (20% each). The most frequent MS misdiagnoses were non‐specific white matter hyperintensities, optic neuritis and cerebrovascular disease. The mean Extended Disability Status Scale and Multiple Sclerosis Severity Score was 0 (SD 2) and 0.6 (SD 2), respectively, in the misdiagnosed group, and 3.5 (SD 5.4) and 3.2 (SD 5.6), respectively, in the control group. From all the variables analyzed, we found that the presence of black holes and spinal cord lesions were predictors of a correct MS diagnosis (P < 0,05).

Conclusions

Our series underlines the need to continuously rethink an MS diagnosis and to thoughtfully use paraclinical tests (oligoclonal bands and magnetic resonance imaging) avoiding an unfounded diagnosis. The first event might not be atypical, as has been reported in other series.
Perspectives on area‐based conservation and its meaning for future biodiversity policy
Authors: Bhola Nina , Klimmek Helen , Kingston Naomi , Burgess Neil D. , van Soesbergen Arnout , Corrigan Colleen , Harrison Jerry , Kok Marcel T. J.
Published: April 2020

During 2021, Parties to the Convention on Biological Diversity (CBD) are expected to meet in Kunming, China, to agree on a new global biodiversity framework aimed at halting and reversing biodiversity loss, encouraging the sustainable use of biodiversity, and ensuring the equitable sharing of its benefits. As the post‐2020 global biodiversity framework evolves, parties to the convention are being exposed to a range of perspectives on the conservation and sustainable use of biodiversity, relating to the future framework as a whole or to aspects of it. Area‐based conservation measures are one such aspect, and there are diverse perspectives on how new targets might be framed in relation to these measures. These perspectives represent different outlooks on the relationship between human and nonhuman life on Earth. However, in most cases there is a lack of clarity on how they would be implemented in practice, the implications this would have for biodiversity and human well‐being, and how they would contribute to achieving the 2050 Vision for Biodiversity of “living in harmony with nature.” We sought to clarify these issues by summarizing some of these perspectives in relation to the future of area‐based biodiversity conservation. We identified these perspectives through a review of the literature and expert consultation workshops and compiled them into 4 main groups: Aichi+, ambitious area‐based conservation perspectives, new conservation, and whole‐earth conservation. We found that although the perspectives Aichi+ and whole earth are in some cases at odds with one another, they also have commonalities, and all perspectives have elements that can contribute to developing and implementing the post‐2020 global biodiversity framework and achieving the longer term CBD 2050 Vision.
Diagnostic accuracy of computed tomography colonography in patients at high risk for colorectal cancer: a meta‐analysis
Authors: Bai W. , Yu D. , Zhu B. , Yu X. , Duan R. , Li Y. , Yu W. , Hua W. , Kou C.
Published: April 2020

Aim

The aim was to explore the diagnostic value of computed tomographic colonography (CTC) compared with conventional colonoscopy in individuals at high risk for colorectal cancer.

Method

PubMed, Embase, the Cochrane Library and the Web of Science were searched by two independent reviewers for potentially eligible studies published up to 31 October 2018 that were based on a per‐patient analysis. stata, meta‐disc and revman were used to perform this meta‐analysis. A random‐effect model was used, and a subgroup analysis was conducted to explore the sources of heterogeneity.

Results

A total of 14 full‐text articles, involving 3578 patients, were included in this meta‐analysis. The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio and the area under the summary receiver operating characteristic curve of CTC for detecting polyps ≥ 6 mm were 0.87 (95% CI 0.83–0.90), 0.90 (95% CI 0.86–0.93), 9.08 (95% CI 6.28–13.13), 0.14 (95% CI 0.11–0.18) and 0.94 (95% CI 0.92–0.96), respectively. For polyps ≥ 10 mm, the pooled sensitivity, specificity, positive likelihood ratio and negative likelihood ratio of CTC were 0.91 (95% CI 0.86–0.94), 0.98 (95% CI 0.95–0.99), 40.36 (95% CI 19.16–85.03), 0.90 (95% CI 0.06–0.14) and 0.98 (95% CI 0.96–0.99), respectively.

Conclusion

In this meta‐analysis, CTC had high diagnostic accuracy for detecting polyps ≥ 6 mm and ≥ 10 mm in patients at high risk of developing colorectal cancer and it had a higher sensitivity and specificity for detecting polyps ≥ 10 mm than polyps ≥ 6 mm. However, the results should be used cautiously due to the significant heterogeneity.
Modeling early stages of endoderm development in epiblast stem cell aggregates with supply of extracellular matrices
Authors: Inamori Sachiko , Fujii Mai , Satake Sayaka , Iida Hideaki , Teramoto Machiko , Sumi Tomoyuki , Meno Chikara , Ishii Yasuo , Kondoh Hisato
Published: April 2020

Endoderm precursors expressing FoxA2 and Sox17 develop from the epiblast through the gastrulation process. In this study, we developed an experimental system to model the endoderm‐generating gastrulation process using epiblast stem cells (EpiSCs). To this end, we established an EpiSC line i22, in which enhanced green fluorescent protein is coexpressed with Foxa2. Culturing i22 EpiSCs as aggregates for a few days was sufficient to initiate Foxa2 expression, and further culturing of the aggregates in Matrigel promoted the sequential activation of transcription factor genes involved in endoderm precursor development, e.g., Eomes, Gsc, and Sox17. In aggregation culture of i22 cells for 3 days, all cells expressed POU5F1, SOX2, and E‐cadherin, a signature of the epiblast, whereas expression of GATA4 and SOX17 was also activated moderately in dispersed cells, suggesting priming of these cells to endodermal development. Embedding the aggregates in Matrigel for further 3 days elicited migration of the cells into the lumen of laminin‐rich matrices covering the aggregates, in which FOXA2 and SOX17 were expressed at a high level with the concomitant loss of E‐cadherin, indicating the migratory phase of endodermal precursors. Prolonged culturing of the aggregates generated three segregating cell populations found in post‐gastrulation stage embryos: (1) definitive endoderm co‐expressing high SOX17, GATA4, and E‐cadherin, (2) mesodermal cells expressing a low level of GATA4 and lacking E‐cadherin, and (3) primed epiblast cells expressing POU5F1, SOX2 without E‐cadherin. Thus, aggregation of EpiSCs followed by embedding of aggregates in the laminin‐rich matrix models the gastrulation‐dependent endoderm precursor development.