bluuebunny/crossref_metadata_2025 huggingface dataset:
Odor concentration change detectors in the Olfactory Bulb
Authors: Parabucki Ana , Bizer Alexander , Morris Genela , Smear Matthew C. , Shusterman Roman
Published: March 2017

Dynamical changes in the environment strongly impact our perception1,2. Consistent with this, sensory systems preferentially represent stimulus changes, enhancing temporal contrast3,4. In olfaction, odor concentration changes across consecutive inhalations (ΔCt) can guide odor source localization. Yet the neural representation of ΔCthas not been studied in vertebrates. We have found that a subset of mitral/tufted (M/T) cells in the olfactory bulb explicitly represent ΔCt. These concentration change detectors are direction selective: some respond to positive ΔCt, while others represent negative ΔCt. This change detection enhances the contrast between different concentrations and the magnitude of contrast enhancement scales with the size of the concentration step. Further, ΔCtcan be read out from the total spike count per sniff, unlike odor identity and intensity, which are represented by fast temporal spike patterns. Our results demonstrate that a subset of M/T cells explicitly represents ΔCt, providing a signal that may instruct navigational decisions in downstream olfactory circuits.
Incorporation of unique molecular identifiers in TruSeq adapters improves the accuracy of quantitative sequencing
Authors: Hong Jungeui , Gresham David
Published: March 2017

Quantitative analysis of next-generation sequencing data requires discriminating duplicate reads generated by PCR from identical molecules that are of unique origin. Typically, PCR duplicates are defined as sequence reads that align to the same genomic coordinates using reference-based alignment. However, identical molecules can be independently generated during library preparation. The false positive rate of coordinate-based deduplication has not been well characterized and may introduce unforeseen biases during analyses. We developed a cost-effective sequencing adapter design by modifying Illumina TruSeq adapters to incorporate a unique molecular identifier (UMI) while maintaining the capacity to undertake multiplexed sequencing. Incorporation of UMIs enables identification of bona fide PCR duplicates as identically mapped reads with identical UMIs. Using TruSeq adapters containing UMIs (TrUMIseq adapters), we find that accurate removal of PCR duplicates results in enhanced data quality for quantitative analysis of allele frequencies in heterogeneous populations and gene expression.

Method Summary

TrUMIseq adapters incorporate unique molecular identifiers in TruSeq adapters while maintaining the capacity to multiplex sequencing libraries using existing workflows. The use of UMIs increases the accuracy of quantitative sequencing assays, including RNAseq and allele frequency estimation, by enabling accurate detection of PCR duplicates.
Early biomarker discovery in urine of Walker 256 subcutaneous rat model
Authors: Wu Jianqiang , Guo Zhengguang , Gao Youhe
Published: March 2017

Despite advances in cancer treatments, early detection of cancer is still the most promising way to improve outcomes. Without homeostatic control, urine reflects early changes in the body and can potentially be used for early cancer diagnosis. In this study, a Walker 256 tumor rat model was established by subcutaneous injection of Walker 256 tumor cells. To identify urinary proteome changes during cancer development, urine samples from Walker 256 tumor-bearing rats were collected at five time points corresponding to before cancer cell implantation, before tumor mass palpability, at tumor mass appearance, during rapid tumor growth, and at cachexia. The urinary protein patterns changed significantly as the tumors progressed, as measured using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). The urinary proteome of tumor-bearing rats was identified using Fusion Lumos mass spectrometry with label-free quantification. Then, 30 dynamically changed urinary proteins during cancer progression were selected as more reliable cancer biomarkers, and they were validated by targeted proteomics. Combined with the results of label-free and targeted proteome quantification, a total of 10 urinary proteins (HPT, APOA4, CO4, B2MG, A1AG, CATC, VCAM1, CALB1, CSPG4, and VTDB) changed significantly even before a tumor mass was palpable, and these early changes in urine could also be identified with differential abundance at late stages of cancer. Our study indicated that urine is a sensitive biomarker source for early detection of cancer.
A novel method for large-scale identification of polymorphic microsatellites through comparative transcriptome analysis
Authors: Luo Wei , Qu Hongyue , Wang Xin , Zhan Qin , Lin Qiang
Published: March 2017

Microsatellite (SSR) is one of the most popular markers for applied genetic research, but generally the current methods to develop SSRs are relatively time-consuming and expensive. Although high-throughput sequencing (HTS) approach has become a practical and relatively inexpensive option so far, only a small percentage of SSR markers turn out to be polymorphic. Here, we designed a new method to enrich polymorphic SSRs through the comparative transcriptome analysis. This program contains five main steps: 1) transcriptome data downloading or RNA-seq; 2) sequence assembly; 3) SSR mining and enrichment of sequences containing SSRs; 4) sequence alignment; 5) enrichment of sequences containing polymorphic SSRs. A validation experiment was performed and the results showed almost all markers (> 90%) that were indicated as putatively polymorphic by this method were indeed polymorphic. The frequency of polymorphic SSRs was significantly higher (P< 0.05) but the cost and running time were much lower than those of traditional and HTS approaches. The method has a practical value for polymorphic SSRs development and might be widely used for genetic analyses in any species.
BRANE Clust: Cluster-Assisted Gene Regulatory Network Inference Refinement
Authors: Pirayre Aurélie , Couprie Camille , Duval Laurent , Pesquet Jean-Christophe
Published: March 2017

Discovering meaningful gene interactions is crucial for the identification of novel regulatory processes in cells. Building accurately the related graphs remains challenging due to the large number of possible solutions from available data. Nonetheless, enforcing apriorion the graph structure, such as modularity, may reduce network indeterminacy issues. BRANE Clust (Biologically-Related A priori Network Enhancement with Clustering) refines gene regulatory network (GRN) inference thanks to cluster information. It works as a post-processing tool for inference methods (i.e. CLR, GENIE3). In BRANE Clust, the clustering is based on the inversion of a system of linear equations involving a graph-Laplacian matrix promoting a modular structure. Our approach is validated on DREAM4 and DREAM5 datasets with objective measures, showing significant comparative improvements. We provide additional insights on the discovery of novel regulatory or co-expressed links in the inferredEscherichia colinetwork evaluated using the STRING database. The comparative pertinence of clustering is discussed computationally (SIMoNe, WGCNA, X-means) and biologically (RegulonDB). BRANE Clust software is available at:http://www-syscom.univ-mlv.fr/∼pirayre/Codes-GRN-BRANE-clust.html
Genome-Wide Analysis of Facial Regionalization in Zebrafish
Authors: Askary Amjad , Xu Pengfei , Barske Lindsey , Bay Maxwell , Bump Paul , Balczerski Bartosz , Bonaguidi Michael A. , Gage Crump J.
Published: March 2017

Patterning of the facial skeleton involves the precise deployment of thousands of genes in distinct regions of the pharyngeal arches. Despite the significance for craniofacial development, how genetic programs drive this regionalization remains incompletely understood. Here we use combinatorial labeling of zebrafish cranial neural crest-derived cells (CNCCs) to define global gene expression along the dorsoventral axis of the developing arches. Intersection of region-specific transcriptomes with expression changes in response to signaling perturbations demonstrates complex roles for Endothelin1 (Edn1) signaling in the intermediate joint-forming region yet a surprisingly minor role in ventral-most regions. Analysis of co-variance across multiple sequencing experiments further reveals clusters of coregulated genes, with in situ hybridization confirming the domain-specific expression of novel genes. We then performed mutational analysis of a number of these genes, which uncovered antagonistic functions of two new Edn1 targets,follistatin a(fsta) andemx2, in regulating cartilaginous joints in the hyoid arch. Our unbiased discovery and functional analysis of genes with regional expression in zebrafish arch CNCCs reveals complex regulation by Ednl and points to novel candidates for craniofacial disorders.

Summary Statement

Using zebrafish to purify distinct groups of embryonic cells, Askary et al. have created a detailed map of how thousands of genes are deployed to shape the developing face.
Spot Dynamics in a Reaction-Diffusion Model of Plant Root Hair Initiation
Authors: Avitabile Daniele , Breña-Medina Victor F. , Ward Michael J.
Published: March 2017

We study pattern formation in a 2-D reaction-diffusion (RD) sub-cellular model characterizing the effect of a spatial gradient of a plant hormone distribution on a family of G-proteins associated with root-hair (RH) initiation in the plant cellArabidopsis thaliana. The activation of these G-proteins, known as the Rho of Plants (ROPs), by the plant hormone auxin, is known to promote certain protuberances on root hair cells, which are crucial for both anchorage and the uptake of nutrients from the soil. Our mathematical model for the activation of ROPs by the auxin gradient is an extension of the model of Payne and Grierson [PLoS ONE,12(4), (2009)], and consists of a two-component Schnakenberg-type RD system with spatially heterogeneous coefficients on a 2-D domain. The nonlinear kinetics in this RD system model the nonlinear interactions between the active and inactive forms of ROPs. By using a singular perturbation analysis to study 2-D localized spatial patterns of active ROPs, it is shown that the spatial variations in the nonlinear reaction kinetics, due to the auxin gradient, lead to a slow spatial alignment of the localized regions of active ROPs along the longitudinal midline of the plant cell. Numerical bifurcation analysis, together with time-dependent numerical simulations of the RD system are used to illustrate both 2-D localized patterns in the model, and the spatial alignment of localized structures.
Unprecedented phase transition sequence in the perovskite Li0.2Na0.8NbO3
Authors: Dixon Charlotte A. L. , McNulty Jason A. , Huband Steven , Thomas Pamela A. , Lightfoot Philip
Published: March 2017

The perovskite Li0.2Na0.8NbO3is shown, by powder neutron diffraction, to display a unique sequence of phase transitions at elevated temperature. The ambient temperature polar phase (rhombohedral, space groupR3c) transformsviaa first-order transition to a polar tetragonal phase (space groupP42mc) in the region 150–300°C; these two phases correspond to Glazer tilt systemsa−a−a−anda+a+c−, respectively. At 500°C a ferroelectric–paraelectric transition takes place fromP42mctoP42/nmc, retaining thea+a+c−tilt. Transformation to a single-tilt system,a0a0c+(space groupP4/mbm), occurs at 750°C, with the final transition to the aristotype cubic phase at 850°C. TheP42mcandP42/nmcphases have each been seen only once and twice each, respectively, in perovskite crystallography, in each case in compositions prepared at high pressure.
The structure of denisovite, a fibrous nanocrystalline polytypic disordered `very complex' silicate, studied by a synergistic multi-disciplinary approach employing methods of electron crystallography and X-ray powder diffraction
Authors: Rozhdestvenskaya Ira V. , Mugnaioli Enrico , Schowalter Marco , Schmidt Martin U. , Czank Michael , Depmeier Wulf , Rosenauer Andreas
Published: March 2017

Denisovite is a rare mineral occurring as aggregates of fibres typically 200–500 nm diameter. It was confirmed as a new mineral in 1984, but important facts about its chemical formula, lattice parameters, symmetry and structure have remained incompletely known since then. Recently obtained results from studies using microprobe analysis, X-ray powder diffraction (XRPD), electron crystallography, modelling and Rietveld refinement will be reported. The electron crystallography methods include transmission electron microscopy (TEM), selected-area electron diffraction (SAED), high-angle annular dark-field imaging (HAADF), high-resolution transmission electron microscopy (HRTEM), precession electron diffraction (PED) and electron diffraction tomography (EDT). A structural model of denisovite was developed from HAADF images and later completed on the basis of quasi-kinematic EDT data byab initiostructure solution using direct methods and least-squares refinement. The model was confirmed by Rietveld refinement. The lattice parameters area= 31.024 (1),b= 19.554 (1) andc= 7.1441 (5) Å, β = 95.99 (3)°,V= 4310.1 (5) Å3and space groupP12/a1. The structure consists of three topologically distinct dreier silicate chains,viz. two xonotlite-like dreier double chains, [Si6O17]10−, and a tubular loop-branched dreier triple chain, [Si12O30]12−. The silicate chains occur between three walls of edge-sharing (Ca,Na) octahedra. The chains of silicate tetrahedra and the octahedra walls extend parallel to thezaxis and form a layer parallel to (100). Water molecules and K+cations are located at the centre of the tubular silicate chain. The latter also occupy positions close to the centres of eight-membered rings in the silicate chains. The silicate chains are geometrically constrained by neighbouring octahedra walls and present an ambiguity with respect to theirzposition along these walls, with displacements between neighbouring layers being either Δz=c/4 or −c/4. Such behaviour is typical for polytypic sequences and leads to disorder along [100]. In fact, the diffraction pattern does not show any sharp reflections withlodd, but continuous diffuse streaks parallel toa* instead. Only reflections withleven are sharp. The diffuse scattering is caused by (100) nanolamellae separated by stacking faults and twin boundaries. The structure can be described according to the order–disorder (OD) theory as a stacking of layers parallel to (100).
Reflections on the Canadian Government in competitive intelligence – programs and impacts
Authors: Calof Jonathan
Published: March 2017

Purpose

This paper aims to present a categorization scheme and use it to classify Canadian Government (federal and provincial) competitive intelligence (CI) programs and to also look at the impact of these programs on sectoral and regional economic development.

Design/methodology/approach

Based on the author’s 25 years of experience designing, running, and studying Canadian Government CI programs, a classification scheme to classify these programs has been developed and used. Also, by using program review information, this paper looks at evidence for program impact on regional and sectoral economic development.

Findings

This paper identifies a broad range of federal and provincially sponsored CI programs aimed at helping both government officers and those outside the department make better decisions. The review identified several roles that the government can play in using CI: creator of CI (both for their own purposes and also for helping Canadian companies), CI environment skills builder (helping Canadian companies develop skills in developing their own CI) and CI partner (working jointly with Canadian companies in developing CI). While there have not been many formal program reviews of the CI programs sponsored by Canadian Government departments and agencies, anecdotal evidence (from training program participant evaluations) and a comprehensive review of a small community CI-based economic development program support positive sectoral and regional economic development results arising from these programs.

Practical implications

CI programs can be used as part of a government’s regional and sectoral economic development approach. CI can be used to assist with decision-making both within and outside the government. This paper identifies several different kinds of programs that can be used to further a government’s economic development agenda.

Originality/value

There are very few articles that examine how governments have helped companies to develop CI and how they have used CI, and none has looked at the impact of these on regional and sectoral economic development. This paper, based on the author’s experiences, provides a view of the Canadian programs and their impact on regional/sectoral economic development.
High-probability and wild-card scenarios for future crimes and terror attacks using the Internet of Things
Authors: Tzezana Roey
Published: March 2017

Purpose

The purpose of this paper is to provide a framework to thinking and creating scenarios about future crimes and terror attacks relying on the Internet of Things (IoT), and to present a crowdsourcing research based on this thinking, which resulted in both high- and low-probability scenarios with dramatic impact.

Design/methodology/approach

The research relies on general morphological analysis for deconstructing wicked problems into core components, and on crowdsourcing 50 experts on Wikistrat’s commercial platform, allowing them to suggest core components, rank them by importance and develop scenarios together. This methodology allowed a wider view than usual, and allowed the experts to examine unorthodox combination of components, leading to the creation of wild-card scenarios.

Findings

Analysis of both the core components and the resulting scenarios indicates that the IoT is set to have a dramatic role in crime and terror attacks in the near future. High-impact high-probability scenarios include attacks on power plants, cyber wallets and personal assistants. High-impact low-probability scenarios include terrorist attacks by environmentalist groups, accidental attacks conducted by immature pranksters and having a computer worm propagating in a low-security but critical facility like a hospital.

Originality/value

This paper brings a standardized method which can be used to examine complex events like crime and terror attacks using a disruptive and emerging technology. The results can be used by practitioners to further study the issue and develop many other scenarios more tailored to their needs. The scenarios presented in this paper can also be of value to security bodies who wish to be better prepared for the future.
Determinants of the level of foreign subsidiaries’ localization of Korean MNCs and performance in China
Authors: Kim Byoung-Goo , Kim Gyu-Bae
Published: March 2017

Purpose

The purpose of this paper is to empirically analyze what effects the headquarters’ (HQ) business strategy and corporate culture, the local network embeddedness of the foreign subsidiary, and HQ-subsidiary communication have on the staff localization of foreign subsidiaries. The authors carry out empirical analysis on how localization of foreign subsidiaries ultimately affects the performance of foreign subsidiaries.

Design/methodology/approach

This study is an empirical analysis on the determinants of staff localization and the relationship between staff localization and corporate performance. In this study, the five hypotheses were proposed and tested using survey data. The authors randomly selected a total of 800 companies as subjects and conducted a survey. The final 222 survey data including HQs and subsidiaries were used for empirical analysis. The statistical analyses such as reliability test, factor analysis and regression were used.

Findings

This study shows that there was a higher level of staff localization by the foreign subsidiary when the investment goal was market-oriented investment, the Korean foreign subsidiary had stronger local network embeddedness and there was better HQ-subsidiary communication. In addition, the relationship between localization and subsidiary performance shows an inverted U-shape. Such results will give various implications to companies.

Originality/value

The research that takes a multilayered consideration on factors of the HQ, subsidiaries, and the HQ-subsidiary relationship is rare. To overcome such limitations, this study carried out a survey in order to find more in-depth decision factors. Specifically, this study analyzed the effects of three large aspects of investment goals and corporate culture from the aspect of the HQ, local network embeddedness from the aspect of foreign subsidiaries, and the level of HQ-subsidiary communication from the aspect of HQ-subsidiary relations, and how they affect staff localization.
Oxidative status and fitness components in the Seychelles warbler
Authors: van de Crommenacker Janske , Hammers Martijn , van der Woude Jildou , Louter Marina , Santema Peter , Richardson David S. , Komdeur Jan
Published: March 2017

Oxidative damage, caused by reactive oxygen species during aerobic respiration, is thought to be an important mediator of life‐history trade‐offs. To mitigate oxidative damage, antioxidant defence mechanisms are deployed, often at the cost of resource allocation to other body functions. Both reduced resource allocation to body functions and direct oxidative damage may decrease individual fitness, through reducing survival and/or reproductive output.

The oxidative costs of reproduction have gained much attention recently, but few studies have investigated the long‐term consequences of oxidative damage on survival and (future) reproductive output under natural conditions.

Using a wild population of the cooperatively breeding Seychelles warbler (Acrocephalus sechellensis), we tested the prediction that high levels of reactive oxygen species, or high antioxidant investments to avoid oxidative damage, have fitness consequences because they reduce survival and/or reproductive output.

We found that individuals with higher circulating non‐enzymatic antioxidant capacity had a lower probability of surviving until the next year. However, neither current reproductive output, nor future reproductive output in the surviving individuals, was associated with circulating non‐enzymatic antioxidant capacity or oxidative damage.

The negative relationship between antioxidant capacity and survival that we observed concurs with the findings of an extensive comparative study on birds, however the mechanisms underlying this association remain to be resolved.

A lay summary is available for this article.
Association of genetic polymorphisms of claudin‐1 with small vessel vascular dementia
Authors: Srinivasan Vivek , Braidy Nady , Xu Ying Hua , Xie Peter , Kancherla Kiran , Chandramohan Sashiruben , Chan Eunice Kar Wing , Chan Daniel KY
Published: March 2017

The most recent hypothesis of the development of small vessel vascular dementia (VaD) emphasises the role of blood‐brain barrier (BBB) dysfunction. It is hypothesised that certain genetic polymorphisms of the BBB tight junction claudin‐1 protein, in combination with adverse environmental risk factors, increase the risk of BBB dysfunction and small vessel VaD. In this case‐control study, 97 control participants, with a mean Mini Mental State Exam (MMSE) score of 29.1, and 38 VaD participants were recruited and completed a questionnaire on their medical history and lifestyle factors. Blood was also collected and two single nucleotide polymorphisms (SNPs), rs17501010 and rs893051 of claudin‐1 genotyping, were analysed by real‐time polymerase chain reaction (PCR) assay. A significantly higher frequency of all rs893051 SNP genotypes (GC and CC) was found in the VaD population (OR=4.8, P=0.006 and OR=6, P<0.001 respectively). Patients with TT genotype of rs17501010 were also more likely to have VaD (OR=3.25, P=0.022). Stratification analysis revealed that having combined haplotype GC+CC of rs893051 and lipid disorders was associated with higher risk of VaD (OR=9.9, P<0.001). For patients with type 2 diabetes the odds ratio of VaD increased significantly in GC+CC genotypes of rs893051 (OR=12.57, P<0.0001) and GT+TT of rs17501010 (OR=5.33, P=0.01).
Bridging the enduring gender gap in political interest in Europe: The relevance of promoting gender equality
Authors: FRAILE MARTA , GOMEZ RAUL
Published: March 2017

Notwithstanding the improvement in gender equality in political power and resources in European democracies, this study shows that, on average, declared interest in politics is 16 per cent lower for women than for men in Europe. This gap remains even after controlling for differences in men's and women's educational attainment, material and cognitive resources. Drawing on the newly developed European Institute for Gender Equality's (EIGE) Gender Equality Index (GEI) and on the European Social Survey (ESS) fifth wave, we show that promoting gender equality contributes towards narrowing the magnitude of the differences in political interest between men and women. However, this effect appears to be conditioned by the age of citizens. More specifically, findings show that in Europe gender‐friendly policies contribute to bridging the gender gap in political engagement only during adulthood, suggesting that childhood socialisation is more strongly affected by traditional family values than by policies promoting gender equality. In contrast, feminising social citizenship does make a difference by reducing the situational disadvantages traditionally faced by women within the family and in society for middle‐aged people and older.
Division of Chinese soft‐shelled turtle intestine with molecular markers is slightly different from the morphological and histological observation
Authors: ZHANG Zuobing , SONG Ruxin , XING Xiao , WANG Lan , NIU Cuijuan
Published: March 2017

The Chinese soft‐shelled turtle (Pelodiscus sinensis) is a commercially important species in Asian countries. Knowledge of its nutritional requirements and physiology is essential for determining the appropriate content of the feed for this animal. However, the lack of functional characterization of the intestine of this turtle limits the understanding of its absorption and utilization of nutritional materials. To solve this problem, this work utilized anatomical and histological methods to characterize 9 segments sampled along the anterior–posterior axis of the intestine. Furthermore, 9 genes, which have been well documented in the intestine division of mammals and fish, were employed to functionally characterize the 9 sampled segments. Our results suggest that regions covering from the starting site to S3 (position at 29.9% of the total length from the starting of the intestine) are the equivalent of mammalian dedumonen, and those covering S4 (40.2%) and S5 (65.4%), posterior to S8 (92.7%), are the equivalent of the mammalian ileum and the large intestine, respectively. As to the region spaning S6 (81.3%) and S7 (87.3%), its functional equivalent (small intestine or large intestine) may be variable and depends on the functional genes. This molecular characterization in relation to the division of the intestine of Chinese soft‐shelled turtle may contribute to the understanding of the nutritional physiology of the turtle, and promote Chinese soft‐shelled turtle production.
The Effect of Buckwheat Hull Extract on Lipid Oxidation in Frozen‐Stored Meat Products
Authors: Hęś Marzanna , Szwengiel Artur , Dziedzic Krzysztof , Le Thanh‐Blicharz Joanna , Kmiecik Dominik , Górecka Danuta
Published: March 2017

This study investigated the effect of antioxidants on lipid stability of frozen‐stored meat products. Buckwheat hull extract was used to enrich fried meatballs made from ground pork. During 180‐d storage of meat products, lipid oxidation (peroxide and 2‐thiobarbituric acid reactive substances [TBARS] value) was periodically monitored. The results were compared with butylated hydroxytoluene (BHT). The addition of antioxidants decreased lipid oxidation in stored meatballs. The highest ability to control peroxide and TBARS values was demonstrated for buckwheat hull extract. Moreover, buckwheat hull extract showed a higher 2,2‐diphenyl‐1‐picrylhydrazyl free radical scavenging activity as well as higher Fe(II) ion chelating ability, as compared with BHT. The total content of phenolic compounds are highly correlated to the individual polyphenols in extract of buckwheat hull, among which the following were assayed: 3,4‐dihydroxybenzoic acid, 4‐hydroxybenzoic acid, gallic acid, isovanillic acid and p‐coumaric acid, and flavonoids: isoorientin, quercetin, quercetin 3‐d‐glucoside, rutin, and vitexin. These results indicate that plant extracts can be used to prolong shelf life of products by protecting them against lipid oxidation and deterioration of their nutritional quality.
Ethanol, TLR3, and TLR4 Agonists Have Unique Innate Immune Responses in Neuron‐Like SH‐SY5Y and Microglia‐Like BV2
Authors: Lawrimore Colleen J. , Crews Fulton T.
Published: March 2017

Background

Ethanol (EtOH) consumption leads to an increase of proinflammatory signaling via activation of Toll‐like receptors (TLRs) such as TLR3 and TLR4 that leads to kinase activation (ERK1/2, p38, TBK1), transcription factor activation (NFκB, IRF3), and increased transcription of proinflammatory cytokines such as TNF‐α, IL‐1β, and IL‐6. This immune signaling cascade is thought to play a role in neurodegeneration and alcohol use disorders. While microglia are considered to be the primary macrophage in brain, it is unclear what if any role neurons play in EtOH‐induced proinflammatory signaling.

Methods

Microglia‐like BV2 and retinoic acid‐differentiated neuron‐like SH‐SY5Y were treated with TLR3 agonist Poly(I:C), TLR4 agonist lipopolysaccharide (LPS), or EtOH for 10 or 30 minutes to examine proinflammatory immune signaling kinase and transcription factor activation using Western blot, and for 24 hours to examine induction of proinflammatory gene mRNA using RT‐PCR.

Results

In BV2, both LPS and Poly(I:C) increased p‐ERK1/2, p‐p38, and p‐NFκB by 30 minutes, whereas EtOH decreased p‐ERK1/2 and increased p‐IRF3. LPS, Poly(I:C), and EtOH all increased TNF‐α and IL‐1β mRNA, and EtOH further increased TLR2, 7, 8, and MD‐2 mRNA in BV2. In SH‐SY5Y, LPS had no effect on kinase or proinflammatory gene expression. However, Poly(I:C) increased p‐p38 and p‐IRF3, and increased expression of TNF‐α, IL‐1β, and IL‐6, while EtOH increased p‐p38, p‐IRF3, p‐TBK1, and p‐NFκB while decreasing p‐ERK1/2 and increasing expression of TLR3, 7, 8, and RAGE mRNA. HMGB1, a TLR agonist, was induced by LPS in BV2 and by EtOH in both cell types. EtOH was more potent at inducing proinflammatory gene mRNA in SH‐SY5Y compared with BV2.

Conclusions

These results support a novel and unique mechanism of EtOH, TLR3, and TLR4 signaling in neuron‐like SH‐SY5Y and microglia‐like BV2 that likely contributes to the complexity of brain neuroimmune signaling.
A cis‐eQTL in OPRM1 is Associated with Subjective Response to Alcohol and Alcohol Use
Authors: Otto Jacqueline M. , Gizer Ian R. , Deak Joseph D. , Fleming Kimberly A. , Bartholow Bruce D.
Published: March 2017

Background

A functional polymorphism within the μ‐opioid receptor (OPRM1) gene, rs1799971 (A118G), previously has been associated with measures of alcohol use and sensitivity to its effects, but findings have been inconclusive. A recent study suggested that a second nearby variant within OPRM1, rs3778150, is robustly associated with heroin dependence and fully explained a smaller observed association with rs1799971. Given evidence that the rs3778150‐C allele is associated with decreased OPRM1 expression levels in the human brain, the current study sought to test the hypothesis that rs3778150 represents a causal variant within OPRM1 that increases risk for a variety of alcohol use phenotypes.

Methods

Participants with genotype and phenotype data from a larger experimental study (N = 152) were assessed on measures of subjective response to alcohol and alcohol use. Measures included (i) the Self‐Rating of the Effects of Alcohol and the Alcohol Sensitivity Questionnaire, (ii) the Biphasic Alcohol Effects Scale (BAES) and ratings of subjective intoxication, and (iii) average number of drinks per week in the past month.

Results

Compared to rs3778150‐T homozygous individuals, carriers of the rs3778150‐C allele exhibited significantly lower retrospective self‐report levels of alcohol sensitivity. Carriers of the rs3778150‐C allele also exhibited lower levels of BAES alcohol‐related stimulation during an alcohol challenge and reported higher levels of drinking in the last 30 days. With the exception of lower levels of BAES alcohol‐related sedation, the rs1799971 variant did not show consistent significant association with any of the alcohol phenotypes in the presence of rs3778150.

Conclusions

Results suggest that rs3778150 may be causally related to alcohol use phenotypes, and could potentially account for previously observed associations of rs1799971 with substance use phenotypes. Future studies may investigate potential causal relations among genetic variants in OPRM1, subjective response to alcohol, and drinking phenotypes to further delineate the effects of rs3778150.
A cross sectional and longitudinal study of endodontic and periapical status in an Australian population
Authors: Timmerman A , Calache H , Parashos P
Published: March 2017

Background

This study describes the cross sectional and longitudinal data of endodontic and periapical status of new patients presenting to a major dental hospital, and assesses the relationships between tooth‐related variables with apical periodontitis.

Methods

The records of 695 patients were randomly selected and the orthopantomograms of these patients up to 31 October 2014 were reviewed by two endodontists. The periapical status of teeth was recorded using the periapical index. The presence and quality of root fillings and coronal restorations were recorded. Statistical analysis included Fleiss’ kappa, Cohen's kappa and logistic regression set at P < 0.05.

Results

Of 695 patient records and 16 936 teeth examined, 138 (19.9%) patients or 284 (1.7%) teeth had root fillings and 179 (25.8%) patients or 325 (1.9%) teeth had apical periodontitis. Root fillings and coronal restorations were adequate in 34.6% and 69.4% teeth, respectively. A large proportion (47%) of teeth with apical periodontitis remained unchanged in subsequent orthopantomograms.

Conclusions

There was lower prevalence of root filled teeth or apical periodontitis in the present study compared with international studies. The frequency of adequate root fillings must be considered unacceptably low. Teeth with apical periodontitis may remain quiescent in the absence of caries or restorative breakdown.
Impacts of terrain attributes on economics and the environment: costs of reducing potential nitrogen pollution in wheat production
Authors: Walters Cory G. , Shumway C. Richard , Huggins David R.
Published: March 2017

The economic cost of achieving desired environmental outcomes from uniform and variable rate fertilizer application technologies depends both on market forces and agronomic properties. Using spatial econometric methods, we analyze the impact of nitrogen fertilizer supply by terrain attribute on the yield and protein content of hard red spring wheat grown in Eastern Washington as well as the impact on residual nitrogen. We find significant association with all three. The economic impact of nitrogen restrictions depends critically on both prices and level of the restriction. Uniform application of nitrogen was found to economically outperform variable rate application, but variable rate application provided positive environmental benefits due to less residual nitrogen.
Work after age 65: A prospective study of Australian men and women
Authors: Majeed Tazeen , Forder Peta M , Tavener Meredith , Vo Kha , Byles Julie
Published: March 2017

Objective

This study describes hours in paid work for Australian men and women aged over 65, focusing on associations between work and education.

Methods

Data were analysed separately for men and women, from baseline and first follow‐up surveys of the 45 and Up Study. Generalised estimating equation models were used to identify associations between work, education and other factors over time.

Results

The odds of doing paid work increased with higher education level and decreased with time, age, poorer physical function and having health conditions (high blood pressure, diabetes, stroke and breast cancer). Un‐partnered women were more likely to work in later life than partnered women.

Conclusion

This study quantifies the importance of education and health factors in determining continued participation of Australian men and women in paid work in later life. These factors need to be considered for policies aiming to increase workforce participation beyond 65 years of age.
mTORC2 controls Th9 polarization and allergic airway inflammation
Authors: Chen H. , Zhang L. , Wang P. , Su H. , Wang W. , Chu Z. , Zhang L. , Zhang X. , Zhao Y.
Published: March 2017

Background

T helper type 9 (Th9) cells, a subpopulation of CD4+ T cells, play a critical role in the pathogenesis of allergic airway inflammation. However, it remains unknown whether mTORC2 regulates Th9 differentiation or function during allergic inflammation.

Methods

T‐cell‐specific Rictor‐deficient mice, a mouse model of allergic airway inflammation induced by ovalbumin (OVA) sensitization and a mouse model of adoptive transfer of induced Th9 cells, were used to address the roles of mTORC2 in the pathogenesis of allergic airway inflammation. The in vitro Th9 induction, multiple colors flow cytometry, real‐time PCR, and Western blots were used to investigate the molecular effects of mTORC2 in Th9 induction.

Results

The differentiation of naïve CD4+ T cells into Th9 cells was significantly diminished in the absence of Rictor, the core component of mTORC2. Using a mouse model of allergic airway inflammation induced by OVA sensitization, T‐cell‐specific Rictor‐deficient mice show much less severe allergic airway inflammation characterized by decreased pathological alterations and fibrosis of the lungs, which was accompanied with reduced Th9 differentiation and infiltration. Importantly, the isolated Rictor‐deficient Th9 cells mediate less severe allergic pathogenesis upon adoptive transfer. Rictor deficiency impairs Th9 cell differentiation by reducing IRF4 expression rather than affecting Foxo1/Foxo3a transcriptional activity, which is likely due to decreased Akt and/or STAT6 activation.

Conclusions

These findings uncover a novel role of mTORC2 in Th9 cell differentiation and may have important implications for therapeutic intervention of allergic diseases.
NLRP3 inflammasome activation is associated with proliferative diabetic retinopathy
Authors: Loukovaara Sirpa , Piippo Niina , Kinnunen Kati , Hytti Maria , Kaarniranta Kai , Kauppinen Anu
Published: March 2017

Purpose

Innate immunity and dysregulation of inflammatory processes play a role in vascular diseases like atherosclerosis or diabetes. Nucleotide‐binding domain and Leucine‐rich repeat Receptor containing a Pyrin domain 3 (NLRP3) inflammasomes are pro‐inflammatory signalling complexes that were found in 2002. In addition to pathogens and other extracellular threats, they can be activated by various endogenous danger signals. The purpose of this study was to find out whether NLRP3 activation occurs in patients with sight‐threatening forms of diabetic retinopathy (DR).

Methods

Inflammasome components NLRP3 and caspase‐1, inflammasome‐related pro‐inflammatory cytokines IL‐1β and IL‐18, vascular endothelial growth factor (VEGF), acute‐phase cytokines TNF‐α and IL‐6, as well as adaptive immunity‐related cytokine interferon gamma (IFN‐γ) were measured from the vitreous samples of 15 non‐proliferative diabetic retinopathy (non‐PDR) and 23 proliferative diabetic retinopathy (PDR) patients using the enzyme‐linked immunosorbent assay (ELISA) method. The adaptor protein apoptosis‐associated speck‐like protein containing a CARD (ASC) was determined using the Western blot technique.

Results

Inflammasome components were present in the vitreous of DR patients. Along with VEGF, the levels of caspase‐1 and IL‐18 were significantly increased, especially in PDR eyes. Interestingly, clearly higher levels of NLRP3 were found in the PDR eyes with tractional retinal detachment (TRD) than from PDR eyes with fully attached retina. There were no significant differences in the amounts of IL‐1β, TNF‐α, IL‐6, and IFN‐γ that were detectable in the vitreous of both non‐PDR and PDR patients.

Conclusion

Our results suggest that NLRP3 inflammasome activation can be associated especially with the pathogenesis of PDR. The lack of differences in TNF‐α, IL‐6, and IFN‐γ also alludes that acute inflammation or T‐cell‐mediated responses do not dominate in PDR pathogenesis.
Psychotropics and weak opioid analgesics in plasma samples of older hip fracture patients – detection frequencies and consistency with drug records
Authors: Waade Ragnhild Birkeland , Molden Espen , Martinsen Mette Irene , Hermann Monica , Ranhoff Anette Hylen
Published: March 2017

Aims

To determine use of psychotropic drugs and weak opioids in hip fracture patients by analysing plasma samples at admission, and compare detected drug frequencies with prescription registry data and drug records.

Methods

Plasma from 250 hip fracture patients aged ≥65 years sampled at hospital admission were analysed by ultra‐performance liquid chromatography–tandem mass spectrometry methods for detection of psychotropic drugs and weak opioid analgesics (alcohol also determined). Odds ratios for drugs detected in plasma of hip fracture patients vs. prescription frequencies of the same drugs in an age‐, time‐ and region‐matched reference population were calculated. Moreover, recorded and measured drugs were compared.

Results

Psychotropic drugs and/or weak opioid analgesics were detected in 158 (63%) of the patients (median age 84 years; 76% females), while alcohol was found in 19 patients (7.6%). The occurrence of diazepam (odds ratio 1.6; 95% confidence interval 1.1–2.4), nitrazepam (2.3; 1.3–4.1), selective serotonin reuptake inhibitors (1.9; 1.3–2.9) and mirtazapine (2.3; 1.2–4.3) was significantly higher in plasma samples of hip fracture patients than in prescription data from the reference population. Poor consistency between recorded and measured drugs was disclosed for z‐hypnotics and benzodiazepines; e.g. diazepam was detected in 29 (11.6%), but only recorded in six (2.4%) of the patients.

Conclusions

Plasma analysis shows that use of antidepressants and benzodiazepines in hip fracture patients is significantly more frequent than respective prescription frequencies in the general elderly population. Moreover, consistency between recorded and actual use of psychotropic fall‐risk drugs is poor at hospital admission of hip fracture patients.
Sequence Robust Association Test for Familial Data
Authors: Dai Wei , Yang Ming , Wang Chaolong , Cai Tianxi
Published: March 2017

Genome-wide association studies (GWAS) and next generation sequencing studies (NGSS) are often performed in family studies to improve power in identifying genetic variants that are associated with clinical phenotypes. Efficient analysis of genome-wide studies with familial data is challenging due to the difficulty in modeling shared but unmeasured genetic and/or environmental factors that cause dependencies among family members. Existing genetic association testing procedures for family studies largely rely on generalized estimating equations (GEE) or linear mixed-effects (LME) models. These procedures may fail to properly control for type I errors when the imposed model assumptions fail. In this article, we propose the Sequence Robust Association Test (SRAT), a fully rank-based, flexible approach that tests for association between a set of genetic variants and an outcome, while accounting for within-family correlation and adjusting for covariates. Comparing to existing methods, SRAT has the advantages of allowing for unknown correlation structures and weaker assumptions about the outcome distribution. We provide theoretical justifications for SRAT and show that SRAT includes the well-known Wilcoxon rank sum test as a special case. Extensive simulation studies suggest that SRAT provides better protection against type I error rate inflation, and could be much more powerful for settings with skewed outcome distribution than existing methods. For illustration, we also apply SRAT to the familial data from the Framingham Heart Study and Offspring Study to examine the association between an inflammatory marker and a few sets of genetic variants.
Outcome-Adaptive Lasso: Variable Selection for Causal Inference
Authors: Shortreed Susan M. , Ertefaie Ashkan
Published: March 2017

Methodological advancements, including propensity score methods, have resulted in improved unbiased estimation of treatment effects from observational data. Traditionally, a “throw in the kitchen sink” approach has been used to select covariates for inclusion into the propensity score, but recent work shows including unnecessary covariates can impact both the bias and statistical efficiency of propensity score estimators. In particular, the inclusion of covariates that impact exposure but not the outcome, can inflate standard errors without improving bias, while the inclusion of covariates associated with the outcome but unrelated to exposure can improve precision. We propose the outcome-adaptive lasso for selecting appropriate covariates for inclusion in propensity score models to account for confounding bias and maintaining statistical efficiency. This proposed approach can perform variable selection in the presence of a large number of spurious covariates, that is, covariates unrelated to outcome or exposure. We present theoretical and simulation results indicating that the outcome-adaptive lasso selects the propensity score model that includes all true confounders and predictors of outcome, while excluding other covariates. We illustrate covariate selection using the outcome-adaptive lasso, including comparison to alternative approaches, using simulated data and in a survey of patients using opioid therapy to manage chronic pain.
Reintroduction of anti‐thrombotic therapy after a gastrointestinal haemorrhage: if and when?
Authors: Scott Martin J. , Veitch Andrew , Thachil Jecko
Published: March 2017

Gastrointestinal haemorrhage is a common clinical scenario and, in those using antithrombotic agents, the risk is significantly increased. Management of these patients, in terms of initial resuscitation is well established and numerous guidelines exist in this area. However, few studies have addressed the subsequent dilemma of if and when antithrombotic agents should be reintroduced. Consequently, practice is variable and not necessarily evidenced‐based. Overall, for patients that are either anticoagulated or using antiplatelet drugs for secondary prophylaxis, there is a clear benefit to restarting these agents. However, there is limited data to guide when this should occur. For individuals at low risk of re‐bleeding, current guidelines suggest single agent aspirin can be continued without interruption, assuming haemostatic control has been confirmed endoscopically. For those at higher bleeding risk, aspirin should be withheld, but reintroduced early (within 3 days of index endoscopy). However, randomised evidence is lacking, as are studies including more modern agents or combined anticoagulant/ antiplatelet regimens. As such, guidance statements are limited and management suggestions must be extrapolated from clinical trials, retrospective studies and data relating specifically to warfarin and aspirin. The intention of this review is to summarise what evidence is available and, where this is lacking, suggest pragmatic management options based on a risk‐benefit assessment of thromboembolism and recurrent bleeding.