bluuebunny/crossref_metadata_2025 huggingface dataset:
TheDrosophilaSWI/SNF chromatin-remodeling complexes BAP and PBAP play separate roles in regulating growth and cell fate during regeneration
Authors: Tian Yuan , Smith-Bolton Rachel K.
Published: May 2018

To regenerate, damaged tissue must heal the wound, regrow to the proper size, replace the correct cell types, and return to the normal gene-expression program. However, the mechanisms that temporally and spatially control the activation or repression of important genes during regeneration are not fully understood. To determine the role that chromatin modifiers play in regulating gene expression after tissue damage, we induced ablation inDrosophilaimaginal wing discs, and screened for chromatin regulators that are required for epithelial tissue regeneration. Here we show that many of these genes are indeed important for promoting or constraining regeneration. Specifically, the two SWI/SNF chromatin-remodeling complexes play distinct roles in regulating different aspects of regeneration. The PBAP complex regulates regenerative growth and developmental timing, and is required for the expression of JNK signaling targets and the growth promoterMyc. By contrast, the BAP complex ensures correct patterning and cell fate by stabilizing expression of the posterior geneengrailed. Thus, both SWI/SNF complexes are essential for proper gene expression during tissue regeneration, but they play distinct roles in regulating growth and cell fate.

Summary statement

During regeneration of theDrosophilawing disc, the SWI/SNF PBAP complex is required for regenerative growth and expression of JNK signaling targets, while the BAP complex maintains posterior cell fate.
Evolution of developmental plasticity by opposing dosage of signalling-modifying enzymes
Authors: Bui Linh T. , Ivers Nicholas A. , Ragsdale Erik J.
Published: May 2018

Polyphenism, the extreme form of developmental plasticity, is the ability of a genotype to produce discrete morphologies matched to alternative environments. Because polyphenism is likely to be under switch-like molecular control, a comparative genetic approach could reveal the molecular targets of plasticity evolution. In the nematodePristionchus pacificus, which form two alternative feeding-morphs, the polyphenism threshold is set by relative dosage of two lineage-specific enzymes that respond to morph-inducing cues. One enzyme, the sulfotransferase SEUD-1, integrates an intercellular signalling mechanism at its ultimate target, the cells producing dimorphic mouthparts. Additionally, multiple alterations ofseud-1support it as a potential target for plasticity evolution. First, a recent duplication ofseud-1in a sister species reveals a direct correlation between genomic dosage and the polyphenism threshold. Second, laboratory selection on the polyphenism threshold resulted in changes in relative transcriptional dosage. Our study thus offers a genetic explanation for how plastic responses evolve.
Molecular dynamics simulation reveals that switchable combinations of β-sheets underlie the prion-like properties of α-synuclein amyloids
Authors: Otaki Hiroki , Taguchi Yuzuru , Nishida Noriyuki
Published: May 2018

Diversity of prion strains is one of the most mysterious traits of prions because they are mere aggregates of abnormally-folded forms of single protein species, prion protein (PrPSc), without genome. Although the strain-specific properties are hypothesized to be enciphered in the strain-specific structures of PrPSc instead of nucleotide genome, specifically what structure can code the information remains an enigma due to the incompatibility of PrPSc with structural analyses. Although the strain diversity was regarded as unique to prions, recently other disease-associated amyloids of α-synuclein (αSyn) or tau are also reported to have “strains”. As detailed structures of αSyn amyloid are already identified and the properties of mutant αSyn associated with familial Parkinson’s diseases, e.g. A53T, H50Q, and G51D, have been characterized, structure-phenotype relations of this type of amyloid could be investigated by using the αSyn amyloid as a model. Here we intensively investigated the mutant αSyn amyloids by molecular dynamics simulation to characterize influences of mutations on the structures of homo- or hetero-oligomer stacks of the amyloid. The simulations revealed directionality of the amyloid stack, remote effects of the mutations on distant β-sheets, existence of at least two switchable interfaces/amyloid cores, and distinct effects of hetero-oligomerization depending on mutation types. Collectively, those findings implied a possible mechanism of the strain diversity of the amyloids which have multiple in-register parallel β-sheets side-by-side, and support the view that their prion-like properties are inherent in the characteristic structures. We expect that the notion is also applicable to PrPSc.
Proteomic Analysis of NRROS Interactome Reveals the Presence of Chaperones and Mediators of the ERAD Pathway
Authors: Noubade Rajkumar , Phung Qui , Phung Wilson , Verschueren Erik , Lau Laura , Konno Hiroyasu , Lill Jennie , Ouyang Wenjun
Published: May 2018

Negative regulator of reactive oxygen species (NRROS, previously called LRRC33) is a leucine-rich repeat (LRR) domain containing, ER-resident transmembrane protein expressed primarily in lymphoid organs, especially in myeloid cells. We have previously demonstrated that NRROS regulates reactive oxygen species production by phagocytic cells by mediating degradation of NOX2 (gp91phox), a component of NOX2 complex responsible for the oxidative burst in these cells. Since LRR is the only functional domain in NRROS, it is likely to interact with other proteins for its biological functions. Here, by performing immunoprecipitation of NRROS and mass spectrometric analysis, we describe the NRROS interactome in macrophages and demonstrate that NRROS interacts with molecular chaperones/co-chaperones and mediators of the endoplasmic reticulum associated degradation (ERAD) pathway such as calnexin, suggesting a broader role for NRROS in protein biosynthesis and the ER quality control machinery.
Replication of MERS and SARS coronaviruses in bat cells offers insights to their ancestral origins
Authors: Lau Susanna K. P. , Fan Rachel Y. Y. , Luk Hayes K. H. , Zhu Longchao , Fung Joshua , Li Kenneth S. M. , Wong Emily Y.M. , Ahmed Syed Shakeel , Chan Jasper F. W. , Kok Raven K. H. , Chan Kwok-Hung , Wernery Ulrich , Yuen Kwok-Yung , Woo Patrick C. Y.
Published: May 2018

Previous findings of Middle East Respiratory Syndrome coronavirus (MERS-CoV)-related viruses in bats, and the ability ofTylonycteris-BatCoV HKU4 spike protein to utilize MERS-CoV receptor, human dipeptidyl peptidase 4 hDPP4, suggest a bat ancestral origin of MERS-CoV. We developed 12 primary bat cell lines from seven bat species, includingTylonycteris pachypus,Pipistrellus abramusandRhinolophus sinicus(hosts ofTylonycteris-BatCoV HKU4,Pipistrellus-BatCoV HKU5 and SARS-related-CoV respectively), and tested their susceptibilities to MERS-CoVs, SARS-CoV and human coronavirus 229E (HCoV-229E). Five cell lines, includingP. abramusandR. sinicusbut notT. pachypuscells, were susceptible to human MERS-CoV EMC/2012. However, three tested camel MERS-CoV strains showed different infectivities, with only two strains capable of infecting three and one cell lines respectively. SARS-CoV can only replicate inR. sinicuscells, while HCoV-229E cannot replicate in any bat cells. Bat dipeptidyl peptidase 4 (DPP4) sequences were closely related to those of human and non-human primates but distinct from dromedary DPP4 sequence. Critical residues for binding to MERS-CoV spike protein were mostly conserved in bat DPP4. DPP4 was expressed in the five bat cells susceptible to MERS-CoV, with significantly higher mRNA expression levels than those in non-susceptible cells (P=0.0174), supporting that DPP4 expression is critical for MERS-CoV infection in bats. However, overexpression ofT. pachypusDPP4 failed to confer MERS-CoV susceptibility inT. pachypuscells, suggesting other cellular factors in determining viral replication. The broad cellular tropism of MERS-CoV should prompt further exploration of host diversity of related viruses to identify its ancestral origin.
Simultaneous CO2and CO methanation using microbes
Authors: Matthias Kohlmayer , Robert Huber , Raimund Brotsack , Wolfgang Mayer
Published: May 2018

In this study, we developed a method for simultaneous bio-methanation of CO2and CO with H2in a single bioreactor using a combination of carboxydotrophic bacteria and methanogenic archaea for industrial applications. Methanogenic archaea generally use H2and CO2to produce methane, whereas very few methanogenic archaea methanize CO, and these grow slowly and consequently produce low reactant gas turnover rates. Thus, to achieve fast and simultaneous transformation of CO and CO2, we identified a combination of carboxydotrophic and hydrogenogenic bacteria and methanogenic archaea that can produce H2and CO2from CO, and then methanize CO2and H2. The present screening experiments identified carboxydotrophic bacteria and methanogenic archaea that can cohabitate at the same thermophilic temperature and pH ranges and in the same growth medium. In these experiments, combinations ofCarboxydocella thermautotrophica(DSM 12326),Carboxydocella sporoproducens(DSM 16521), and three thermophilic rod-shaped methanogenic archaeal cultures from MicroPyros GmbH formed unique microbial co-cultures that transformed CO2, H2, and CO to methane. The successful combination of these microbes could be used to gasify biowastes, such as sewage sludge, as alternative sources of hydrogen for microbial power-to-gas processes. Accordingly, gasification under these conditions produced H2-rich gas containing CO2and CO, theoretically allowing various types of biowastes to be converted to biomethane, which is CO2-neutral, storable, and widely applicable as an energy source.
Correlation of invitro susceptibility based on MICs and SQLE mutations with clinical response to terbinafine in patients with tinea corporis/cruris
Authors: Khurana Ananta , Masih Aradhana , Chowdhary Anuradha , Sardana Kabir , Borker Sagar , Gupta Aastha , Gautam R K , Sharma P K , Jain Dhruv
Published: May 2018

Recalcitrant dermatophytoses are on the rise and recent publications have documented high minimum inhibitory concentrations (MICs) to TRB and squalene epoxidase (SQLE) mutations. However, literature correlating the laboratory the data with clinical response is lacking.

This study was conducted to study the clinico-mycological profile of tinea corporis and cruris, including antifungal susceptibility testing (AFST) and SQLE mutation analysis and correlate these with clinical response to TRB. Skin scrapings of patients with tinea corporis with/without tinea cruris were subjected to species identification, AFST and SQLE gene analysis (on 15 isolates). KOH confirmed cases were started on TRB 250mg once a day (OD). If >50% clinical clearance was achieved by 3 weeks; the same dose was continued.(Group 1). If clinical clearance at 3 weeks was <50%, the dose was increased to 250mg twice a day (BD) (Group 2). If the response still remained below 50% after 3 weeks of BD, the patients were treated with itraconazole (ITR)(Group 3). Trichophyton interdigitale was confirmed on all 64 isolates obtained on culture. Forty four (68.7%) isolates had high (≥1 μg/ml) MICs to TRB. Six isolates were found to have aminoacid substitution Leu393Phe in SQLE protein, while one had the substitution Phe397Leu. The difference in modal MICs to TRB between the 3 clinical response groups (1.5157μg/ml, 5.0396 μg/ml and 20.1587μg/ml respectively for group 1,2 and 3) was highly significant. Clinical response was achieved in 68% of those resistant by MIC data, and 42.8% of SQLE mutation harboring isolates, by increasing drug (TRB) exposure.

We infer that TRB resistance in dermatophytes has reached alarming proportions in our patients. Though improved outcomes were achieved with higher drug exposure, with the high failure rate seen in the study, the case for shifting to another class of antifungals as first line agent against dermatophytoses is strong.
Degenerative expansion of a young supergene
Authors: Stolle Eckart , Pracana Rodrigo , Howard Philip , Paris Carolina I. , Brown Susan J. , Castillo-Carrillo Claudia , Rossiter Stephen J. , Wurm Yannick
Published: May 2018

Suppressed recombination ultimately leads to gene loss, as demonstrated by the depauperate Y chromosomes of long-established XY pairs. To understand the shorter term effects, we used high-resolution optical mapping and k-mer distribution analysis on a young non-recombining region of fire ant social chromosomes. Instead of shrinking, the region has increased in length by more than 30%. This demonstrates that degenerative expansion can occur during the early evolution of non-recombining regions.
Oncogenic Wnt/STOP signaling regulates ribosome biogenesis in vivo
Authors: Madan Babita , Harmston Nathan , Nallan Gahyathiri , Montoya Alex , Faull Peter , Petretto Enrico , Virshup David M.
Published: May 2018

Activating mutations in the Wnt pathway drive a variety of cancers, but the specific targets and pathways activated by Wnt ligands are not fully understood. To bridge this knowledge gap, we performed a comprehensive time-course analysis of Wnt-dependent signaling pathways in an orthotopic model of Wnt-addicted pancreatic cancer, using a PORCN inhibitor currently in clinical trials, and validated key results in additional Wnt-addicted models. The analysis of temporal changes following Wnt withdrawal demonstrated direct and indirect regulation of >3,500 Wnt activated genes (23% of the transcriptome). Regulation was both transcriptional via Wnt/β-catenin, and through the modulation of protein abundance of important transcription factors including MYC via Wnt/STOP. Our study identifies a central role of Wnt /β-catenin and Wnt/STOP signaling in controlling ribosomal biogenesis, a key driver of cancer proliferation.
RNA components of the spliceosome regulate tissue- and cancer-specific alternative splicing
Authors: Dvinge Heidi , Guenthoer Jamie , Porter Peggy L. , Bradley Robert K.
Published: May 2018

Alternative splicing of pre-mRNAs plays a pivotal role during the establishment and maintenance of human cell types. Characterizing thetrans-acting regulatory proteins that control alternative splicing in both healthy and malignant cells has therefore been the focus of much research. Recent work has established that even core protein components of the spliceosome, which are required for splicing to proceed, can nonetheless contribute to splicing regulation by modulating splice site choice. We here demonstrate that the RNA components of the spliceosome likewise influence alternative splicing decisions and contribute to the establishment of global splicing programs. Although these small nuclear RNAs (snRNAs), termed U1, U2, U4, U5, and U6 snRNA, are present in equal stoichiometry within the spliceosome, we found that their relative levels vary by an order of magnitude during development, across tissues, and between normal and malignant cells. Physiologically relevant perturbation of individual snRNAs drove widespread gene-specific differences in alternative splicing, but not transcriptome-wide splicing failure. Genes that were particularly sensitive to variations in snRNA abundance in a breast cancer cell line model were likewise preferentially mis-spliced within a clinically diverse cohort of invasive breast ductal carcinomas. As aberrant mRNA splicing is prevalent in many solid and liquid tumors, we propose that a full understanding of dysregulated pre-mRNA processing in cancers requires study of the RNA as well as protein components of the splicing machinery.
Genome sequence and description of Blautia brookingsii str SG772 nov., a new species of anaerobic bacterium isolated from healthy human gut
Authors: Ghimire Sudeep , Kumar Roshan , Nelson Eric , Christopher-Hennings Jane , Scaria Joy
Published: May 2018

Strain SG-772 is a Gram positive, strictly anoxic bacterium isolated from the feces of a healthy human fecal donor. Based on 16S rRNA gene sequence, the strain showed maximum similarity (94.39%) with Blautia stercoris GAM6-1 in EZ-Taxon server and thus assigned the genus Blautia. The scanning electron micrograph of the bacterium revealed the characteristic coccobacillus shape as well as the complete absence of flagellum, suggesting its non-motile phenotype. This strain was found to utilize 27 substrates based on Biolog AN plates assay, with maximum preference for D-mannitol. Additionally, the strain was found to be resistant to tetracycline and streptomycin. Genome sequencing and analysis revealed an overall genome size of 3.49 Mbp and GC content of 43.97%. Based on RAST annotation server, the closest neighbor was Blautia hansenii DSM20583. Average Nucleotide Identity (ANI) of these strains were 81.69%, suggesting a high level of genomic variation. The comparative genome analysis of strain SG772 with B. hansenii DSM20583 revealed a total of 411 orthologous genes coding for basic metabolic functions. Furthermore, the genomes were functionally distinct based on COG categories. Thus, based on all these differences, we propose a novel species of genus Blautia named as Blautia brookingsii SG772.
Identification of a post-transcriptional regulatory element that responds to glucose in the African trypanosome
Authors: Qiu Yijian , Shankar Vijay , Noorai Rooksana E. , Yeung Nelson , McAlpine Sarah Grace , Morris James
Published: May 2018

The ability to adapt to varying nutrient availability in changing environments is critical for successful parasitism. The lifecycle stages of the African trypanosome,Trypanosoma brucei, that infect the host mammalian bloodstream utilize glucose exclusively for ATP production. The finding that trypanosomes also inhabit other tissues that frequently contain lower glucose concentrations suggests blood stage parasites may have to respond to a dynamic environment with changing nutrient availability in order to survive. However, little is known about how the parasites coordinate gene expression with nutrient availability. Through transcriptome analysis, we have found blood stage parasites deprived of glucose alter gene expression in a pattern similar to transcriptome changes triggered by other stresses. A surprisingly low concentration of glucose (<10 μM) was required to initiate the response. To further understand the dynamic regulation of gene expression that occurs in response to altered glucose availability in the environment, we have interrogated the 3’UTR of cytochrome c oxidase subunit VI, a known lifecycle stage regulated gene, and have identified a stem-loop structure that confers glucose-responsive regulation at the translational level.
The Host Fruit Amplifies Mutualistic Interactions between Ceratitis Capitata Larvae and Associated Bacteria
Authors: Zaada Doron Shalom Yishai , Ben-Yosef Michael , Yuval Boaz , Jurkevitch Edouard
Published: May 2018

Background:

The Mediterranean fruit fly Ceratitis capitata is a major pest in horticulture. The development of fly larvae is mediated by bacterial decay in the fruit tissue. Despite the importance of bacteria on larval development, very little is known about the interaction between bacteria and larvae in their true ecological context. Understanding their relationship and inter-dependence in the host fruit is important for the development of new pest control interfaces to deal with this pest.

Results:

We find no negative effects on egg hatch or larval development brought about by the bacterial isolates tested. The various symbionts inhabiting the fly’s digestive system differ in their degree of contribution to the development of fly larvae depending on the given host and their sensitivity to induced inhibition caused by female produced antimicrobial peptides. These differences were observed not only at the genus or species level but also between isolates of the same species. We demonstrate how the microbiota from the mother’s gut supports the development of larvae in the fruit host and show that larvae play a major role in spreading the bacterial contagion in the infected fruit itself. In addition, we present (for the first time) evidence for horizontal transfer of bacteria between larvae of different maternal origin that develop together in the same fruit.

Conclusions:

Larvae play a major role in the spread and shaping of the microbial population in the fruit. The transfer of bacteria between different individuals developing in the same fruit suggests that the infested fruit serves as a microbial hub for the amplification and spread of bacterial strains between individuals.
The new intellectual property race
Authors: Silvernagel Craig , Langelett George , Tande Brian
Published: May 2018

Purpose

The purpose of this paper is to investigate how entrepreneurs are reacting to the recent change in patent priority rules under the America Invents Act (AIA). The authors sought to examine the relationship between a significant change in policy concerning a class of intellectual property (IP), patents in this case, and resulting perceptions and attitudes among entrepreneurs.

Design/methodology/approach

The authors designed a survey and collected data from 36 practicing entrepreneurs in the upper Midwest. The survey respondents completed either a paper hard-copy survey that was available at a regional entrepreneurship and innovation conference, or an electronic version of the survey (administered through QuestionPro.com). The survey included questions about entrepreneurship experience, area of expertise, IP use history and knowledge, risk tolerance, and demographics.

Findings

The empirical findings suggest that entrepreneur practitioners have not thoroughly reviewed FTF, but they are seeking legal advice. Also, entrepreneurs disagree with the notion that they are more likely to innovate under FTF. With regard to entrepreneurial knowledge, speaking with an attorney had a significant impact on entrepreneurs’ attitudes toward FTF, leading them to worry more about how they might compete with larger firms and about sharing their ideas. Finally, after controlling for demographics, the authors find that attitudes toward FTF have already significantly impacted recent past and future intended entrepreneurial behavior.

Originality/value

While the literature is rich with information about the AIA, the history of IP and patenting in the USA, and the merits and challenges of first-to-file vs first-to-invent patenting policy, little has been done to study entrepreneur attitudes and perceptions regarding the implementation of AIA and its policy provisions. Understanding entrepreneur perspectives concerning AIA is a critical component in assessing impacts regarding the critical area of innovation and new venture creation.
Concurrent sponsorship: implications for sponsoring brands and sponsored property
Authors: Yousaf Anish , Mishra Abhishek , Gupta Anil
Published: May 2018

Purpose

The purpose of this paper is to examine the interesting dynamics of image transfer when multiple brands get together to sponsor a property, referred to as concurrent sponsorship, and its effects on the consumer-based brand equity (CBBE) of the sponsor or the sponsored property, in the context of Indian Premier League of cricket.

Design/methodology/approach

Two pre-tests, for identifying the sponsored property and sponsors, were followed by the main experiment, involving 500 respondents. A general linear model was used for data analysis.

Findings

The findings reveal that for brands with high CBBE, investment in concurrent sponsorship leads to larger benefits, especially if they have similar associations to the sponsored property. This study also shows that image of the sponsored property is strongly dependent on combined CBBE of the sponsors. Finally, it is found that brands with high (low) CBBE are benefited more in concurrent (solo) sponsorship conditions.

Originality/value

This paper is an original contribution in this field, with limited works studying the impact of concurrent sponsorship on the brand equity of sponsors or the sponsored property.
Aridity preferences alter the relative importance of abiotic and biotic drivers on plant species abundance in global drylands
Authors: Berdugo Miguel , Maestre Fernando T. , Kéfi Sonia , Gross Nicolas , Le Bagousse‐Pinguet Yoann , Soliveres Santiago
Published: May 2018

Disentangling the interplay between species‐specific environmental preferences and micro‐ and macroscale determinants of species abundance within plant communities remains challenging. Most existing studies addressing this issue either lack empirical data regarding species interactions and local abundances or cover a narrow range of environmental conditions.

We merged species distribution models and local spatial patterns to investigate the relative importance of key macro‐ (aridity) and micro(facilitation and competition)scale determinants of plant species abundance along aridity gradients in drylands world‐wide. We used information derived from the environmental niches of species to evaluate how species‐specific aridity preferences modulate the importance of such factors to drive species relative abundance.

Facilitation and aridity preferences were more important than competition to explain species local abundances in global drylands. The specialization of communities (i.e. their compositional shifts from species with a large range of aridity preferences towards only aridity specialists) also modulated the effect of aridity and plant–plant interactions on species abundances. The importance of facilitation to drive species abundances decreased with aridity, as species preferred arid conditions and did not need neighbours to thrive. Instead, competition showed stronger relationships with species abundances under high levels of aridity. As composition became dominated by aridity specialists, the importance of aridity in shaping dryland plant communities did not increase further from moderate to high aridity levels.

Synthesis. Our results showed that: (a) the degree of community specialization to aridity mediates the relative importance of plant–plant interactions in determining species abundances and (b) facilitation and competition were more strongly related to species abundance in communities dominated by generalists and specialists, respectively. We observed a shift from facilitation to competition as drivers of species abundances as aridity increases in global drylands. Our findings also pave the way to develop more robust predictions about the consequences of ongoing climate change on the assemblage of plant communities in drylands, the largest terrestrial biome.
Is there a disease‐free halo at species range limits? The codistribution of anther‐smut disease and its host species
Authors: Bruns Emily L. , Antonovics Janis , Hood Michael
Published: May 2018

While disease is widely recognized as affecting host population size, it has rarely been considered to play a role in determining host range limits. Many diseases may not be able to persist near the range limit if host population density falls below the critical threshold level for pathogen invasion. However, in vector‐ and sexually transmitted diseases, pathogen transmission may be largely independent of host density and theory demonstrates that diseases with frequency‐dependent transmission may persist in small populations near the range limit.

Empirical studies of disease at species range limits have lagged behind the theory, and to date, no previous study has tested the hypothesis that vector or sexually transmitted diseases can be maintained at host range limits.

We studied the distribution of anther‐smut disease, a sterilizing pollinator‐transmitted disease, on four alpine plant species to determine whether disease was present at the host range limits.

We found that host abundance declined towards the elevational range limits, and disease extended to the most extreme elevational range limits in three of the four host species. Maximum likelihood estimation of the magnitude of the disease‐free halo showed that it was small or nonexistent for all host species. Moreover, disease prevalence within populations was often higher nearer the host's range limit than in the range centre and was independent of host density.

Synthesis. Our results show that diseases where transmission is frequency‐dependent have the potential to affect host distributions not just in theory, but also in real world populations.
Cyanidin‐3‐glucoside inhibits inflammatory activities in human fibroblast‐like synoviocytes and in mice with collagen‐induced arthritis
Authors: Sun Yan , Li Lingling
Published: May 2018

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint tissue inflammation. Cyanidin‐3‐glucoside (C3G) is a major component in the flavonoid family and has shown anti‐inflammatory, anti‐oxidant and anti‐tumour activity. In this study, we investigated the effects of C3G on lipopolysaccharides (LPS)‐induced inflammation on human rheumatoid fibroblast‐like synoviocytes (FLS) and on collagen‐induced arthritis (CIA) mice model. We treated FLS with C3G followed by LPS induction, the expressions of tumour necrosis factor alpha (TNF‐α), interleukin 1 beta (IL‐1β) and IL‐6 and the activation of nuclear factor kappa‐light‐chain‐enhancer of activated B cells (NF‐κB) and mitogen‐activated protein kinase (MAPK) signalling pathway were analyzed. CIA was induced in mice and the arthritic mice were treated with C3G for 3 weeks. The disease severity was compared between control and C3G treated mice. The serum levels of TNF‐α, IL‐1β and IL‐6 were analyzed by ELISA. C3G inhibited LPS‐induced TNF‐α, IL‐1β and IL‐6 expression in FLS. Moreover, C3G inhibited LPS‐induced p65 production and IκBa, p38, ERK and JNK phosphorylation. Administration of C3G significantly attenuated disease in mice with CIA and decreased the serum level of TNF‐α, IL‐1β and IL‐6. C3G inhibited LPS‐induced inflammation in human FLS by inhibiting activation of NF‐κB and MAPK signalling pathway. C3G exhibited therapeutic effects in mice with CIA.
Pericardial Cyst: Cause of Sudden Cardiac Death?
Authors: Ley Marie Brix , Larsen Maiken Kudahl
Published: May 2018

Cardiovascular disease is the leading cause of sudden death in the world. The etiology of sudden cardiac death involves a wide range of diseases, but seldom pericardial cysts. A pericardial cyst is an uncommon cyst usually located in the middle mediastinum and rarely in the posterior part. They are usually harmless and asymptomatic. Here, we present a case of a 63‐year‐old woman who presented with dyspnea and hoarseness, but died suddenly after a CT scan was attempted. The detailed forensic pathologic and histologic examination revealed a pericardial cyst located in the posterior mediastinum. Toxicology and biochemistry tests, including tryptase, found no competing cause of death.
Hot Off the Press: SGEM #215 Aortic Dissection—Love Will Tear Us Apart
Authors: Heitz Corey , Morgenstern Justin , Bond Christopher , Milne William K.
Published: May 2018

This systematic review provides an assessment of the diagnostic accuracy of various historical, physical, and clinical examination features for aortic dissection. Nine articles were included, with moderate to high heterogeneity. Limitations to general practice include risk of selection bias and partial verification bias. Risk scores were included, but their use is not recommended at this time.
Fetal assessment in buprenorphine‐maintained women using fetal magnetoencephalography: a pilot study
Authors: Escalona‐Vargas Diana , Coker Jessica L. , Ray‐Griffith Shona , Siegel Eric R. , Lowery Curtis L. , Stowe Zachary N. , Eswaran Hari
Published: May 2018

Background and Aims

In‐utero exposure to opioids including buprenorphine (BUP) has been shown to affect fetal activity, specifically heart‐rate variability (FHRV) and fetal movement (FM). Our objective was to extract simultaneous recordings of fetal cardiac and brain‐related activity in BUP‐maintained and non‐opioid exposed pregnant women using a novel non‐invasive biomagnetic technique.

Design

A pilot study was conducted, recording and analyzing biomagnetic data from fetuses of BUP‐maintained and non‐opioid exposed pregnant women. Signals were acquired with the non‐invasive 151‐channel SARA (SQUID‐Array for Reproductive Assessment) system. Advanced signal‐processing techniques were applied to extract fetal heart and brain activity.

Setting

University of Arkansas for Medical Sciences (UAMS, Little Rock, Arkansas, USA).

Participants

Eight BUP‐maintained pregnant women from UAMS Women's Mental Health Program between gestational ages (GA) of 29–37 weeks who were treated with 8–24 mg of BUP daily. Sixteen pregnant women with no known opioid exposure in the same GA range were also included.

Measurements

Outcome measures from the fetal heart and brain signals included: heart rate (FHR), FM, FHR accelerations, FHR–FM coupling, FHRV, fetal behavioral states (FBS) and power spectral density (PSD) of spontaneous brain activity. These measures were analyzed at three GA intervals.

Findings

Fetal heart and brain activity parameters were extracted and quantified successfully from 18 non‐opioid and 16 BUP recordings. Overall analysis in both groups show that: FHR and FM ranged from 131 to 141 beats per minute (b.p.m.) and 5 to 11 counts, respectively. In the 35–37 weeks GA, the coupling duration (~9 s) was the shortest, while three of the FHRV parameters were the highest. The PSD of brain activity revealed highest power in 0.5‐4 Hz bandwidth. Transitions in FBS from quiet to active sleep were > 50% of sessions.

Conclusions

This pilot study showed that a novel biomagnetic technique allows simultaneous quantification of cardiac and brain activities of a group of buprenorphine‐exposed and non‐exposed fetuses in the third trimester.
Modelling the impact of a national scale‐up of interventions on hepatitis C virus transmission among people who inject drugs in Scotland
Authors: Fraser Hannah , Mukandavire Christinah , Martin Natasha K. , Goldberg David , Palmateer Norah , Munro Alison , Taylor Avril , Hickman Matthew , Hutchinson Sharon , Vickerman Peter
Published: May 2018

Background and Aims

To reduce hepatitis C virus (HCV) transmission among people who inject drugs (PWID), Scottish Government‐funded national strategies, launched in 2008, promoted scaling‐up opioid substitution therapy (OST) and needle and syringe provision (NSP), with some increases in HCV treatment. We test whether observed decreases in HCV incidence post‐2008 can be attributed to this intervention scale‐up.

Design

A dynamic HCV transmission model among PWID incorporating intervention scale‐up and observed decreases in behavioural risk, calibrated to Scottish HCV prevalence and incidence data for 2008/09.

Setting

Scotland, UK.

Participants

PWID.

Measurements

Model projections from 2008 to 2015 were compared with data to test whether they were consistent with observed decreases in HCV incidence among PWID while incorporating the observed intervention scale‐up, and to determine the impact of scaling‐up interventions on incidence.

Findings

Without fitting to epidemiological data post‐2008/09, the model incorporating observed intervention scale‐up agreed with observed decreases in HCV incidence among PWID between 2008 and 2015, suggesting that HCV incidence decreased by 61.3% [95% credibility interval (CrI) = 45.1–75.3%] from 14.2/100 person‐years (py) (9.0–20.7) to 5.5/100 py (2.9–9.2). On average, each model fit lay within 84% (10.1/12) of the confidence bounds for the 12 incidence data points against which the model was compared. We estimate that scale‐up of interventions (OST + NSP + HCV treatment) and decreases in high‐risk behaviour from 2008 to 2015 resulted in a 33.9% (23.8–44.6%) decrease in incidence, with the remainder [27.4% (17.6–37.0%)] explained by historical changes in OST + NSP coverage and risk pre‐2008. Projections suggest that scaling‐up of all interventions post‐2008 averted 1492 (657–2646) infections over 7 years, with 1016 (308–1996), 404 (150–836) and 72 (27–137) due to scale‐up of OST + NSP, decreases in high‐risk behaviour and HCV treatment, respectively.

Conclusions

Most of the decline in hepatitis C virus (HCV) incidence in Scotland between 2008 and 2015 appears to be attributable to intervention scale‐up (opioid substitution therapy and needle and syringe provision) due to government strategies on HCV and drugs.
Gata3 hypermethylation and Foxp3 hypomethylation are associated with sustained protection and bystander effect following epicutaneous immunotherapy in peanut‐sensitized mice
Authors: Mondoulet L. , Dioszeghy V. , Busato F. , Plaquet C. , Dhelft V. , Bethune K. , Leclere L. , Daviaud C. , Ligouis M. , Sampson H. , Dupont C. , Tost J.
Published: May 2018

Background

Epicutaneous immunotherapy (EPIT) is a promising method for treating food allergies. In animal models, EPIT induces sustained unresponsiveness and prevents further sensitization mediated by Tregs. Here, we elucidate the mechanisms underlying the therapeutic effect of EPIT, by characterizing the kinetics of DNA methylation changes in sorted cells from spleen and blood and by evaluating its persistence and bystander effect compared to oral immunotherapy (OIT).

Methods

BALB/c mice orally sensitized to peanut proteins (PPE) were treated by EPIT using a PPE‐patch or by PPE‐OIT. Another set of peanut‐sensitized mice treated by EPIT or OIT were sacrificed following a protocol of sensitization to OVA. DNA methylation was analyzed during immunotherapy and 8 weeks after the end of treatment in sorted cells from spleen and blood by pyrosequencing. Humoral and cellular responses were measured during and after immunotherapy.

Results

Analyses showed a significant hypermethylation of the Gata3 promoter detectable only in Th2 cells for EPIT from the 4th week and a significant hypomethylation of the Foxp3 promoter in CD62L+ Tregs, which was sustained only for EPIT. In addition, mice treated with EPIT were protected from subsequent sensitization and maintained the epigenetic signature characteristic for EPIT.

Conclusions

Our study demonstrates that EPIT leads to a unique and stable epigenetic signature in specific T‐cell compartments with downregulation of Th2 key regulators and upregulation of Treg transcription factors, likely explaining the sustainability of protection and the observed bystander effect.
Children who face development risks due to maternal addiction during pregnancy require extra medical and psychosocial resources
Authors: Rangmar Jenny , Lilja Maria , Köhler Marie , Reuter Antonia
Published: May 2018

Aim

This study examined medical and psychosocial risk factors in children born to women with addiction problems during pregnancy and the children's needs for extra medical and psychosocial resources.

Methods

Swedish midwives routinely screen pregnant women for drugs and alcohol and refer women with addictions to the Maternity and Child Healthcare Resource Team. We investigated the medical records of 127 children (51% girls) whose mothers were referred to the Resource Team from 2009 to 2015. Additional data were obtained from local child healthcare services (CHS), which provide routine paediatric care.

Results

More than three‐quarters (76%) of the children had prenatal exposure to alcohol and drugs, and 17% were born with withdrawal symptoms. The mothers had a high rate of psychiatric diagnoses (38%) and were more likely to smoke after delivery and less likely to breastfeed than the general population. However, adherence to the CHS programme was generally high. Additional visits to the nurse, referrals to specialists, collaboration meetings and reports of concerns to social services decreased when the children began attending ordinary CHS centres.

Conclusion

Children born to women with addictions during pregnancy faced a high risk of developmental problems and should be offered additional CHS resources to minimise negative long‐term consequences.
The analgesic efficacy and pharmacokinetics of epidural oxycodone after gynaecological laparotomy: a randomized, double‐blind, double‐dummy comparison with intravenous administration
Authors: Piirainen Panu , Kokki Hannu , Hautajärvi Heidi , Ranta Veli‐Pekka , Kokki Merja
Published: May 2018

Aim

The aim of the present study was to compare the analgesic efficacy of epidural and intravenous (i.v.) oxycodone at the same dose.

Methods

In this randomized, double‐blind, double‐dummy clinical trial, 30 women, aged 24–67 years, undergoing elective gynaecological laparotomy, were administrated either i.v. saline and epidural oxycodone 0.1 mg·kg−1 (EPI group; n = 15) or i.v. oxycodone 0.1 mg·kg−1 and epidural saline (IV group; n = 15). For multimodal analgesia, patients received i.v. paracetamol and dexketoprofen, and a triple‐mixture epidural infusion after the first 4 h postoperatively. The primary outcome was the total dose of i.v. fentanyl for rescue analgesia during the first 4 h postoperatively.

Results

All patients required fentanyl during the first 4 h. The median number of fentanyl doses were three (quartiles 1, 8) in the EPI group and seven (6, 9) in the IV group (mean difference 3.1; 95% confidence interval 0.9, 5.2; P = 0.01). After the first 4 h, the two groups needed a similar total dose of epidural infusion. Patient satisfaction was similarly high in both groups, and both administration routes were well tolerated.

Conclusions

The data support the superiority of epidural oxycodone compared with that of i.v. administration in pain management after laparotomy.
Conditioned Reward of Opioids, but not Psychostimulants, is Impaired in GABA‐A Receptor δ Subunit Knockout Mice
Authors: Siivonen Milo S. , de Miguel Elena , Aaltio Juho , Manner Aino K. , Vahermo Mikko , Yli‐Kauhaluoma Jari , Linden Anni‐Maija , Aitta‐aho Teemu , Korpi Esa R.
Published: May 2018

Extrasynaptic δ subunit‐containing γ‐aminobutyric acid type A receptors (δ‐GABAARs) are emerging as targets for a number of neuropsychopharmacological drugs, including the direct GABA site agonist gaboxadol and neuroactive steroids. Among other regions, these δ‐GABAARs are functionally expressed in the ventral tegmental area (VTA), the cell body region of mesocorticolimbic dopamine (DA) system important for motivated behaviours, and in the target region, the nucleus accumbens. Gaboxadol and neurosteroids induce VTA DA neuron plasticity ex vivo, by inhibiting the VTA GABA neurons, and aversive place conditioning, which are absent in the δ‐GABAAR knockout mice (δ‐KO). It is not known whether δ‐GABAARs are important for the effects of other drugs, such as opioids (that also inhibit GABA neurons) and stimulants (that primarily elevate monoamine levels). Here, we used δ‐KO mice and conditioned place preference (CPP) test to study the rewarding effects of morphine (20 mg/kg), methamphetamine (1 mg/kg) and mephedrone (5 mg/kg). Morphine‐induced nociception was also assessed using tail‐flick and hot‐plate tests. We found that the δ‐KO mice failed to express morphine‐induced CPP, but that they were more sensitive to morphine‐induced analgesia in the tail‐flick test. In contrast, stimulant‐induced CPP in the δ‐KO mice was similar to that in the wild‐type controls. Thus, the conditioned rewarding effect by opioids, but not that of stimulants, was impaired in the absence of δ‐GABAARs. Further studies are warranted to assess the potential of δ‐GABAAR antagonists as possible targets for reducing morphine reward and potentiating morphine analgesia.
Immersion and the illusion of presence in virtual reality
Authors: Slater Mel
Published: May 2018

This commentary briefly reviews the history of virtual reality and its use for psychology research, and clarifies the concepts of immersion and the illusion of presence.
REGIME DEPENDENT EFFECT OF OUTPUT GROWTH ON OUTPUT GROWTH UNCERTAINTY: EVIDENCE FROM OECD COUNTRIES
Authors: Chowdhury Kushal Banik , Sarkar Nityananda
Published: May 2018

This paper studies the impact of output growth on output growth uncertainty by considering two important issues hitherto not properly and adequately addressed to in the existing empirical studies specifying this relationship. These are: (i) the possible existence of a threshold level of output growth, and the consequent identification of two regimes characterized by high and low output growth, and (ii) whether or not the coefficient capturing the causal link is different in these two output growth states. This paper proposes a regime switching model to study this asymmetric effect for 16 OECD countries. Based on monthly time‐series observations, our results strongly support that the impact varies significantly between the two output growth regimes with the coefficient in the high growth regime being negative for majority of the countries.
Luteolin ameliorates rat myocardial ischaemia–reperfusion injury through activation of peroxiredoxin II
Authors: Wei Bo , Lin Qiao , Ji Ya‐Ge , Zhao Yi‐Can , Ding Li‐Na , Zhou Wen‐Juan , Zhang Li‐Hua , Gao Chuan‐Yu , Zhao Wen
Published: May 2018

Background and Purpose

Antioxidants provide a promising therapeutic effect for the cardiovascular disease. Luteolin, a polyphenolic bioflavonoid, is known to confer cardioprotection, although the underlying mechanisms, especially the role of luteolin on the antioxidant enzymes, such as the peroxiredoxin family, remain unknown.

Experimental Approach

We measured the effects of luteolin on myocardial ischaemia/reperfusion (MI/R) injury in vivo (Sprague‐Dawley rats) and in vitro, together with the underlying mechanisms, with a focus on signalling by peroxiredoxins. H9c2 cells were used to assess the changes in peroxiredoxins and the other antioxidant enzymes. Oxidative stress, cardiac function, LDH release, ROS and infarct size were also assayed.

Key Results

Luteolin exerted significant cardioprotective effects in vivo and in vitro via improving cardiac function, increasing the expression of anti‐apoptotic protein Bcl‐2 and decreasing the pro‐apoptotic protein Bax and active caspases 3 and 9, associated with MI/R. Mechanistically, luteolin markedly enhanced expression of peroxiredoxin II, without significant effects on other forms of peroxiredoxin, catalase or SOD1. Molecular docking showed that luteolin could indeed bind to the enzymic active pocket of peroxiredoxin II. Furthermore, down‐regulation of peroxiredoxin II by peroxiredoxin II‐antisense, administered by adenovirus infection of H9c2 cardiomyocytes, and inhibition of peroxiredoxin II in vivo significantly reversed the cardioprotective effects of luteolin.

Conclusions and Implications

Our findings, for the first time, demonstrate that luteolin protects against MI/R injury through promoting signalling through the endogenous antioxidant enzyme, peroxiredoxin II, indicating the important beneficial role of this antioxidant system in the heart.