bluuebunny/crossref_metadata_2025 huggingface dataset:
Glycerophosphodiesterase GDE2 affects pancreas differentiation in zebrafish
Authors: van Veen Michiel , van Pelt Jason , Mans Laurie A. , Moolenaar Wouter H. , Haramis Anna-Pavlina G.
Published: February 2017

Notch signaling plays an essential role in the proliferation, differentiation and cell fate determination of various tissues, including the developing pancreas. One regulator of the Notch pathway is GDE2 (or GDPD5), a transmembrane ecto-phosphodiesterase that cleaves GPI-anchored proteins at the plasma membrane, including a Notch ligand regulator. Here we report that Gde2 knockdown in zebrafish embryos leads to developmental defects, particularly, impaired motility and reduced pancreas differentiation, as shown by decreased expression of insulin and other pancreatic markers. Exogenous expression of human GDE2, but not catalytically dead GDE2, similarly leads to developmental defects. These data reveal functional conservation between zebrafish and human GDE2, and suggest that strict regulation of GDE2 expression and catalytic activity is critical for correct embryonic patterning. In particular, our data uncover a role for GDE2 in regulating pancreas differentiation.
[Re] Optimization of a free water elimination two-compartment model for diffusion tensor imaging
Authors: Henriques Rafael Neto , Rokem Ariel , Garyfallidis Eleftherios , St-Jean Samuel , Peterson Eric Thomas , Correia Marta Morgado
Published: February 2017

Typical diffusion-weighted imaging (DWI) is susceptible to partial volume effects: different types of tissue that reside in the same voxel are inextricably mixed. For instance, in regions near the cerebral ventricles or parenchyma, fractional anisotropy (FA) from diffusion tensor imaging (DTI) may be underestimated, due to partial volumes of cerebral spinal fluid (CSF). Free-water can be suppressed by adding parameters to diffusion MRI models. For example, the DTI model can be extended to separately take into account the contributions of tissue and CSF, by representing the tissue compartment with an anisotropic diffusion tensor and the CSF compartment as an isotropic free water diffusion coefficient. Recently, two procedures were proposed to fit this two-compartment model to diffusion-weighted data acquired for at least two different non-zero diffusion MRI b-values. In this work, the first open-source reference implementation of these procedures is provided. In addition to presenting some methodological improvements that increase model fitting robustness, the free water DTI procedures are re-evaluated using Monte-Carlo multicompartmental simulations. Analogous to previous studies, our results show that the free water elimination DTI model is able to remove confounding effects of fast diffusion for typical FA values of brain white matter. In addition, this study confirms that for a fixed scanning time the fwDTI fitting procedures have better performance when data is acquired for diffusion gradient direction evenly distributed along two b-values of 500 and 1500 s/mm2.
Variance in Estimated Pairwise Genetic Distance Under High versus Low Coverage Sequencing: the Contribution of Linkage Disequilibrium
Authors: Shpak Max , Ni Yang , Lu Jie , Müller Peter
Published: February 2017

The mean pairwise genetic distance among haplotypes is an estimator of the population mutation rateθand a standard measure of variation in a population. With the advent of next-generation sequencing (NGS) methods, this and other population parameters can be estimated under different modes of sampling. One approach is to sequence individual genomes with high coverage, and to calculate genetic distance over all sample pairs. The second approach, typically used for microbial samples or for tumor cells, is sequencing a large number of pooled genomes with very low individual coverage. With low coverage, pairwise genetic distances are calculated across independently sampled sites rather than across individual genomes. In this study, we show that the variance in genetic distance estimates is reduced with low coverage sampling if the mean pairwise linkage disequilibrium weighted by allele frequencies is positive. Practically, this means that if on average the most frequent alleles over pairs of loci are in positive linkage disequilibrium, low coverage sequencing results in improved estimates ofθ, assuming similar per-site read depths. We show that this result holds under the expected distribution of allele frequencies and linkage disequilibria for an infinite sites model at mutation-drift equilibrium. From simulations, we find that the conditions for reduced variance only fail to hold in cases where variant alleles are few and at very low frequency. These results are applied to haplotype frequencies from a lung cancer tumor to compute the weighted linkage disequilibria and the expected error in estimated genetic distance using high versus low coverage.
Updating of aversive memories after temporal error detection is differentially modulated by mTOR across development
Authors: Tallot Lucille , Diaz-Mataix Lorenzo , Perry Rosemarie E. , Wood Kira , LeDoux Joseph E. , Mouly Anne-Marie , Sullivan Regina M. , Doyère Valérie
Published: February 2017

The updating of a memory is triggered whenever it is reactivated and a mismatch from what is expected (i.e., prediction error) is detected, a process that can be unraveled through the memory's sensitivity to protein synthesis inhibitors (i.e., reconsolidation). As noted in previous studies, in Pavlovian threat/aversive conditioning in adult rats, prediction error detection and its associated protein synthesis-dependent reconsolidation can be triggered by reactivating the memory with the conditioned stimulus (CS), but without the unconditioned stimulus (US), or by presenting a CS–US pairing with a different CS–US interval than during the initial learning. Whether similar mechanisms underlie memory updating in the young is not known. Using similar paradigms with rapamycin (an mTORC1 inhibitor), we show that preweaning rats (PN18–20) do form a long-term memory of the CS–US interval, and detect a 10-sec versus 30-sec temporal prediction error. However, the resulting updating/reconsolidation processes become adult-like after adolescence (PN30–40). Our results thus show that while temporal prediction error detection exists in preweaning rats, specific infant-type mechanisms are at play for associative learning and memory.
Recollection-dependent memory for event duration in large-scale spatial navigation
Authors: Brunec Iva K. , Ozubko Jason D. , Barense Morgan D. , Moscovitch Morris
Published: February 2017

Time and space represent two key aspects of episodic memories, forming the spatiotemporal context of events in a sequence. Little is known, however, about how temporal information, such as the duration and the order of particular events, are encoded into memory, and if it matters whether the memory representation is based on recollection or familiarity. To investigate this issue, we used a real world virtual reality navigation paradigm where periods of navigation were interspersed with pauses of different durations. Crucially, participants were able to reliably distinguish the durations of events that were subjectively “reexperienced” (i.e., recollected), but not of those that were familiar. This effect was not found in temporal order (ordinal) judgments. We also show that the active experience of the passage of time (holding down a key while waiting) moderately enhanced duration memory accuracy. Memory for event duration, therefore, appears to rely on the hippocampally supported ability to recollect or reexperience an event enabling the reinstatement of both its duration and its spatial context, to distinguish it from other events in a sequence. In contrast, ordinal memory appears to rely on familiarity and recollection to a similar extent.
Probe reconstruction for holographic X-ray imaging
Authors: Hagemann Johannes , Robisch Anna-Lena , Osterhoff Markus , Salditt Tim
Published: February 2017

In X-ray holographic near-field imaging the resolution and image quality depend sensitively on the beam. Artifacts are often encountered due to the strong focusing required to reach high resolution. Here, two schemes for reconstructing the complex-valued and extended wavefront of X-ray nano-probes, primarily in the planes relevant for imaging (i.e. focus, sample and detection plane), are presented and compared. Firstly, near-field ptychography is used, based on scanning a test pattern laterally as well as longitudinally along the optical axis. Secondly, any test pattern is dispensed of and the wavefront reconstructed only from data recorded for different longitudinal translations of the detector. For this purpose, an optimized multi-plane projection algorithm is presented, which can cope with the numerically very challenging setting of a divergent wavefront emanating from a hard X-ray nanoprobe. The results of both schemes are in very good agreement. The probe retrieval can be used as a tool for optics alignment, in particular at X-ray nanoprobe beamlines. Combining probe retrieval and object reconstruction is also shown to improve the image quality of holographic near-field imaging.
Magnetic design and modelling of a 14 mm-period prototype superconducting undulator
Authors: Mishra G. , Gehlot Mona , Sharma Geetanjali , Trillaud Frederic
Published: February 2017

The magnetic design of a ten-period (each period 14 mm) prototype superconducting undulator is reported using RADIA. The results of modelling the magnetic flux density are presented in an analytical formula. The dependence of the field integrals and phase error on the current density and undulator gap has been calculated, and temperature curves are determined for the models and are compared with earlier reported Moser–Rossmanith fits.
The phase problem for one-dimensional crystals
Authors: Millane Rick P.
Published: February 2017

The phase problem for diffraction amplitudes measured from a one-dimensional crystal is examined. In the absence of any a priori information, the solution to this problem is shown to be unique up to a parameterized, low-dimensional set of solutions. Minimal additional a priori information is expected to render the solution unique. The effects of additional information such as positivity, molecular envelope and helical symmetry on uniqueness are characterized. The results are pertinent to structural studies of polymeric and rod-like biomolecular assemblies that form one-dimensional, rather than three-dimensional, crystals. This shows the potential for ab initio phasing of diffraction data from single such assemblies measured using new X-ray free-electron laser sources. Such an approach would circumvent the complicated inversion of cylindrically averaged diffraction that is necessary in traditional X-ray fibre diffraction analysis.
Crystal structure of 5-O-benzoyl-2,3-O-isopropylidene-D-ribono-1,4-lactone
Authors: Bortoluzzi Adailton J. , Silveira Gustavo P. , Sá Marcus M.
Published: February 2017

In the title compound, C15H16O6, obtained from the acylation reaction between 2,3-O-isopropylidene-D-ribono-1,4-lactone and benzoyl chloride, the known absolute configuration for the lactone moiety of the ester substituent has been confirmed. The five-membered rings of the bicyclic lactone–dioxolane moiety both show envelope conformations and form a dihedral angle of 19.82 (7)° between the lactone ring and the benzene ring. In the crystal, molecules of the acylated sugar are linked by very weak intermolecular C—H...O interactions, forming a three-dimensional network.
1,3,5-Trichloro-2,4,6-tris(dichloromethyl)benzene
Authors: Tober Natalie , Schollmeyer Dieter , Detert Heiner
Published: February 2017

The asymmetric unit of the title compound, C9H3Cl9, contains one molecule. Two slightly different conformations with nearlyC3hsymmetry are mutually disordered in a 1:1 ratio. This disorder enhances the overall structural symmetry toD3h.
(2E,2′E)-3,3′-(1,4-Phenylene)bis[1-(4-fluorophenyl)prop-2-en-1-one]
Authors: Chidan Kumar C. S. , Quah Ching Kheng , Chandraju S. , Lokanath N. K. , Naveen S. , Abdoh Muneer
Published: February 2017

The title bis-chalcone compound, C24H16F2O2, crystallizes with one half-molecule in the asymmetric unit. The molecule lies about an inversion centre at the centroid of the central benzene ring. The olefinic double bonds adoptEconformations. In the crystal, C—H...O hydrogen bonds form sheets of molecules in theacplane and C—H...F hydrogen bonds form zigzag chains along thea-axis direction. These combine to generate a three-dimensional network of molecules stacked along thec-axis direction.
Piperazine-1,4-diium bis(3-carboxy-2,3-dihydroxypropanoate)
Authors: Asserar Fatima , Guenoun Farhate , Sekkat Chakib , Labrim Hicham , Marah Hamid , Zouihri Hafid , Yamni Khalid
Published: February 2017

The asymmetric unit of the title salt, C4H12N22+·2C4H5O6−, comprises one half of the piperazine-1,4-diium dication lying on a twofold rotation axis and one 3-carboxy-2,3-dihydroxypropanoate anion. In the crystal, the ions are linked into a three-dimensional network by N—H...O, C—H...O and O—H...O hydrogen bonds.
(4Z)-4-[1-(2-Aminoanilino)ethylidene]-3-methyl-1-phenyl-4,5-dihydro-1H-pyrazol-5-one
Authors: Samba Mohamed , Djerrari Bahia , Minnih Mohamed Said , Ramli Youssef , Essassi El Mokhtar , Mague Joel T.
Published: February 2017

The conformation of the title compound, C18H18N4O, is partly determined by an intramolecular N—H...O hydrogen bond that imposes planarity on the central aminoethylidene-3-methylpyrazol-5-one segment of the molecule. In the crystal, N—H...O hydrogen and N—H...N hydrogen bonds both form centrosymmetric dimers that encloseR22(18) rings. These, together with C—H...N and π–π stacking interactions between centrosymmetrically related pyrazalone rings, stack the molecules along theb-axis direction.
Arts entrepreneurship education in the UK and Germany
Authors: Thom Marco
Published: February 2017

Purpose

The purpose of this paper is to report on the current state of arts entrepreneurship education at higher educational institutions (HEIs) in the UK and Germany. It is based on findings from questionnaire surveys among 210 lecturers in fine art at 89 HEIs in the UK and Germany.

Design/methodology/approach

This paper explores issues related to fine art curriculum in higher education in the UK and Germany via survey questionnaires among 210 fine art lecturers with focus on arts entrepreneurship.

Findings

The study shows evidence that an arts entrepreneurship education, although considered by lecturers to be important and necessary for the professional and entrepreneurial preparation of fine art graduates, is definitely not implemented at HEIs, in neither the UK nor Germany.

Practical implications

The findings stimulate the discussion in the field of arts entrepreneurship and the redesigning of fine art curriculum to prepare fine art graduates for their entrepreneurial and professional careers.

Originality/value

There is still a marked paucity of research that focusses on arts entrepreneurship education. This study contributes to the knowledge by presenting specific findings related to fine art curriculum.
Forms of graduate capital and their relationship to graduate employability
Authors: Tomlinson Michael
Published: February 2017

Purpose

In the context of far-reaching changes in higher education and the labour market, there has been extensive discussion on what constitutes graduate employability and what shapes graduates’ labour market outcomes. Many of these discussions are based on skills-centred approaches and related supply-side logic. The purpose of this paper is to develop an alternative, relational conceptualisation of employability based on the concept of capitals. It discusses how this provides a more detailed and multi-dimensional account of the resources graduates draw upon when transitioning to the labour market.

Design/methodology/approach

The paper presents a new model on graduate employability, linked to five areas of capital which are seen as constitutive of graduates’ employability and significant to their transitions to the labour market. The paper draws together existing conceptual approaches and research studies to illustrate the different features of the model and how they relate to graduate employability. It also discusses some practical implications for those helping to facilitate graduates’ transitions to the job market.

Findings

The paper argues that the graduate capital model presents a new way of understanding graduate employability which addresses the challenges of facilitating graduates’ transitions and early career management. The forms of capital outlined are conceived as key resources that confer benefits and advantages onto individuals. These resources encompass a range of human, social, cultural, identity and psycho-social dimensions and are acquired through graduates’ formal and informal experiences.

Research limitations/implications

Whilst this is a conceptual model, it has potentially strong implications for future research in this area in terms of further research exploration on the core components and their application in the labour market.

Practical implications

This re-conceptualization of graduate employability has significant implication for graduates’ career management and strategising in developing resources for enhancing their transitions to and progression within the labour market. It also has implications for career educators in developing practical employability strategies that can be used within institutional settings.

Social implications

The paper raises salient implications for the effective and equitable management of graduate outcomes post-graduation which has clear relevance for all stakeholders in graduate employability, including students/graduates, career educators and employers.

Originality/value

The paper develops a new model for conceptualising graduate employability and illustrates and applies this to discussion of graduate employability. It also raises practical applications around the different components of the model.
Verticillium dahliae manipulates plant immunity by glycoside hydrolase 12 proteins in conjunction with carbohydrate‐binding module 1
Authors: Gui Yue‐Jing , Chen Jie‐Yin , Zhang Dan‐Dan , Li Nan‐Yang , Li Ting‐Gang , Zhang Wen‐Qi , Wang Xin‐Yan , Short Dylan P. G. , Li Lei , Guo Wei , Kong Zhi‐Qiang , Bao Yu‐Ming , Subbarao Krishna V. , Dai Xiao‐Feng
Published: February 2017

Glycoside hydrolase 12 (GH12) proteins act as virulence factors and pathogen‐associated molecular patterns (PAMPs) in oomycetes. However, the pathogenic mechanisms of fungal GH12 proteins have not been characterized. In this study, we demonstrated that two of the six GH12 proteins produced by the fungus Verticillium dahliae Vd991, VdEG1 and VdEG3 acted as PAMPs to trigger cell death and PAMP‐triggered immunity (PTI) independent of their enzymatic activity in Nicotiana benthamiana. A 63‐amino‐acid peptide of VdEG3 was sufficient for cell death‐inducing activity, but this was not the case for the corresponding peptide of VdEG1. Further study indicated that VdEG1 and VdEG3 trigger PTI in different ways: BAK1 is required for VdEG1‐ and VdEG3‐triggered immunity, while SOBIR1 is specifically required for VdEG1‐triggered immunity in N. benthamiana. Unlike oomycetes, which employ RXLR effectors to suppress host immunity, a carbohydrate‐binding module family 1 (CBM1) protein domain suppressed GH12 protein‐induced cell death. Furthermore, during infection of N. benthamiana and cotton, VdEG1 and VdEG3 acted as PAMPs and virulence factors, respectively indicative of host‐dependent molecular functions. These results suggest that VdEG1 and VdEG3 associate differently with BAK1 and SOBIR1 receptor‐like kinases to trigger immunity in N. benthamiana, and together with CBM1‐containing proteins manipulate plant immunity.
The direct and moderating effect of learning orientation on individual performance in the banking industry in China: contextualization of high‐performance work systems
Authors: Ning Nan , Wang Jue , Lin Zhaohong , Zheng Zhiyu
Published: February 2017

Extant research on learning orientation (LO) has primarily examined the effects of LO on organizational‐level performance from a management perspective. Meanwhile, the black box relationship between high‐performance work systems (HPWS) and individual outcomes has not been fully explored. The current study examines the cross‐level relationship between perceived unit‐level LO and individual‐level performance and investigates the moderation effect of LO in the HPWS – individual performance relationship. With a participant sample of 1887 individuals from 74 work‐units in the banking industry in China, a cross‐level model was tested using hierarchical linear modeling. Work‐unit‐level LO was found to have significant impact on individual performance and positively moderate the relationship between HPWS and individual performance. The implications of these findings and the research limitations were also discussed.
Association between leukocyte telomere length and angiogenic cytokines in knee osteoarthritis
Authors: Poonpet Thitiya , Saetan Natthaphon , Tanavalee Aree , Wilairatana Vajara , Yuktanandana Pongsak , Honsawek Sittisak
Published: February 2017

Aim

The aims of this study were to compare leukocyte relative telomere length (RTL) in knee osteoarthritis (OA) patients and healthy controls and to investigate associations between plasma angiogenic cytokine concentrations and leukocyte RTL.

Method

Eighty knee OA patients and 60 age‐matched controls were enrolled. Leukocyte RTL was assessed using real‐time quantitative polymerase chain reaction (qPCR). Angiogenic cytokines were measured by a multiplex immunoassay.

Results

Leukocyte RTL in knee OA patients was significantly lower than that in healthy controls (1.1 ± 0.4 vs. 1.3 ± 0.6, P = 0.039). Plasma angiopoietin‐2, follistatin, granulocyte‐colony stimulating factor (G‐CSF), hepatocyte growth factor (HGF), interleukin‐8 (IL‐8), platelet endothelial cell adhesion molecule‐1 (PECAM‐1), and vascular endothelial growth factor (VEGF) levels in knee OA patients were higher than those in controls (P < 0.01). Correlation analysis revealed significant negative correlations between leukocyte RTL and plasma levels of HGF (r = −0.377, P = 0.017), VEGF (r = −0.405, P = 0.009) and G‐CSF (r = −0.347, P = 0.026). In contrast, plasma angiopoietin‐2, follistatin, IL‐8, leptin, platelet‐derived growth factor‐BB and PECAM‐1 were not correlated with leukocyte RTL.

Conclusion

Telomere length was shortened in knee OA patients compared to healthy controls. Plasma HGF, VEGF and G‐CSF were negatively correlated with leukocyte RTL, suggesting involvement of telomere shortening and these cytokines in knee OA.
A multiparametric magnetic resonance imaging‐based risk model to determine the risk of significant prostate cancer prior to biopsy
Authors: van Leeuwen Pim J. , Hayen Andrew , Thompson James E. , Moses Daniel , Shnier Ron , Böhm Maret , Abuodha Magdaline , Haynes Anne‐Maree , Ting Francis , Barentsz Jelle , Roobol Monique , Vass Justin , Rasiah Krishan , Delprado Warick , Stricker Phillip D.
Published: February 2017

Objective

To develop and externally validate a predictive model for detection of significant prostate cancer.

Patients and Methods

Development of the model was based on a prospective cohort including 393 men who underwent multiparametric magnetic resonance imaging (mpMRI) before biopsy. External validity of the model was then examined retrospectively in 198 men from a separate institution whom underwent mpMRI followed by biopsy for abnormal prostate‐specific antigen (PSA) level or digital rectal examination (DRE). A model was developed with age, PSA level, DRE, prostate volume, previous biopsy, and Prostate Imaging Reporting and Data System (PIRADS) score, as predictors for significant prostate cancer (Gleason 7 with >5% grade 4, ≥20% cores positive or ≥7 mm of cancer in any core). Probability was studied via logistic regression. Discriminatory performance was quantified by concordance statistics and internally validated with bootstrap resampling.

Results

In all, 393 men had complete data and 149 (37.9%) had significant prostate cancer. While the variable model had good accuracy in predicting significant prostate cancer, area under the curve (AUC) of 0.80, the advanced model (incorporating mpMRI) had a significantly higher AUC of 0.88 (P < 0.001). The model was well calibrated in internal and external validation. Decision analysis showed that use of the advanced model in practice would improve biopsy outcome predictions. Clinical application of the model would reduce 28% of biopsies, whilst missing 2.6% significant prostate cancer.

Conclusions

Individualised risk assessment of significant prostate cancer using a predictive model that incorporates mpMRI PIRADS score and clinical data allows a considerable reduction in unnecessary biopsies and reduction of the risk of over‐detection of insignificant prostate cancer at the cost of a very small increase in the number of significant cancers missed.
Computer‐aided drug design to explore cyclodextrin therapeutics and biomedical applications
Authors: Abdolmaleki Azizeh , Ghasemi Fatemeh , Ghasemi Jahan B.
Published: February 2017

Cyclodextrin (CD) is a subset of the macrocyclic structural class, which is an important class of small organic agents that are useful functional excipients. They have wide range application possibilities in different fields of sciences such as material preparation, medicine, analytical chemistry, and separation processes. They are used widely in pharmaceutical formulations and drug delivery for increasing the water solubility of low soluble drugs and drug candidates. Due to the ring structure, they behave differently than smaller molecules and may be capable of hitting new classes of targets. A macrocyclic molecule presents varied functionality and stereochemical complexity in a pre‐organized conformation of the ring structure. This can result in high selectivity and affinity for protein targets while conserving enough bioavailability to arrive at intracellular locations. Regardless of these valuable features, and the verified success of several marketed macrocycle drugs isolated from natural compounds, this class has been little explored in drug development. This study describes some of the key features of the CDs therapeutic discovery. Also, the application of computational chemistry approaches such as QSAR/QSPR, molecular docking, and molecular/quantum mechanics for modeling of CD–drug system is reviewed briefly.
Novel heterogeneous photocatalysts prepared with waste wool and Fe3+ or Cu2+ ions for degradation of CI Reactive Red 195: a comparative study
Authors: Cui Guixin , Dong Yongchun , Li Yingchao , Shen Weifeng , Chen Zhenlei
Published: February 2017

In order to reuse waste wool, two transition metal ions, Fe3+ and Cu2+, were coordinated to with it to prepare a series of metal–wool complexes as new heterogeneous Fenton photocatalysts for the degradation of a typical azo dye, CI Reactive Red 195, in aqueous solution. The effect of the initial metal ion concentration and temperature on the reaction was investigated. Furthermore, the catalytic performance of the resulting metal–wool complexes was evaluated with respect to the dye decoloration efficiency at different pH levels under visible irradiation. The results demonstrated that increasing the initial metal ion concentration and temperature enhanced ion coordination to produce complexes of increased metal content. The obtained Fe–wool showed a higher metal content than the Cu–wool. The light adsorption performance in the UV and visible regions of Cu–Fe–wool is stronger than that of Fe–wool or Cu–wool. Furthermore, Cu–Fe–Wool was found to have a higher catalytic activity than the other two complexes under visible irradiation, especially in the alkaline pH range.
Opposite effects of a glucokinase activator and metformin on glucose‐regulated gene expression in hepatocytes
Authors: Al‐Oanzi Ziad H. , Fountana Sophia , Moonira Tabassum , Tudhope Susan J. , Petrie John L. , Alshawi Ahmed , Patman Gillian , Arden Catherine , Reeves Helen L. , Agius Loranne
Published: February 2017

Aim

Small molecule activators of glucokinase (GKAs) have been explored extensively as potential anti‐hyperglycaemic drugs for type 2 diabetes (T2D). Several GKAs were remarkably effective in lowering blood glucose during early therapy but then lost their glycaemic efficacy chronically during clinical trials.

Materials and Methods

We used rat hepatocytes to test the hypothesis that GKAs raise hepatocyte glucose 6‐phosphate (G6P, the glucokinase product) and down‐stream metabolites with consequent repression of the liver glucokinase gene (
Gck). We compared a GKA with metformin, the most widely prescribed drug for T2D.

Results

Treatment of hepatocytes with 25 mM glucose raised cell G6P, concomitantly with Gck repression and induction of G6pc (glucose 6‐phosphatase) and Pklr (pyruvate kinase). A GKA mimicked high glucose by raising G6P and fructose‐2,6‐bisphosphate, a regulatory metabolite, causing a left‐shift in glucose responsiveness on gene regulation. Fructose, like the GKA, repressed Gck but modestly induced G6pc. 2‐Deoxyglucose, which is phosphorylated by glucokinase but not further metabolized caused Gck repression but not G6pc induction, implicating the glucokinase product in Gck repression. Metformin counteracted the effect of high glucose on the elevated G6P and fructose 2,6‐bisphosphate and on Gck repression, recruitment of Mlx‐ChREBP to the G6pc and Pklr promoters and induction of these genes.

Conclusions

Elevation in hepatocyte G6P and downstream metabolites, with consequent liver
Gck repression, is a potential contributing mechanism to the loss of GKA efficacy during chronic therapy. Cell metformin loads within the therapeutic range attenuate the effect of high glucose on G6P and on glucose‐regulated gene expression.
Potential trajectories of old‐growth Neotropical forest functional composition under climate change
Authors: Chain‐Guadarrama Adina , Imbach Pablo , Vilchez‐Mendoza Sergio , Vierling Lee A. , Finegan Bryan
Published: February 2017

Quantifying relationships between plant functional traits and abiotic gradients is valuable for evaluating potential responses of forest communities to climate change. However, the trajectories of change expected to occur in tropical forest functional characteristics as a function of future climate variation are largely unknown. We modeled community level trait values of Costa Rican rain forests as a function of current and future climate, and quantified potential changes in functional composition. We calculated per‐plot community weighted mean (CWM) trait values for leaf area (LA), specific leaf area (SLA), leaf dry matter content (LDMC), leaf nitrogen (N) and phosphorus (P) content, and wood basic specific gravity (WSG), for tree and palm species in 127 0.25 ha plots. We modeled the response of CWM traits to current temperature and precipitation gradients using generalized additive modeling. We then predicted and mapped CWM traits values under current and future climate, and quantified potential changes under a global warming scenario (RCP8.5, year 2050). We calculated the area within the multi trait functional space occupied by forest plots under both current and future climate, and determined potential changes in functional space occupied by forest plots. Overall, precipitation predicted CWM traits better than temperature. Models indicated increases in CWM SLA, N and P, and a decrease in CWM LDMC under climate change. Lowland forest communities converged on a single direction of change towards more acquisitive CWM trait values, indicating a change in forest functional composition resulting from a changed climate. Functional space occupied by forest plots was reduced by 50% under the future climate. Functional composition changes may have further effects on forests ecosystem services. Assessing functional trait spatial‐gradients can help bridge the gap between species‐based biogeography and biogeochemical approaches to strengthen biodiversity and ecosystem services conservation efforts.
From salmon to shad: Shifting sources of marine‐derived nutrients in the Columbia River Basin
Authors: Haskell Craig A.
Published: February 2017

Like Pacific salmon (Oncorhynchus spp.), nonnative American shad (Alosa sapidissima) have the potential to convey large quantities of nutrients between the Pacific Ocean and freshwater spawning areas in the Columbia River Basin (CRB). American shad are now the most numerous anadromous fish in the CRB, yet the magnitude of the resulting nutrient flux owing to the shift from salmon to shad is unknown. Nutrient flux models revealed that American shad conveyed over 15,000 kg of nitrogen (N) and 3,000 kg of phosphorus (P) annually to John Day Reservoir, the largest mainstem reservoir in the lower Columbia River. Shad were net importers of N, with juveniles and postspawners exporting just 31% of the N imported by adults. Shad were usually net importers of P, with juveniles and postspawners exporting 46% of the P imported by adults on average. American shad contributed <0.2% of the total annual P load into John Day Reservoir, but during June when most adult shad are migrating into John Day Reservoir, they contributed as much as 2.0% of the P load. Nutrient inputs by American shad were similar to current but far less than historical inputs of Pacific salmon owing to their smaller size. Given the relatively high background P levels and low retention times in lower Columbia River reservoirs, it is unlikely that shad marine‐derived nutrients affect nutrient balances or food web productivity through autotrophic pathways. However, a better understanding of shad spawning aggregations in the CRB is needed.
Natural history and clinical characteristics of inhibitors in previously treated haemophilia A patients: a case series
Authors: Iorio A. , Barbara A. M. , Makris M. , Fischer K. , Castaman G. , Catarino C. , Gilman E. , Kavakli K. , Lambert T. , Lassila R. , Lissitchkov T. , Mauser‐Bunschoten E. , Mingot‐Castellano M. E. , Ozdemir N. , Pabinger I. , Parra R. , Pasi J. , Peerlinck K. , Rauch A. , Roussel‐Robert V. , Serban M. , Tagliaferri A. , Windyga J. , Zanon E.
Published: February 2017

Background

Development of inhibitors is the most serious complication in haemophilia A treatment. The assessment of risk for inhibitor formation in new or modified factor concentrates is traditionally performed in previously treated patients (PTPs). However, evidence on risk factors for and natural history of inhibitors has been generated mostly in previously untreated patients (PUPs). The purpose of this study was to examine cases of de novo inhibitors in PTPs reported in the scientific literature and to the EUropean HAemophilia Safety Surveillance (EUHASS) programme, and explore determinants and course of inhibitor development.

Methods

We used a case series study design and developed a case report form to collect patient level data; including detection, inhibitor course, treatment, factor VIII products used and events that may trigger inhibitor development (surgery, vaccination, immune disorders, malignancy, product switch).

Results

We identified 19 publications that reported 38 inhibitor cases and 45 cases from 31 EUHASS centres. Individual patient data were collected for 55/83 (66%) inhibitor cases out of 12 330 patients. The median (range) peak inhibitor titre was 4.4 (0.5–135.0), the proportion of transient inhibitors was 33% and only two cases of 12 undergoing immune tolerance induction failed this treatment. In the two months before inhibitor development, surgery was reported in nine (22%) cases, and high intensity treatment periods reported in seven (17%) cases.

Conclusions

By studying the largest cohort of inhibitor development in PTPs assembled to date, we showed that inhibitor development in PTPs, is on average, a milder event than in PUPs.
Can the diagnostic reliability of the thrombin generation test as a global haemostasis assay be improved? The impact of calcium chloride concentration
Authors: Parunov L. A. , Surov S. S. , Liang Y. , Lee T. K. , Ovanesov M. V.
Published: February 2017

Background

Thrombin generation test (TGT) is a global haemostasis assay with a potential to predict bleeding tendencies and treatment effects in patients with haemophilia. Despite 15 years of clinical research, the diagnostic value of TGT remains controversial, possibly due to suboptimal sensitivity to coagulation deficiencies, robustness and reproducibility.

Objective

The goal of this study was to explore the effect of calcium chloride (CaCl2) concentration on the TGT's response to intrinsic coagulation factors (F) VIII, IX and XIa.

Methods

Normal and factor‐deficient plasmas supplemented with lacking coagulation factor and different CaCl2 levels were tested by calibrated thrombinography assay.

Results

Thrombin peak height (TPH) was strongly CaCl2 dependent, increasing sharply from no TG at 5 mm to a peak at 13.8 mm of CaCl2 (95% confidence interval [CI]: 13.0, 14.5) in normal and normalized deficient plasmas and at 11.9 mm (CI: 9.7, 14.2) in deficient plasmas, and then decreasing slowly to a complete inhibition at 30–40 mm. In contrast, TG lag time, time to peak and endogenous thrombin potential were nearly insensitive to CaCl2 concentrations between 10 and 20 mm. The maximal difference between the TPH in deficient and supplemented plasmas was observed at 15.5 mm (CI: 12.8, 18.1).

Conclusion

Variations in CaCl2 concentration in the assay mixture and sodium citrate concentrations in patient plasma samples may affect TGT responses, sensitivity and result in increased inter‐ and intra‐laboratory variance. Implementation of TGT by clinical and quality control laboratories may require optimization of CaCl2 concentration.
Prominent subcutaneous oedema as a masquerading symptom of an underlying inflammatory myopathy
Authors: Anantharajah Anthea , Vucic Steve , Tarafdar Surjit , Vongsuvanh Roslyn , Wilcken Nicholas , Swaminathan Sanjay
Published: February 2017

The inflammatory myopathies are a group of immune‐mediated inflammatory muscle disorders that typically present with marked proximal muscle weakness. We report four cases of inflammatory myopathies with marked subcutaneous oedema as their main complaint. Three of the four patients had normal or low levels of creatine kinase, an enzyme often markedly elevated in these disorders. Magnetic resonance imaging of the muscles, followed by a muscle biopsy were used to make a definitive diagnosis.
Antigenic cross‐reactivity between Schistosoma mansoni and peanut: a role for cross‐reactive carbohydrate determinants (CCDs) and implications for the hygiene hypothesis
Authors: Igetei Joseph E. , El‐Faham Marwa , Liddell Susan , Doenhoff Michael J.
Published: February 2017

The antigenic reactivity of constituents of Schistosoma mansoni and peanut (Arachis hypogaea) was investigated to determine whether identical antigenic epitopes possessed by both organisms provided a possible explanation for the negative correlation between chronic schistosome infection and atopy to allergens. Aqueous extracts of peanuts were probed in Western immunoblots with rabbit IgG antibodies raised against the egg, cercarial and adult worm stages of S. mansoni. Several molecules in the peanut extract were antigenically reactive with antibodies from the various rabbit anti‐schistosome sera. A pair of cross‐reactive peanut molecules at ~30 000–33 000 molecular weight was purified and both proteins were identified by mass spectrometric analysis as the peanut allergen Ara h 1. Anti‐S. mansoni soluble egg antigen antibodies that were eluted off the peanut molecules reacted with two S. mansoni egg antigens identified by mass spectrometry as IPSE/α‐1 and κ‐5. Alignments of the amino acid sequences of Ara h 1 and either IPSE/α‐1 or κ‐5 revealed a low level of peptide sequence identity. Incubation of nitrocellulose paper carrying electrophoresed peanut molecules, six constituents of other allergic plants and S. mansoni egg antigens in a mild solution of sodium metaperiodate before probing with antibodies, inhibited most of the cross‐reactivities. The results are consistent with the antigenic cross‐reactive epitopes of S. mansoni egg antigens, peanut and other allergic plants being cross‐reactive carbohydrate determinants (CCDs). These findings are novel and an explanation based on ‘blocking antibodies’ could provide an insight for the inverse relationship observed between schistosome infection and allergies.
Structural and functional changes to lymph nodes in ageing mice
Authors: Turner Vivian M. , Mabbott Neil A.
Published: February 2017

Lymph nodes (LN) are secondary lymphoid organs spread throughout the lymphatic system. They function to filter pathogenic material from the lymphatic fluid to maintain the health of the organism. Subcapsular sinus macrophages (SCSM) are among the first‐responders within the LN due to their strategic location within the subcapsular sinus region. These macrophages aid the delivery of immune complexes to B cells and follicular dendritic cells (FDC) within the LN. Here we show an increase in SCSM and other macrophage populations within aged LN. However, immune complex uptake by macrophages within LN was not altered with age, nor was immune complex uptake by B cells. LN stromal cell populations, important in immune responses and the localization and survival of leucocytes, were altered in their representation and distribution in aged LN. In particular, FDC regions were decreased in size and had decreased chemokine CXCL13 expression. Furthermore, the retention of immune complexes by FDC was decreased in aged LN at 24 hr post‐injection. As FDC are important in the maintenance of germinal centre responses, the decreased retention of immune complex in aged LN may contribute to the reduced germinal centre responses observed in aged mice.
Novel multiplex assay platforms to detect influenza A hemagglutinin subtype‐specific antibody responses for high‐throughput and in‐field applications
Authors: Li Zhu‐Nan , Trost Jessica F. , Weber Kimberly M. , LeMasters Elizabeth H. , Nasreen Sharifa , Esfandiari Javan , Gunasekera Angelo H. , McCausland Megan , Sturm‐Ramirez Katharine , Wrammert Jens , Gregory Sean , Veguilla Vic , Stevens James , Miller Joseph D. , Katz Jacqueline M. , Levine Min Z.
Published: February 2017

Background

Detections of influenza A subtype‐specific antibody responses are often complicated by the presence of cross‐reactive antibodies. We developed two novel multiplex platforms for antibody detection. The multiplexed magnetic fluorescence microsphere immunoassay (MAGPIX) is a high‐throughput laboratory‐based assay. Chembio Dual Path Platform (DPP) is a portable and rapid test that could be used in the field.

Methods

Twelve recombinant globular head domain hemagglutinin (GH HA1) antigens from A(H1N1)pdm09 (pH1N1), A(H2N2), A(H3N2), A(H5N1), A(H7N9), A(H9N2), A(H13N9), B/Victoria lineage, B/Yamagata lineage viruses, and protein A control were used. Human sera from U.S. residents either vaccinated (with H5N1 or pH1N1) or infected with pH1N1 influenza viruses and sera from live bird market workers in Bangladesh (BDPW) were evaluated. GH HA1 antigens and serum adsorption using full ectodomain recombinant hemagglutinins from A(pH1N1) and A(H3N2) were introduced into the platforms to reduce cross‐reactivity.

Results

Serum adsorption reduced cross‐reactivity to novel subtype HAs. Compared to traditional hemagglutination inhibition or microneutralization assays, when serum adsorption and the highest fold rise in signals were used to determine positivity, the correct subtype‐specific responses were identified in 86%‐100% of U.S. residents exposed to influenza antigens through vaccination or infection (N=49). For detection of H5N1‐specific antibodies in sera collected from BDPW, H5 sensitivity was 100% (six of six) for MAGPIX, 83% (five of six) for DPP, H5 specificity was 100% (15/15), and cross‐reactivity against other subtype was 0% (zero of six) for both platforms.

Conclusion

MAGPIX and DPP platforms can be utilized for high‐throughput and in‐field detection of novel influenza virus infections.
Supporting existential care with protected mealtimes: patients' experiences of a mealtime intervention in a neurological ward
Authors: Beck Malene , Birkelund Regner , Poulsen Ingrid , Martinsen Bente
Published: February 2017

Aim

The aim of this study was to explore the experiences of patients who were admitted to the neurological ward during an intervention – inspired by Protected Mealtime – that changed the traditional mealtime practice.

Background

Mealtimes are busy events in hospitals and patients are often interrupted by high‐priority tasks (e.g. taking blood samples) while eating. Protected mealtimes is a British concept that changes the organizational structure of mealtimes and provides a focus on the mealtime by ceasing all non‐acute activities while patients are eating.

Design

Influenced by protected mealtimes and based on the British Medical Research Council (MRC) guidelines, a clinical intervention called Quiet Please was developed, modified and tested in a department of neurology in November 2014.

Methods

To evaluate the Quiet Please intervention, 13 semi‐structured interviews were conducted with patients who were admitted to the neurological ward. The interviews were recorded and transcribed. These data were thoroughly analysed and interpreted with inspiration from the French philosopher, Paul Ricouer.

Findings

Three themes were identified from the analysis and interpretation: (1) being powered by the bell; (2) being embraced by calmness and aesthetics and (3) being in a trust‐bearing agreement.

Conclusions

Patients experienced mealtimes as meaningful events that nourished them in an existential manner because the calming and aesthetically pleasing environment made them feel embraced and allowed them to reflect on the day for a while. The mealtime change, influenced by protected mealtimes, made the patients feel recognized as humans and established positive mealtime experiences that were considered professional and trust bearing.
Parental psychopathology and expectations for the futures of children with autism spectrum disorder
Authors: Thomas Paul Andrew , King Jake S , Mendelson Jenna L , Nelson‐Gray Rosemery O
Published: February 2017

Background

The influence of parental psychopathology and parental expectations on child well‐being is well documented among typically developing populations. However, to date little research has examined the relationship among these factors in families of children with autism spectrum disorder (ASD). This study examines an observed relationship between parental psychopathology and expectations in families with children with ASD in the light of research in other populations.

Method

Twenty‐four parents of children diagnosed with ASD were assessed for symptoms of psychopathology. Parents completed measures of child ASD severity as well as their expectations for possible outcomes of their child.

Results

Two main effects were found: higher parental psychopathology and ASD severity were both related to lower expectations. Interaction of ASD severity and parental psychopathology in relation to parent expectations was not observed.

Conclusion

These results emphasize the necessity of providing services not only to individuals diagnosed with ASD, but to caregivers as well.