bluuebunny/crossref_metadata_2025 huggingface dataset:
Coupling intercellular molecular signalling with multicellular deformation for simulating three-dimensional tissue morphogenesis
Authors: Okuda Satoru , Inoue Yasuhiro , Watanabe Tadashi , Adachi Taiji
Published: April 2015

During morphogenesis, three-dimensional (3D) multicellular structures emerge from biochemical and mechanical interplays among cells. In particular, by organizing their gradient within tissues, the diffusible signalling molecules play an essential role in producing the spatio-temporal patterns of cell status such as the differentiation states. Notably, this biochemical patterning can be dynamically coupled with multicellular deformations by signal-dependent cell activities such as contraction, adhesion, migration, proliferation and apoptosis. However, the mechanism by which these cellular activities mediate the interactions between multicellular deformations and patterning is still unknown. Herein, we propose a novel framework of a 3D vertex model to express molecular signalling among the mechanically deforming cells. By specifying a density of signalling molecules for each cell, we express their transport between neighbouring cells. By simulating signal-dependent epithelial growth, we found various types of tissue morphogenesis such as arrest, expansion, invagination and evagination. In the expansion phase, growth molecules were widely diffused with increasing tissue volume, which diluted the growth molecules in order to support the autonomous suppression of tissue growth. These results indicate that the proposed model successfully expresses 3D multicellular deformations dynamically coupled with biochemical patterning. We expect our proposed model to be a useful tool for predicting new phenomena emerging from mechanochemical coupling in multicellular morphogenesis.
Accuracy of the Michaelis–Menten approximation when analysing effects of molecular noise
Authors: Lawson Michael J. , Petzold Linda , Hellander Andreas
Published: April 2015

Quantitative biology relies on the construction of accurate mathematical models, yet the effectiveness of these models is often predicated on making simplifying approximations that allow for direct comparisons with available experimental data. The Michaelis–Menten (MM) approximation is widely used in both deterministic and discrete stochastic models of intracellular reaction networks, owing to the ubiquity of enzymatic activity in cellular processes and the clear biochemical interpretation of its parameters. However, it is not well understood how the approximation applies to the discrete stochastic case or how it extends to spatially inhomogeneous systems. We study the behaviour of the discrete stochastic MM approximation as a function of system size and show that significant errors can occur for small volumes, in comparison with a corresponding mass-action system. We then explore some consequences of these results for quantitative modelling. One consequence is that fluctuation-induced sensitivity, or stochastic focusing, can become highly exaggerated in models that make use of MM kinetics even if the approximations are excellent in a deterministic model. Another consequence is that spatial stochastic simulations based on the reaction–diffusion master equation can become highly inaccurate if the model contains MM terms.
Ancient collagen reveals evolutionary history of the endemic South American ‘ungulates’
Authors: Buckley Michael
Published: April 2015

Since the late eighteenth century, fossils of bizarre extinct creatures have been described from the Americas, revealing a previously unimagined chapter in the history of mammals. The most bizarre of these are the ‘native’ South American ungulates thought to represent a group of mammals that evolved in relative isolation on South America, but with an uncertain affinity to any particular placental lineage. Many authors have considered them descended from Laurasian ‘condylarths’, which also includes the probable ancestors of perissodactyls and artiodactyls, whereas others have placed them either closer to the uniquely South American xenarthrans (anteaters, armadillos and sloths) or the basal afrotherians (e.g. elephants and hyraxes). These hypotheses have been debated owing to conflicting morphological characteristics and the hitherto inability to retrieve molecular information. Of the ‘native’ South American mammals, only the toxodonts and litopterns persisted until the Late Pleistocene–Early Holocene. Owing to known difficulties in retrieving ancient DNA (aDNA) from specimens from warm climates, this research presents a molecular phylogeny for bothMacrauchenia patachonica(Litopterna) andToxodon platensis(Notoungulata) recovered using proteomics-based (liquid chromatography–tandem mass spectrometry) sequencing analyses of bone collagen. The results place both taxa in a clade that is monophyletic with the perissodactyls, which today are represented by horses, rhinoceroses and tapirs.
Distributed nestmate recognition in ants
Authors: Esponda Fernando , Gordon Deborah M.
Published: April 2015

We propose a distributed model of nestmate recognition, analogous to the one used by the vertebrate immune system, in which colony response results from the diverse reactions of many ants. The model describes how individual behaviour produces colony response to non-nestmates. No single ant knows the odour identity of the colony. Instead, colony identity is defined collectively by all the ants in the colony. Each ant responds to the odour of other ants by reference to its own unique decision boundary, which is a result of its experience of encounters with other ants. Each ant thus recognizes a particular set of chemical profiles as being those of non-nestmates. This model predicts, as experimental results have shown, that the outcome of behavioural assays is likely to be variable, that it depends on the number of ants tested, that response to non-nestmates changes over time and that it changes in response to the experience of individual ants. A distributed system allows a colony to identify non-nestmates without requiring that all individuals have the same complete information and helps to facilitate the tracking of changes in cuticular hydrocarbon profiles, because only a subset of ants must respond to provide an adequate response.
Fertility decline and the changing dynamics of wealth, status and inequality
Authors: Colleran Heidi , Jasienska Grazyna , Nenko Ilona , Galbarczyk Andrzej , Mace Ruth
Published: April 2015

In the course of demographic transitions (DTs), two large-scale trends become apparent: (i) the broadly positive association between wealth, status and fertility tends to reverse, and (ii) wealth inequalities increase and then temporarily decrease. We argue that these two broad patterns are linked, through a diversification of reproductive strategies that subsequently converge as populations consume more, become less self-sufficient and increasingly depend on education as a route to socio-economic status. We examine these links using data from 22 mid-transition communities in rural Poland. We identify changing relationships between fertility and multiple measures of wealth, status and inequality. Wealth and status generally have opposing effects on fertility, but these associations vary by community. Where farming remains a viable livelihood, reproductive strategies typical of both pre- and post-DT populations coexist. Fertility is lower and less variable in communities with lower wealth inequality, and macro-level patterns in inequality are generally reproduced at the community level. Our results provide a detailed insight into the changing dynamics of wealth, status and inequality that accompany DTs at the community level where peoples' social and economic interactions typically take place. We find no evidence to suggest that women with the most educational capital gain wealth advantages from reducing fertility, nor that higher educational capital delays the onset of childbearing in this population. Rather, these patterns reflect changing reproductive preferences during a period of profound economic and social change, with implications for our understanding of reproductive and socio-economic inequalities in transitioning populations.
Avoidable errors in the modelling of outbreaks of emerging pathogens, with special reference to Ebola
Authors: King Aaron A. , Domenech de Cellès Matthieu , Magpantay Felicia M. G. , Rohani Pejman
Published: April 2015

As an emergent infectious disease outbreak unfolds, public health response is reliant on information on key epidemiological quantities, such as transmission potential and serial interval. Increasingly, transmission models fit to incidence data are used to estimate these parameters and guide policy. Some widely used modelling practices lead to potentially large errors in parameter estimates and, consequently, errors in model-based forecasts. Even more worryingly, in such situations, confidence in parameter estimates and forecasts can itself be far overestimated, leading to the potential for large errors that mask their own presence. Fortunately, straightforward and computationally inexpensive alternatives exist that avoid these problems. Here, we first use a simulation study to demonstrate potential pitfalls of the standard practice of fitting deterministic models to cumulative incidence data. Next, we demonstrate an alternative based on stochastic models fit to raw data from an early phase of 2014 West Africa Ebola virus disease outbreak. We show not only that bias is thereby reduced, but that uncertainty in estimates and forecasts is better quantified and that, critically, lack of model fit is more readily diagnosed. We conclude with a short list of principles to guide the modelling response to future infectious disease outbreaks.
Bacillus
taiwanensis sp. nov., isolated from a soil sample from Taiwan
Authors: Liu Bo , Liu Guo-Hong , Sengonca Cetin , Schumann Peter , Wang Ming-Kuang , Xiao Rong-Feng , Zheng Xue-Fang , Chen Zheng
Published: April 2015

A Gram-stain-positive, rod-shaped, endospore-forming, aerobic bacterium (FJAT-14571T) was isolated from a soil sample in Taiwan. Strain FJAT-14571T grew at 20–40 °C (optimum 35 °C), pH 6–10 (optimum pH 8) and 0–2 % (w/v) NaCl (optimum 0 %). Phylogenetic analyses based on 16S rRNA gene sequences showed that strain FJAT-14571T was a member of the genus Bacillus and was most closely related to Bacillus oceanisediminis DSM 24771T (96.2 %). DNA–DNA relatedness between strain FJAT-14571T and B. oceanisediminis DSM 24771T was low (32.0 % ± 0.88 %). The diagnostic diamino acid of the peptidoglycan of strain FJAT-14571T was meso-diaminopimelic acid and the predominant menaquinone was MK-7 (96.6 %). The major cellular fatty acids were iso-C15 : 0 (46.4 %), anteiso-C15 : 0 (7.6 %), iso-C17 : 0 (8.2 %) and iso-C16 : 0 (10.0 %) and the DNA G+C content was 40.8 mol%. Phenotypic, chemotaxonomic and genotypic properties clearly indicated that strain FJAT-14571T represents a novel species within the genus Bacillus, for which the name Bacillus taiwanensis sp. nov. is proposed. The type strain is FJAT-14571T ( = DSM 27845T = CGMCC1.1 2698T).
GLO-Roots: an imaging platform enabling multidimensional characterization of soil-grown roots systems
Authors: Rellán-Álvarez Rubén , Lobet Guillaume , Lindner Heike , Pradier Pierre-Luc M , Sebastian Jose , Yee Muh-Ching , Geng Yu , Trontin Charlotte , LaRue Therese , Schrager Lavelle Amanda , Haney Cara H , Nieu Rita , Maloof Julin N , Vogel John P , Dinneny José R
Published: April 2015

Root systems develop different root types that individually sense cues from their local environment and integrate this information with systemic signals. This complex multi-dimensional amalgam of inputs enables continuous adjustment of root growth rates, direction and metabolic activity that define a dynamic physical network. Current methods for analyzing root biology balance physiological relevance with imaging capability. To bridge this divide, we developed an integrated imaging system called Growth and Luminescence Observatory for Roots (GLO-Roots) that uses luminescence-based reporters to enable studies of root architecture and gene expression patterns in soil-grown, light-shielded roots. We have developed image analysis algorithms that allow the spatial integration of soil properties such as soil moisture with root traits. We propose GLO-Roots as a system that has great utility in presenting environmental stimuli to roots in ways that evoke natural adaptive responses and in providing tools for studying the multi-dimensional nature of such processes.
Ambient temperature and genotype differentially affect developmental and phenotypic plasticity inArabidopsis thaliana
Authors: Ibañez Carla , Poeschl Yvonne , Peterson Tom , Bellstädt Julia , Denk Kathrin , Gogol-Döring Andreas , Quint Marcel , Delker Carolin
Published: April 2015

Background

Global increase in ambient temperatures constitute a significant challenge to wild and cultivated plant species. Forward genetic analyses of individual temperature-responsive traits have resulted in the identification of several signaling and response components. However, a comprehensive knowledge about temperature sensitivity of different developmental stages and the contribution of natural variation is still scarce and fragmented at best.

Results

Here, we systematically analyze thermomorphogenesis throughout a complete life cycle in ten naturalArabidopsis thalianaaccessions grown in four different temperatures ranging from 16 to 28 °C. We used Q10, GxE, phenotypic divergence and correlation analyses to assess temperature sensitivity and genotype effects of more than 30 morphometric and developmental traits representing five phenotype classes. We found that genotype and temperature differentially affected plant growth and development with variing strengths. Furthermore, overall correlations among phenotypic temperature responses was relatively low which seems to be caused by differential capacities for temperature adaptations of individual accessions.

Conclusion

Genotype-specific temperature responses may be attractive targets for future forward genetic approaches and accession-specific thermomorphogenesis maps may aid the assessment of functional relevance of known and novel regulatory components.
Neanderthal Genomics Suggests a Pleistocene Time Frame for the First Epidemiologic Transition
Authors: Houldcroft Charlotte Jane , Underdown Simon
Published: April 2015

High quality Altai Neanderthal and Denisovan genomes are revealing which regions of archaic hominin DNA have persisted in the modern human genome. A number of these regions are associated with response to infection and immunity, with a suggestion that derived Neanderthal alleles found in modern Europeans and East Asians may be associated with autoimmunity. Independent sources of DNA-based evidence allow a re-evaluation of the nature and timing of the first epidemiologic transition. By combining skeletal, archaeological and genetic evidence we question whether the first epidemiologic transition in Eurasia was as tightly tied to the onset of the Holocene as has previously been assumed. There is clear evidence to suggest that this transition began before the appearance of agriculture and occurred over a timescale of tens of thousands of years. The transfer of pathogens between human species may also have played a role in the extinction of the Neanderthals.
Concentration and Purification of Rabies Viral and Lentiviral Vectors
Authors: Sullivan Heather A. , Wickersham Ian R.
Published: April 2015

Rabies viral and lentiviral vectors are very useful tools for neuroscientists, but high titer and purity are critical for in vivo applications. Here we present a protocol for concentration and purification of viral stocks by ultracentrifugation on a sucrose step gradient to remove impurities of both higher and lower densities than the virus itself, with sucrose removed by a subsequent pelleting step. The final stocks are concentrated in volume by a factor of up to 1000, with higher expected purity than is obtained following previously published protocols for preparing G-deleted rabies viral vectors.
Quantification of Cell, Actin, and Nuclear DNA Morphology with High-Throughput Microscopy and CalMorph
Authors: Okada Hiroki , Ohnuki Shinsuke , Ohya Yoshikazu
Published: April 2015

Automated image acquisition and processing systems have been developed to quantitatively describe yeast cell morphology. These systems are superior to the preceding qualitative methods in terms of reproducibility, as they completely avoid subjective recognition of images. Because high-throughput microscopy has enabled rapid production of numerous cellular images, reinforcement of high-performance and high-throughput automated image-processing techniques has been in increasing demand in the field of biology. This protocol describes how to use a high-throughput microscope in conjunction with the image-processing software CalMorph, which outputs more than 500 morphological parameters, for quantification of cell, actin, and nuclear DNA morphology.
Online Resources for Genomic Analysis Using High-Throughput Sequencing
Authors: Blankenberg Daniel , Taylor James , Nekrutenko Anton
Published: April 2015

The availability of high-throughput sequencing has created enormous possibilities for scientific discovery. However, the massive amount of data being generated has resulted in a severe informatics bottleneck. A large number of tools exist for analyzing next-generation sequencing (NGS) data, yet often there remains a disconnect between these research tools and the ability of many researchers to use them. As a consequence, several online resources and communities have been developed to assist researchers with both the management and the analysis of sequencing data sets. Here we describe the use and applications of common file formats for coding and storing genomic data, consider several web-accessible open-source resources for the visualization and analysis of NGS data, and provide examples of typical analyses with links to further detailed exercises.
pH Regulation by NHX-Type Antiporters Is Required for Receptor-Mediated Protein Trafficking to the Vacuole in Arabidopsis
Authors: Reguera Maria , Bassil Elias , Tajima Hiromi , Wimmer Monika , Chanoca Alexandra , Otegui Marisa S. , Paris Nadine , Blumwald Eduardo
Published: April 2015

Protein trafficking requires proper ion and pH homeostasis of the endomembrane system. The NHX-type Na+/H+ antiporters NHX5 and NHX6 localize to the Golgi, trans-Golgi network, and prevacuolar compartments and are required for growth and trafficking to the vacuole. In the nhx5 nhx6 T-DNA insertional knockouts, the precursors of the 2S albumin and 12S globulin storage proteins accumulated and were missorted to the apoplast. Immunoelectron microscopy revealed the presence of vesicle clusters containing storage protein precursors and vacuolar sorting receptors (VSRs). Isolation and identification of complexes of VSRs with unprocessed 12S globulin by 2D blue-native PAGE/SDS-PAGE indicated that the nhx5 nhx6 knockouts showed compromised receptor-cargo association. In vivo interaction studies using bimolecular fluorescence complementation between VSR2;1, aleurain, and 12S globulin suggested that nhx5 nhx6 knockouts showed a significant reduction of VSR binding to both cargoes. In vivo pH measurements indicated that the lumens of VSR compartments containing aleurain, as well as the trans-Golgi network and prevacuolar compartments, were significantly more acidic in nhx5 nhx6 knockouts. This work demonstrates the importance of NHX5 and NHX6 in maintaining endomembrane luminal pH and supports the notion that proper vacuolar trafficking and proteolytic processing of storage proteins require endomembrane pH homeostasis.
Control of downy mildew (Peronospora sparsa) in arctic bramble (Rubus arcticus ssp. arcticus)
Authors: Kostamo K. , Toljamo A. , Palonen P. , Valkonen J.P.T. , Kärenlampi S.O. , Kokko H.
Published: April 2015

Downy mildew, inflicted by Peronospora sparsa, causes yield losses in arctic bramble (Rubus arcticus ssp. arcticus), boysenberry (Rubus spp. hybrid) and blackberry (Rubus fruticosus), and is a serious threat to the cultivation. Arctic bramble is a high‐value crop but its commercial potential is not realisable partly due to downy mildew. Although P. sparsa has been associated with yield losses in arctic bramble, this has not been experimentally proven, nor have the downy mildew symptoms in arctic bramble fruits been described in a controlled experiment. In this study, downy mildew was found to affect the fruits and reduce the yield of arctic bramble. There was a direct correlation between the number of infected leaves and hard fruits resulting from the infection. Owing to the new pesticide legislation in the European Union, it is important to find alternatives to fungicides in the control of downy mildew. The products ALIETTE (fungicide), PHOSFIK (leaf fertiliser) and BION (pathogen defence elicitor) were effective in downy mildew control, Aliette and Phosfik being more effective than Bion especially in preventing yield losses. No arctic bramble cultivars known to be resistant to downy mildew are available. Evaluation of cultivars Alli, Mesma and Pima in the field showed that Mesma is more resistant to downy mildew than are Alli and Pima. Currently the main cultivar grown in Finland, Pima, was the most susceptible variety. The results of this study suggest that the yields and profitability of arctic bramble production could be improved by selecting more resistant varieties, combined with the application of agrochemicals that can suppress the development of downy mildew.
Trends and timing of cigarette smoking uptake among US young adults: survival analysis using annual national cohorts from 1976 to 2005
Authors: Terry‐McElrath Yvonne M. , O'Malley Patrick M.
Published: April 2015

Aims

To measure changes over time in cigarette smoking uptake prevalence and timing during young adulthood (ages 19–26 years), and associations between time‐invariant/‐varying characteristics and uptake prevalence/timing.

Design

Discrete‐time survival modeling of data collected from United States high school seniors (modal age 17/18) enrolled in successive graduating classes from 1976 to 2005 and participating in four follow‐up surveys (to modal age 25/26).

Setting

The longitudinal component of the Monitoring the Future study.

Participants

A total of 10 758 individuals reporting no life‐time smoking when first surveyed as high school seniors.

Measurements

Smoking uptake (any, experimental, occasional and regular); socio‐demographic variables; marital, college and work status; time spent socializing.

Findings

The percentage of young adults moving from non‐smoker to experimental smoking [slope estimate 0.11, standard error (SE) = 0.04, P = 0.005] or occasional smoking (slope estimate 0.17, SE = 0.03, P < 0.001) increased significantly across graduating classes; the percentage moving from non‐smoker to regular smoker remained stable. All forms of smoking uptake were most likely to occur at age 19/20, but uptake prevalence at older ages increased over time [e.g. cohort year predicting occasional uptake at modal age 25/26 adjusted hazard odds ratio (AHOR) = 1.05, P = 0.002]. Time‐invariant/‐varying characteristics had unique associations with the timing of various forms of smoking uptake (e.g. at modal age 21/22, currently attending college increased occasional uptake risk (AHOR = 2.11, P < 0.001) but decreased regular uptake risk (AHOR = 0.69, P = 0.026).

Conclusions

Young adult occasional and experimental smoking uptake increased in the United States for non‐smoking high school seniors graduating from 1976 to 2005. Smoking uptake for these cohorts remained most likely to occur at age 19/20, but prevalence of uptake at older ages increased.
Flexible razor blade for harvesting tumours in Mohs micrographic surgery
Authors: Tan Eugene , Mortimer Neil , Salmon Paul J
Published: April 2015

A useful application of the flexible razor blade in Mohs micrographic surgery that can save time and result in a well‐presented specimen is described.
Refraction and visual acuity in a national Danish cohort of 4‐year‐old children of extremely preterm delivery
Authors: Fledelius Hans C. , Bangsgaard Regitze , Slidsborg Carina , laCour Morten
Published: April 2015

Purpose

A recent threefold increase in laser treatment for advanced retinopathy of prematurity (ROP) triggered a nationwide preschool ophthalmic and developmental status among extremely preterm survivors. Here, we discuss refraction and visual acuity.

Methods

Survivors (n = 178) from a national birth cohort (February 2004 to March 2006) of gestational age <28 weeks (PT) and 56 full‐term (FT) controls attended for evaluation at age 4 years. Cycloplegic refraction and keratometry were achieved by Retinomax autokeratorefractor and visual acuities by symbol recognition (HOTV, logMAR).

Results

The refractive distribution presented a myopic tail (4.5%) and a hyperopic tail (11.9% ≥+2.5 D) as special preterm features, and corneas were more curved. Astigmatism and anisometropia were only marginally increased, and visual acuities were generally good. Best‐corrected binocular median logMAR visual acuity was 0.1 in FT and 0.2 in PT, in Snellen equivalents 0.8 and 0.63. Snellen acuity ≤0.5 occurred across the ROP subgroups, but mainly in those with at least ROP stage 3. Two children had low vision.

Conclusions

The overall fair outcome for refraction and function is in accordance with other recent northern Europe experience. The results differ in particular from the poorer ophthalmic outcomes reported in the pioneer US treatment studies (cryotherapy for ROP and ETROP). The diode laser ablations (n = 32) appeared effective in our series; except one child, all treated subjects had good or fair social vision at the age of 4 years.
Brain imaging in cooled encephalopathic neonates does not differ between four and 11 days after birth
Authors: Skranes Janne Helen , Cowan Frances Mary , Stiris Tom , Fugelseth Drude , Thoresen Marianne , Server Andres
Published: April 2015

Aim

The optimal timing of magnetic resonance imaging (MRI) in encephalopathic infants treated with hypothermia is unknown, and this study examined whether early scans differed from later scans.

Methods

We assessed paired MRI scans carried out on 41 cooled encephalopathic infants at a median of four and 11 days using two scoring systems: the Rutherford injury scores for the basal ganglia and thalami (BGT), white matter and the posterior limb of the internal capsule, and the Bonifacio injury scores for the BGT and watershed area.

Results

Both systems produced consistent injury severity scores in 37 of 41 infants on both days, with Rutherford scores predicting poor outcome in six early scans and seven later scans (K = 0.91) and Bonifacio doing the same in seven and nine scans (K = 0.85). A white matter/watershed score of two or a BGT score of one indicated severe changes by day 11 in three infants, but lower scores did not.

Conclusion

Magnetic resonance imaging scans indicated that the Rutherford and Bonifacio systems produced similar scores in 37 of 41 cooled encephalopathic infants at a median of four and 11 days. Infants with an early white matter/watershed scores of two or a BGT score of one may worsen and should be rescanned.
The long‐acting β2‐adrenoceptor agonist olodaterol attenuates pulmonary inflammation
Authors: Wex Eva , Kollak Ines , Duechs Matthias J , Naline Emmanuel , Wollin Lutz , Devillier Philippe
Published: April 2015

Background and Purpose

β2‐adrenoceptor agonists are widely used in the management of obstructive airway diseases. Besides their bronchodilatory effect, several studies suggest inhibitory effects on various aspects of inflammation. The aim of our study was to determine the efficacy of the long‐acting β2‐adrenoceptor agonist olodaterol to inhibit pulmonary inflammation and to elucidate mechanism(s) underlying its anti‐inflammatory actions.

Experimental Approach

Olodaterol was tested in murine and guinea pig models of cigarette smoke‐ and LPS‐induced lung inflammation. Furthermore, effects of olodaterol on the LPS‐induced pro‐inflammatory mediator release from human parenchymal explants, CD11b adhesion molecule expression on human granulocytes TNF‐α release from human whole blood and on the IL‐8‐induced migration of human peripheral blood neutrophils were investigated.

Key Results

Olodaterol dose‐dependently attenuated cell influx and pro‐inflammatory mediator release in murine and guinea pig models of pulmonary inflammation. These anti‐inflammatory effects were observed at doses relevant to their bronchodilatory efficacy. Mechanistically, olodaterol attenuated pro‐inflammatory mediator release from human parenchymal explants and whole blood and reduced expression of CD11b adhesion molecules on granulocytes, but without direct effects on IL‐8‐induced neutrophil transwell migration.

Conclusions and Implications

This is the first evidence for the anti‐inflammatory efficacy of a β2‐adrenoceptor agonist in models of lung inflammation induced by cigarette smoke. The long‐acting β2‐adrenoceptor agonist olodaterol attenuated pulmonary inflammation through mechanisms that are separate from direct inhibition of bronchoconstriction. Furthermore, the in vivo data suggest that the anti‐inflammatory properties of olodaterol are maintained after repeated dosing for 4 days.
Acute morphine affects the rat circadian clock via rhythms of phosphorylated ERK1/2 and GSK3β kinases and Per1 expression in the rat suprachiasmatic nucleus
Authors: Pačesová Dominika , Volfová Barbora , Červená Kateřina , Hejnová Lucie , Novotný Jiří , Bendová Zdeňka
Published: April 2015

Background and Purpose

Opioids affect the circadian clock and may change the timing of many physiological processes. This study was undertaken to investigate the daily changes in sensitivity of the circadian pacemaker to an analgesic dose of morphine, and to uncover a possible interplay between circadian and opioid signalling.

Experimental Approach

A time‐dependent effect of morphine (1 mg·kg−1, i.p.) applied either during the day or during the early night was followed, and the levels of phosphorylated ERK1/2, GSK3β, c‐Fos and Per genes were assessed by immunohistochemistry and in situ hybridization. The effect of morphine pretreatment on light‐induced pERK and c‐Fos was examined, and day/night difference in activity of opioid receptors was evaluated by [35S]‐GTPγS binding assay.

Key Results

Morphine stimulated a rise in pERK1/2 and pGSK3β levels in the suprachiasmatic nucleus (SCN) when applied during the day but significantly reduced both kinases when applied during the night. Morphine at night transiently induced Period1 but not Period2 in the SCN and did not attenuate the light‐induced level of pERK1/2 and c‐Fos in the SCN. The activity of all three principal opioid receptors was high during the day but decreased significantly at night, except for the δ receptor. Finally, we demonstrated daily profiles of pERK1/2 and pGSK3β levels in the rat ventrolateral and dorsomedial SCN.

Conclusions and Implications

Our data suggest that the phase‐shifting effect of opioids may be mediated via post‐translational modification of clock proteins by means of activated ERK1/2 and GSK3β.
Evaluating stakeholder's perspective on referred out genetic testing in Canada: a discrete choice experiment
Authors: Blumenschein P. , Lilley M. , Bakal J.A. , Christian S.
Published: April 2015

The expanding number and increasing utility of clinical genetic tests is creating a growing burden on the Canadian healthcare system. Administrators are faced with the challenge of determining which genetic tests should be publicly funded. A discrete choice experiment (DCE) was utilized to assess the importance stakeholders place on five attributes of a genetic test. One hundred ninety individuals completed the DCE questions. Analysis of the data revealed that medical benefit of a test had the greatest impact on a respondent's decision to select a test for funding. The detection rate of the test ranked second in importance followed by severity of the condition, aim of the test, and cost. With limited resources available for referred out molecular genetic testing within a public healthcare setting such as Canada's, funding guidelines are critical. Our findings provide further evidence for the value of a decision‐making framework and the relative importance of specific test attributes within such a framework.
The diagnostic role of 18F fluorodeoxyglucose positron emission tomography in patients with fever of unknown origin
Authors: Sioka Chrissa , Assimakopoulos Assimakis , Fotopoulos Andreas
Published: April 2015

Background

Identification of aetiology for fever of unknown origin (FUO) is challenging, due to the high rates of undiagnosed cases. The current diagnostic approach includes initially first‐line procedures such as general examination and various laboratory tests and basic imaging techniques followed by second‐line tests such as more advanced imaging techniques including 18F fluorodeoxyglucose positron emission tomography (FDG PET) and tissue biopsies. If no diagnosis is obtained, more invasive measures may be in order such as liver biopsy and exploratory laparotomy.

Materials and methods

This review article is based on the relative published material found on MEDLINE and PubMed up to August 2014. We looked for the terms ‘fever of unknown origin, FDG PET’ in combination with ‘cancer, infection and autoimmune disease’.

Results

Several clinical studies have investigated the utility of the FDG PET during the diagnostic approach of FUO. Recent evidence suggests that FDG PET has the advantage of total body imaging and may depict all common causes of FUO such as infections, noninfectious inflammatory causes and tumours because they all exhibit glucose hypermetabolism. Depiction of an abnormal lesion on FDG PET could guide clinicians to the next diagnostic procedure (another imaging method, culture, biopsy or surgery) to establish the diagnosis.

Conclusions

Emerging evidence suggests that FDG PET, when available, may provide critical diagnostic information early during evaluation of FUO.
The Ras/MAPK pathway and hepatocarcinoma: pathogenesis and therapeutic implications
Authors: Delire Bénédicte , Stärkel Peter
Published: April 2015

Background

Hepatocellular carcinoma (HCC) is still a major health problem, often diagnosed at an advanced stage. The multikinase inhibitor sorafenib is to date the sole approved systemic therapy. Several signalling pathways are implicated in tumour development and progression. Among these pathways, the Ras/MAPK pathway is activated in 50–100% of human HCCs and is correlated with a poor prognosis. The aim of this work was to review the main intracellular mechanisms leading to aberrant Ras pathway activation in HCC and the potential therapeutic implications.

Materials and methods

This review is based on the material found on PubMed up to December 2014. ‘Ras signaling, Ras dysregulation, Ras inhibition, MAPK pathway, cancer, hepatocarcinoma and liver cancer’ alone or in combination were the main terms used for online research.

Results

Multiple mechanisms lead to the deregulation of the Ras pathway in liver cancer. Ras and Raf gene mutations are rare events in human hepatocarcinogenesis in contrast to experimental models in rodents. Downregulation of several Ras/MAPK pathway inhibitors such as GAPs, RASSF proteins, DUSP1, Sprouty and Spred proteins is largely implicated in the aberrant activation of this pathway in the context of wild‐type Ras and Raf genes. Epigenetic or post‐transcriptional mechanisms lead to the downregulation of these tumour suppressor genes.

Conclusion

Ras/MAPK pathway effectors may be considered as potential therapeutic targets in the field of HCC. In particular after the arrival of sorafenib, more Ras/MAPK inhibitors have emerged and are still in preclinical or clinical investigation for HCC therapy.
Soluble triggering receptor expressed on myeloid cells‐1 is a biomarker of anti‐CCP‐positive, early rheumatoid arthritis
Authors: Molad Yair , Ofer‐Shiber Shachaf , Pokroy‐Shapira Elisheva , Oren Shirly , Shay‐Aharoni Hagit , Babai Ilan
Published: April 2015

Objectives

To assess serum soluble triggering receptor expressed on myeloid cells‐1 (sTREM‐1) levels in disease‐modifying antirheumatic drug (DMARD)‐naïve early rheumatoid arthritis (ERA), to investigate the association of sTREM‐1 levels with Disease Activity Score in 28 joints (DAS28) and seropositivity for anti‐cyclic citrullinated peptide (CCP) antibody and to determine the predictive value of sTREM‐1 with respect to clinical response to DMARD therapy.

Methods

Twenty‐two consecutive patients with DMARD‐naïve ERA were prospectively evaluated for serum sTREM‐1 by means of ELISA at diagnosis and at the following clinic visit after prednisone and/or DMARD has been administered, and related to DAS28 and serum level of anti‐CCP antibody. We compared the sTREM‐1 level to that of 31 patients with established RA as well as to 24 controls.

Results

Serum sTREM‐1 level was significantly higher in the DMARD‐naïve ERA group (2122·9 ± 388·9 ρg/mL) compared to established RA group (1478·0 ± 280·0 ρg/mL, P = 0·001) and normal control (34·4 ± 7·4 ρg/mL, P < 0·001). In the ERA group, elevated basal sTREM‐1 level correlated with higher DAS28‐CRP score (P = 0·001, HR 3·23, 95% CI 1·4–8·12), DAS28‐ESR (P = 0·04, HR 2·34 95% CI 0·1–8·12), as well as predicted higher DAS28 score at the following encounter after DMARD treatment was administered (P = 0·001, HR 3·2 95% CI 1·1–7·2). Higher serum level of sTREM‐1 correlated with higher titres of anti‐CCP antibody (P < 0·001).

Conclusions

Our results suggest that serum sTREM‐1 may provide a novel biomarker for DMARD‐naïve ERA as well as for seropositivity for anti‐CCP antibody and RA activity.
Genetic mapping of ASIC4 and contrasting phenotype to ASIC1a in modulating innate fear and anxiety
Authors: Lin Shing‐Hong , Chien Ya‐Chih , Chiang Wei‐Wei , Liu Yan‐Zhen , Lien Cheng‐Chang , Chen Chih‐Cheng
Published: April 2015

Although ASIC4 is a member of the acid‐sensing ion channel (ASIC) family, we have limited knowledge of its expression and physiological function in vivo. To trace the expression of this ion channel, we generated the ASIC4‐knockout/CreERT2‐knockin (Asic4CreERT2) mouse line. After tamoxifen induction in the Asic4CreERT2::CAG‐STOPfloxed‐Td‐tomato double transgenic mice, we mapped the expression of ASIC4 at the cellular level in the central nervous system (CNS). ASIC4 was expressed in many brain regions, including the olfactory bulb, cerebral cortex, striatum, hippocampus, amygdala, thalamus, hypothalamus, brain stem, cerebellum, spinal cord and pituitary gland. Colocalisation studies further revealed that ASIC4 was expressed mainly in three types of cells in the CNS: (i) calretinin (CR)‐positive and/or vasoactive intestine peptide (VIP)‐positive interneurons; (ii) neural/glial antigen 2 (NG2)‐positive glia, also known as oligodendrocyte precursor cells; and (iii) cerebellar granule cells. To probe the possible role of ASIC4, we hypothesised that ASIC4 could modulate the membrane expression of ASIC1a and thus ASIC1a signaling in vivo. We conducted behavioral phenotyping of Asic4CreERT2 mice by screening many of the known behavioral phenotypes found in Asic1a knockouts and found ASIC4 not involved in shock‐evoked fear learning and memory, seizure termination or psychostimulant‐induced locomotion/rewarding effects. In contrast, ASIC4 might play an important role in modulating the innate fear response to predator odor and anxious state because ASIC4‐mutant mice showed increased freezing response to 2,4,5‐trimethylthiazoline and elevated anxiety‐like behavior in both the open‐field and elevated‐plus maze. ASIC4 may modulate fear and anxiety by counteracting ASIC1a activity in the brain.
The TUDCA trial – innovative trial designs for amyotrophic lateral sclerosis drugs?
Authors: Ludolph A. C.
Published: April 2015

Click here to view the accompanying paper in this issue.
Diffusion of mepivacaine to adjacent synovial structures after intrasynovial analgesia of the digital flexor tendon sheath
Authors: Jordana M. , Martens A. , Duchateau L. , Haspeslagh M. , Vanderperren K. , Oosterlinck M. , Pille F.
Published: April 2015

Reasons for performing study

Controversy exists about the specificity of diagnostic analgesia of the digital flexor tendon sheath (DFTS) in horses.

Objectives

To evaluate the degree of diffusion of mepivacaine from the equineDFTSto adjacent synovial structures.

Study design

Crossover experiment.

Methods

Under general anaesthesia, theDFTSof one front and one hindlimb of 8 horses were injected simultaneously with mepivacaine. Synovial fluid samples of the injectedDFTS, the adjacent metacarpo‐/metatarsophalangeal (MCP/MTP) joint, proximal interphalangeal joint, distal interphalangeal joint, navicular bursa and contralateralMCP/MTPjoint were collected 15 min post injection (T15) from one of the injected limbs and 60 min post injection (T60) from the other limb. Venous blood samples were obtained at T0, T15 and T60 to evaluate systemic distribution of mepivacaine. After a 2‐week washout period, the procedure was repeated using the same limbs but reversing the time of sampling (front vs. hindlimbs). The concentration of mepivacaine in samples was measured with a commercialELISAkit.

Results

Mepivacaine concentrations in theDFTSsamples, at both T15 (5077 mg/l) and T60 (3503 mg/l), exceeded those estimated sufficient to produce synovial analgesia (100 mg/l or 300 mg/l). Mepivacaine was found in all synovial structures adjacent to the injectedDFTSand in the contralateralMCP/MTPjoints, but concentrations were low, with a maximum value of only 3.2 mg/l. With the exception of the navicular bursa samples, the mepivacaine concentrations in the adjacent synovial structures were significantly higher at T60 than at T15 (P<0.03). Significantly higher mepivacaine concentrations were found in the ipsilateral than the contralateralMCP/MTPjoints at T60 (P<0.001). Blood samples had significantly higher mepivacaine concentrations at T15 and T60 than at T0 (P<0.001).

Conclusions

Mepivacaine injected into theDFTSof horses diffuses towards adjacent synovial structures without achieving clinically relevant concentrations.
CCL7 contributes to the TNF‐alpha‐dependent inflammation of lesional psoriatic skin
Authors: Brunner Patrick M. , Glitzner Elisabeth , Reininger Baerbel , Klein Irene , Stary Georg , Mildner Michael , Uhrin Pavel , Sibilia Maria , Stingl Georg
Published: April 2015

Chemokines are small chemotactic proteins that have a crucial role in leukocyte recruitment into tissue. Targeting these mediators has been suggested as a potential therapeutic option in inflammatory skin diseases such as psoriasis. Using quantitative RT‐PCR, we found CCL7, a chemokine ligand known to interact with multiple C‐C chemokine receptors, to be markedly increased in lesional psoriasis as opposed to atopic dermatitis, lichen planus, non‐lesional psoriatic and normal control skin. Surprisingly, this increase in CCL7 mRNA expression exceeded that of all other chemokines investigated, and keratinocytes and dermal blood endothelial cells were identified as its likely cellular sources. In an imiquimod‐induced psoriasis‐like mouse model, CCL7 had a profound impact on myeloid cell inflammation as well as on the upregulation of key pro‐psoriatic cytokines such as CCL20, IL‐12p40 and IL‐17C, while its blockade led to an increase in the antipsoriatic cytokine IL‐4. In humans receiving the TNF‐α‐blocker infliximab, CCL7 was downregulated in lesional psoriatic skin already within 16 hours after a single intravenous infusion. These data suggest that CCL7 acts as a driver of TNF‐α‐dependent Th1/Th17‐mediated inflammation in lesional psoriatic skin.
Generation of Helios reporter mice and an evaluation of the suppressive capacity of Helios+ regulatory T cells in vitro
Authors: Sugita Kazunari , Hanakawa Sho , Honda Tetsuya , Kondoh Gen , Miyachi Yoshiki , Kabashima Kenji , Nomura Takashi
Published: April 2015

Helios is a member of the Ikaros transcription factor family and has been reported to be a marker of thymus‐derived regulatory T cells (Treg). Helios is an intracellular protein, however, and hence cannot be used as a marker to separate living Tregs. To solve this problem, we generated Helios reporter mice in which Helios+ cells selectively express Venus, a variant of green fluorescent protein. Most of the Tregs in the thymus expressed Helios, whereas its expression was varied in peripheral lymphoid organs. The Helios+ Treg‐population was superior in ability to suppress both antigen‐specific and TCR‐stimulated T cell responses. We also showed that Helios+ Tregs inhibited the cytokine production by T cells more efficiently than Helios‐ Tregs. We conclude that Helios reporter mouse strain is a useful tool to study function of Helios and that Helios+ Tregs represent the highly suppressive population.
Seasonal and diel changes in fish distribution in a tropical hydropower plant tailrace: evidence from hydroacoustic and gillnet sampling
Authors: Loures R. C. , Pompeu P. S.
Published: April 2015

Hydropower plant operation can lead to direct impacts on fish near the dam, causing injuries and death. In Brazil, it is more common to observe these impacts in the tailrace. To understand temporal and spatial variations in fish abundance in the tailrace, to assist plant operation management, surveys were performed in Três Marias Hydropower Plant using hydroacoustics and multimesh gillnets. Data were collected in the tailrace backwater over 1 year, during 18 field trips, each covering a 24‐h cycle with six sampling intervals. A greater abundance of fish was found in the tailrace during the wet season, mainly explained by total discharge. More fish were detected by hydroacoustics and gill nets during night sampling. Siluriformes, which are known to exhibit nocturnal habits, were the predominant species in both dry and wet seasons. Thus, damaging operational procedures for fish should be planned in the dry season, low‐abundance period.
Leaf‐trait plasticity and species vulnerability to climate change in a Mongolian steppe
Authors: Liancourt Pierre , Boldgiv Bazartseren , Song Daniel S. , Spence Laura A. , Helliker Brent R. , Petraitis Peter S. , Casper Brenda B.
Published: April 2015

Climate change is expected to modify plant assemblages in ways that will have major consequences for ecosystem functions. How climate change will affect community composition will depend on how individual species respond, which is likely related to interspecific differences in functional traits. The extraordinary plasticity of some plant traits is typically neglected in assessing how climate change will affect different species. In the Mongolian steppe, we examined whether leaf functional traits under ambient conditions and whether plasticity in these traits under altered climate could explain climate‐induced biomass responses in 12 co‐occurring plant species. We experimentally created three probable climate change scenarios and used a model selection procedure to determine the set of baseline traits or plasticity values that best explained biomass response. Under all climate change scenarios, plasticity for at least one leaf trait correlated with change in species performance, while functional leaf‐trait values in ambient conditions did not. We demonstrate that trait plasticity could play a critical role in vulnerability of species to a rapidly changing environment. Plasticity should be considered when examining how climate change will affect plant performance, species' niche spaces, and ecological processes that depend on plant community composition.