bluuebunny/crossref_metadata_2025 huggingface dataset:
Cation Diffusion Facilitator family: Structure and function
Authors: Kolaj-Robin Olga , Russell David , Hayes Kevin A. , Pembroke J. Tony , Soulimane Tewfik
Published: April 2015

The Cation Diffusion Facilitators (CDFs) form a family of membrane‐bound proteins capable of transporting zinc and other heavy metal ions. Involved in metal tolerance/resistance by efflux of ions, CDF proteins share a two‐modular architecture consisting of a transmembrane domain (TMD) and C‐terminal domain (CTD) that protrudes into the cytoplasm. Discovery of a Zn2+ and Cd2+ CDF transporter from a marine bacterium Maricaulis maris that does not possess the CTD questions current perceptions regarding this family of proteins. This article describes a new, CTD‐lacking subfamily of CDFs and our current knowledge about this family of proteins in the view of these findings.
Baicalin promotes embryo adhesion and implantation by upregulating fucosyltransferase IV (FUT4) via Wnt/beta‐catenin signaling pathway
Authors: Zhang Yu-Mei , Zhang Yuan-Yuan , Bulbul Ahmmed , Shan Xiu , Wang Xiao-Qi , Yan Qiu
Published: April 2015

Glycosylation plays a significant role in determining the receptivity of the uterine endometrium to embryo. Fucosyltransferase IV (FUT4) is expressed stage‐specifically in the uterine endometrium of mammalians, and considered as a marker of the endometrial receptivity. Baicalin, a monomer of flavonoids, is known to have functions in improving reproduction. However, the mechanism by which baicalin regulates the expression of FUT4 in embryo‐endometrium adhesion remains unclear. Our results showed that baicalin significantly increased FUT4 mRNA and protein expression levels both in human endometrial cells and mouse endometrial tissue, and consistently elevated embryo adhesion rate during implantation in vitro and embryonic implantation competence in pregnant mouse. This study suggests that baicalin facilitates endometrial reproduction via elevating FUT4 expression through Wnt/β‐catenin signaling pathway.
Advanced microscopy methods for visualizing chromatin structure
Authors: Lakadamyali Melike , Cosma Maria Pia
Published: April 2015

In the recent years it has become clear that our genome is not randomly organized and its architecture is tightly linked to its function. While genomic studies have given much insight into genome organization, they mostly rely on averaging over large populations of cells, are not compatible with living cells and have limited resolution. For studying genome organization in single living cells, microscopy is indispensable. In addition, the visualization of biological structures helps to understand their function. Up to now, fluorescence microscopy has allowed us to probe the larger scale organization of chromosome territories in the micron length scales, however, the smaller length scales remained invisible due to the diffraction limited spatial resolution of fluorescence microscopy. Thanks to the advent of super‐resolution microscopy methods, we are finally starting to be able to probe the nanoscale organization of chromatin in vivo and these methods have the potential to greatly advance our knowledge about chromatin structure and function relationship.
A single amino acid of a Salmonella virulence protein contributes to pathogenicity by protecting from the FtsH‐mediated proteolysis
Authors: Choi Eunna , Kwon Kyoung , Lee Eun-Jin
Published: April 2015

FtsH is a membrane‐bound ATP‐dependent protease in bacteria that is critical for degrading membrane proteins. The MgtC virulence protein from Salmonella enterica is located at the inner membrane and required for survival inside macrophages. Here we report that a single substitution at tryptophan 226 of the MgtC protein to alanine promotes the FtsH‐mediated proteolysis. The Trp residue is located at the very C‐terminus of the cytoplasmic domain of the MgtC protein and conserved only in intracellular pathogens surviving within a macrophage phagosome, suggesting that Salmonella may acquire the tryptophan residue to prevent MgtC degradation by the FtsH protease. Moreover, the reduced proteolytic activity of the FtsH protease during infection further increases MgtC production, promoting Salmonella's pathogenicity inside phagocytic cells.
Immunoglobulin isotype isolated from human placental extract does not interfere in complement‐mediated bacterial opsonization within the wound milieu
Authors: Sharma Kanika , Bhattacharyya Debasish
Published: April 2015

The wound healing potency of an aqueous extract of placenta can be evaluated through the presence of numerous regulatory components. The presence of glycans was detected by thin layer chromatography and fluorophore‐assisted carbohydrate electrophoresis. Mass spectrometric analysis revealed the existence of multiple fragments of immunoglobulin G (IgG). IgG was present in the extract at a concentration of 25.2 ± 3.97 μg/ml. IgG possesses anti‐complementary activity by diverting the complement activation from target surface. Thus, effect of placental IgG on complement–bacteria interaction was investigated through classical and alternative pathway and the preparation was ascertained to be safe with respect to their interference in the process of bacterial opsonization.
Fertility after ectopic pregnancy in a district hospital in Cameroon
Authors: Kenfack Bruno , Nguefack‐Tsague Georges , Ateudjeu Jerôme , Che Gilbert A. , Mboudou Emile T.
Published: April 2015

Objective

To assess spontaneous conception after an ectopic pregnancy (EP) in a rural area of a low‐resource country.

Methods

The present prospective cohort study enrolled patients aged 15–45 years who were treated for EP at Sangmelima District Hospital, Cameroon, between January 2006 and December 2008. All patients who wished to become pregnant in the future were included and followed up from treatment for EP either until termination of a subsequent pregnancy or for 3 years if they did not become pregnant, whichever came first. Patients who were followed up for less than 18 months without a pregnancy were excluded from analysis.

Results

The final analysis included 56 women, of whom 23 (41%) became pregnant (21 [38%] had intrauterine pregnancies, 2 [4%] EPs). The mean interval between treatment for EP and first conception was 11.82 ± 7.46 months. In multivariate analysis, absence of contralateral adnexal pathology was significantly associated with higher fertility (hazard ratio 9.00, 95% confidence interval 1.48–54.67; P = 0.017).

Conclusion

Fertility after EP in a rural area of Cameroon was found to be low, but recurrence of EP was rare.
Cluster dynamics models of irradiation damage accumulation in ferritic iron. II. Effects of reaction dimensionality
Authors: Kohnert Aaron A. , Wirth Brian D.
Published: April 2015

The black dot damage features which develop in iron at low temperatures exhibit significant mobility during in situ irradiation experiments via a series of discrete, intermittent, long range hops. By incorporating this mobility into cluster dynamics models, the temperature dependence of such damage structures can be explained with a surprising degree of accuracy. Such motion, however, is one dimensional in nature. This aspect of the physics has not been fully considered in prior models. This article describes one dimensional reaction kinetics in the context of cluster dynamics and applies them to the black dot problem. This allows both a more detailed description of the mechanisms by which defects execute irradiation-induced hops while allowing a full examination of the importance of kinetic assumptions in accurately assessing the development of this irradiation microstructure. Results are presented to demonstrate whether one dimensional diffusion alters the dependence of the defect population on factors such as temperature and defect hop length. Finally, the size of interstitial loops that develop is shown to depend on the extent of the reaction volumes between interstitial clusters, as well as the dimensionality of these interactions.
Can siting algorithms assist in prioritizing for conservation in a densely populated and land use allocated country? – Israel as a case study
Authors: Weil Gilad , Levin Noam
Published: April 2015

Over the years, Israel's centralized national planning framework and the intense competition on the limited available land played a crucial factor in designing the spatial distribution of the protected areas in Israel. When examining the spatial properties of the protected areas, it was found that they do not adequately represent the variety of the ecosystems in Israel. According to the systematic conservation planning approach, we aimed to examine how optimization algorithms (e.g., MARXAN) would inform us on high priority areas for conservation. We created proxies for anthropogenic disturbance, and for the susceptibility of designating new protected areas subject to existing national and regional land use master plans. Our conservation targets were defined on the basis of the spatial distribution of 461 endangered vertebrate and plant species (red species), as well as by defining and mapping 21 main ecosystems. The results highlight the limited options of significantly improving the representativeness provided by the existing protected areas, due to the diminishing availability of open areas, which may be available to be designated as protected areas. However, the results also emphasize the conservation potential of agricultural land, as well as the need for preserving small and fragmented rare habitats.
Increasing the efficiency and yield of a tuberculosis contact investigation through electronic data systems matching
Authors: Sanderson Jennifer M , Proops Douglas C , Trieu Lisa , Santos Eloisa , Polsky Bruce , Ahuja Shama Desai
Published: April 2015

Background Electronic health data may improve the timeliness and accuracy of resource-intense contact investigations (CIs) in healthcare settings.

Methods In September 2013, we initiated a CI around a healthcare worker (HCW) with infectious tuberculosis (TB) who worked in a maternity ward. Two sources of electronic health data were employed: hospital-based electronic medical records (EMRs), to identify patients exposed to the HCW, and an electronic immunization registry, to obtain contact information for exposed infants and their providers at two points during follow-up.

Results Among 954 patients cared for in the maternity ward during the HCW’s infectious period, the review of EMRs identified 285 patients (30%) who interacted with the HCW and were, thus, exposed to TB. Matching infants to the immunization registry offered new provider information for 52% and 30% of the infants in the first and second matches. Providers reported evaluation results for the majority of patients (66%).

Conclusion Data matching improved the efficiency and yield of this CI, thereby demonstrating the usefulness of enhancing CIs with electronic health data.
Supporting health insurance expansion: do electronic health records have valid insurance verification and enrollment data?
Authors: Heintzman John , Marino Miguel , Hoopes Megan , Bailey Steffani R , Gold Rachel , O’Malley Jean , Angier Heather , Nelson Christine , Cottrell Erika , Devoe Jennifer
Published: April 2015

Objective To validate electronic health record (EHR) insurance information for low-income pediatric patients at Oregon community health centers (CHCs), compared to reimbursement data and Medicaid coverage data.

Materials and Methods Subjects Children visiting any of 96 CHCs (N = 69 189) from 2011 to 2012. Analysis The authors measured correspondence (whether or not the visit was covered by Medicaid) between EHR coverage data and (i) reimbursement data and (ii) coverage data from Medicaid.

Results Compared to reimbursement data and Medicaid coverage data, EHR coverage data had high agreement (87% and 95%, respectively), sensitivity (0.97 and 0.96), positive predictive value (0.88 and 0.98), but lower kappa statistics (0.32 and 0.49), specificity (0.27 and 0.60), and negative predictive value (0.66 and 0.45). These varied among clinics.

Discussion/Conclusions EHR coverage data for children had a high overall correspondence with Medicaid data and reimbursement data, suggesting that in some systems EHR data could be utilized to promote insurance stability in their patients. Future work should attempt to replicate these analyses in other settings.
Lethal Anaphylactic Reaction to Intravenous Gelatin in the Course of Surgery
Authors: Ventura Spagnolo Elvira , Calapai Gioacchino , Minciullo Paola L. , Mannucci Carmen , Asmundo Alessio , Gangemi Sebastiano
Published: April 2015

Plasma volume expanders (PVEs) are widely used to increase circulating blood volume. Gelatins used as PVEs are heterogeneous mixtures of polypeptides, usually prepared by hydrolysis of bovine collagen containing large amounts of proline and hydroxyproline residues. It has been shown that gelatins can cause anaphylactic reactions. We describe the case of a 73-year-old man who during surgery for intestinal obstruction presented a lethal anaphylactic reaction after the administration of a PVE containing gelatin lysate. The reaction occurred 10 minutes after the start of plasma expander infusion. Then, patient became comatose, and he died without awakening after 76 days. Necroptic aspects and histologic evaluation suggested the occurrence of anaphylactic reaction. According to pharmacovigilance algorithm, the causality relationship between PVE administration and adverse reaction has been considered as probable. We described a new lethal adverse reaction caused by PVEs containing gelatin. It is currently considered a very rare event, but we believe that it represents an important signal suggesting for a critical surveillance comprising a complete evaluation of individual's allergic susceptibility.
Procedural Timeout Compliance Is Improved With Real-Time Clinical Decision Support
Authors: Shear Torin , Deshur Mark , Avram Michael J. , Greenberg Steven B. , Murphy Glenn S. , Ujiki Michael , Szokol Joseph W. , Vender Jeffery S. , Patel Aashka , Wijas Bryan
Published: April 2015

Purpose

The goal of this study was to assess compliance with a presurgical safety checklist before and after the institution of a surgical flight board displaying a surgical safety checklist with embedded real-time clinical decision support (CDS). We hypothesized that the institution of a surgical flight board with embedded real-time data support would improve compliance with the presurgical safety checklist.

Methods

In this prospective, observational trial, surgeon-led procedural timeout compliance for 300 procedures was studied. In phase I (PI), procedural timeouts were performed using a simple paper checklist. In phase II (PII), an electronic surgical flight board with an embedded safety checklist was installed in each operating room, but the timeout procedure consisted of the same paper process as in PI. In phase III (PIII), the flight board safety checklist was used. Ten procedures each from 10 surgeons were evaluated in each phase. Compliance was scored on a 12-point scale with each point representing a different item on the checklist.

Results

Timeout compliance in PI ranged from 4.5 to 8.6 and 8.75 to 12 in PIII. All 10 surgeons demonstrated statistically improved compliance from PI to PIII. Compliance was significantly improved in 8 of 12 safety check items. Decreased compliance was not seen with any checklist item. Of the items with CDS, compliance with procedure consent and special safety precautions improved from PI to PIII, as did compliance with display of essential imaging, critical events or concerns, and number of procedures (i.e., >1 surgeon performing procedures).

Conclusions

Using the electronic medical record with real-time CDS improves compliance with presurgical safety checklists.
Chlamydia psittaci comparative genomics reveals intraspecies variations in the putative outer membrane and type III secretion system genes
Authors: Wolff Bernard J. , Morrison Shatavia S. , Pesti Denise , Ganakammal Satishkumar Ranganathan , Srinivasamoorthy Ganesh , Changayil Shankar , Weil M. Ryan , MacCannell Duncan , Rowe Lori , Frace Michael , Ritchie Branson W. , Dean Deborah , Winchell Jonas M.
Published: April 2015

Chlamydia psittaci is an obligate intracellular bacterium that can cause significant disease among a broad range of hosts. In humans, this organism may cause psittacosis, a respiratory disease that can spread to involve multiple organs, and in rare untreated cases may be fatal. There are ten known genotypes based on sequencing the major outer-membrane protein gene, ompA, of C. psittaci. Each genotype has overlapping host preferences and virulence characteristics. Recent studies have compared C. psittaci among other members of the Chlamydiaceae family and showed that this species frequently switches hosts and has undergone multiple genomic rearrangements. In this study, we sequenced five genomes of C. psittaci strains representing four genotypes, A, B, D and E. Due to the known association of the type III secretion system (T3SS) and polymorphic outer-membrane proteins (Pmps) with host tropism and virulence potential, we performed a comparative analysis of these elements among these five strains along with a representative genome from each of the remaining six genotypes previously sequenced. We found significant genetic variation in the Pmps and tbl3SS genes that may partially explain differences noted in C. psittaci host infection and disease.
Low levels of transposable element activity inDrosophila mauritiana: causes and consequences
Authors: Kofler Robert , Schlötterer Christian
Published: April 2015

Transposable elements (TEs) are major drivers of genomic and phenotypic evolution, yet many questions about their biology remain poorly understood. Here, we compare TE abundance between populations of the two sister speciesD. mauritianaundD. simulansand relate it to the more distantly relatedD. melanogaster. The low population frequency of most TE insertions inD. melanogasterandD. simulanshas been a key feature of several models of TE evolution. InD. mauritiana, however, the majority of TE insertions are fixed (66%). We attribute this to a lower transposition activity of up to 47 TE families inD. mauritiana, rather than stronger purifying selection. Only three families, including the extensively studiedMariner,may have a higher activity inD. mauritiana. This remarkable difference in TE activity between two recently divergedDrosophilaspecies (≈ 250,000 years), also supports the hypothesis that TE copy numbers inDrosophilamay not reflect a stable equilibrium where the rate of TE gains equals the rate of TE losses by negative selection. We propose that the transposition rate heterogeneity results from the contrasting ecology of the two species: the extent of vertical extinction of TE families and horizontal acquisition of active TE copies may be very different between the colonizingD. simulansand the island endemicD. mauritiana. Our findings provide novel insights in the evolution of TEs inDrosophilaand suggest that the ecology of the host species could be a major, yet underappreciated, factor governing the evolutionary dynamics of TEs.
Loss of TET2 in hematopoietic cells leads to DNA hypermethylation of active enhancers and induction of leukemogenesis
Authors: Rasmussen Kasper D. , Jia Guangshuai , Johansen Jens V. , Pedersen Marianne T. , Rapin Nicolas , Bagger Frederik O. , Porse Bo T. , Bernard Olivier A. , Christensen Jesper , Helin Kristian
Published: April 2015

DNA methylation is tightly regulated throughout mammalian development, and altered DNA methylation patterns are a general hallmark of cancer. The methylcytosine dioxygenase TET2 is frequently mutated in hematological disorders, including acute myeloid leukemia (AML), and has been suggested to protect CG dinucleotide (CpG) islands and promoters from aberrant DNA methylation. In this study, we present a novel Tet2-dependent leukemia mouse model that closely recapitulates gene expression profiles and hallmarks of human AML1-ETO-induced AML. Using this model, we show that the primary effect of Tet2 loss in preleukemic hematopoietic cells is progressive and widespread DNA hypermethylation affecting up to 25% of active enhancer elements. In contrast, CpG island and promoter methylation does not change in a Tet2-dependent manner but increases relative to population doublings. We confirmed this specific enhancer hypermethylation phenotype in human AML patients with TET2 mutations. Analysis of immediate gene expression changes reveals rapid deregulation of a large number of genes implicated in tumorigenesis, including many down-regulated tumor suppressor genes. Hence, we propose that TET2 prevents leukemic transformation by protecting enhancers from aberrant DNA methylation and that it is the combined silencing of several tumor suppressor genes in TET2 mutated hematopoietic cells that contributes to increased stem cell proliferation and leukemogenesis.
The clustering of functionally related genes contributes to CNV-mediated disease
Authors: Andrews Tallulah , Honti Frantisek , Pfundt Rolph , de Leeuw Nicole , Hehir-Kwa Jayne , Vulto-van Silfhout Anneke , de Vries Bert , Webber Caleb
Published: April 2015

Clusters of functionally related genes can be disrupted by a single copy number variant (CNV). We demonstrate that the simultaneous disruption of multiple functionally related genes is a frequent and significant characteristic of de novo CNVs in patients with developmental disorders (P = 1 × 10−3). Using three different functional networks, we identified unexpectedly large numbers of functionally related genes within de novo CNVs from two large independent cohorts of individuals with developmental disorders. The presence of multiple functionally related genes was a significant predictor of a CNV's pathogenicity when compared to CNVs from apparently healthy individuals and a better predictor than the presence of known disease or haploinsufficient genes for larger CNVs. The functionally related genes found in the de novo CNVs belonged to 70% of all clusters of functionally related genes found across the genome. De novo CNVs were more likely to affect functional clusters and affect them to a greater extent than benign CNVs (P = 6 × 10−4). Furthermore, such clusters of functionally related genes are phenotypically informative: Different patients possessing CNVs that affect the same cluster of functionally related genes exhibit more similar phenotypes than expected (P < 0.05). The spanning of multiple functionally similar genes by single CNVs contributes substantially to how these variants exert their pathogenic effects.
A Secreted Effector Protein ofUstilago maydisGuides Maize Leaf Cells to Form Tumors
Authors: Redkar Amey , Hoser Rafal , Schilling Lena , Zechmann Bernd , Krzymowska Magdalena , Walbot Virginia , Doehlemann Gunther
Published: April 2015

The biotrophic smut fungus Ustilago maydis infects all aerial organs of maize (Zea mays) and induces tumors in the plant tissues. U. maydis deploys many effector proteins to manipulate its host. Previously, deletion analysis demonstrated that several effectors have important functions in inducing tumor expansion specifically in maize leaves. Here, we present the functional characterization of the effector See1 (Seedling efficient effector1). See1 is required for the reactivation of plant DNA synthesis, which is crucial for tumor progression in leaf cells. By contrast, See1 does not affect tumor formation in immature tassel floral tissues, where maize cell proliferation occurs independent of fungal infection. See1 interacts with a maize homolog of SGT1 (Suppressor of G2 allele of skp1), a factor acting in cell cycle progression in yeast (Saccharomyces cerevisiae) and an important component of plant and human innate immunity. See1 interferes with the MAPK-triggered phosphorylation of maize SGT1 at a monocot-specific phosphorylation site. We propose that See1 interferes with SGT1 activity, resulting in both modulation of immune responses and reactivation of DNA synthesis in leaf cells. This identifies See1 as a fungal effector that directly and specifically contributes to the formation of leaf tumors in maize.
Land abandonment and intensification diminish spatial and temporal β‐diversity of grassland plants and herbivorous insects within paddy terraces
Authors: Uchida Kei , Ushimaru Atushi
Published: April 2015

Although traditional land‐use and management practices are known to enhance environmental heterogeneity in agricultural lands, loss of heterogeneity resulting from recent land‐use changes can lead to spatiotemporal β‐diversity losses (biotic homogenization). However, patterns and causes of β‐diversity loss, especially at a within‐field scale, have remained unexplored.

We examined β‐diversity declines in plants, butterflies and orthopterans resulting from land abandonment and intensification in semi‐natural grasslands on paddy margins at a within‐field scale in relation to changes in disturbance frequency and surrounding landscapes by surveying eight abandoned, thirteen traditional and ten intensive paddy terraces. Three indices, the additive partitioning of species richness (βadd) and the turnover (βtu) and nestedness (βne) components of Jaccard dissimilarity of plants and herbivores, were used to evaluate different aspects of β‐diversity. We hypothesized that biotic homogenization due to abandonment and intensification would be expressed as low spatiotemporal βadd and βtu, low spatial βne and high temporal βne.

The spatial and temporal βadd of plants and herbivores were higher in traditional terraces than in others. Changes in mowing frequency caused direct declines in butterfly βadd and indirectly decreased herbivore βadd through diminished plant βadd in abandoned and intensified terraces.

Neighbouring forests increased plant spatial and butterfly temporal βadd and βtu. Abandoned terraces had higher orthopteran spatial and plant temporal βtu than traditional terraces. Mowing frequency generally did not influence spatial and temporal βtu of plants and herbivores. In intensive terraces, temporal βne of plants were higher than in traditional terraces, suggesting dominance by plant species sharing similar phenologies.

Synthesis and applications. These results suggest that traditional mowing practices are essential for maintaining plant and herbivore βadd, and consequently, species pools within terraces. The higher spatial or temporal species turnover of plants and orthopterans in abandoned terraces and higher temporal plant nestedness in intensive than in traditional terraces were not due to increases in species pools within terraces. Because within‐terrace environmental heterogeneity is thought to remain in abandoned and intensive terraces, we recommend reduction in mowing frequency in intensive terraces and reintroduction of mowing in abandoned terraces for biodiversity restoration.
Scale‐dependent responses of longleaf pine vegetation to fire frequency and environmental context across two decades
Authors: Palmquist Kyle A. , Peet Robert K. , Mitchell Stephen R.
Published: April 2015

Disturbance is an important driver of plant community structure in many grasslands and woodlands, and alteration of disturbance regimes can have large consequences for species richness and composition. However, the response of vegetation to disturbance may change with environmental context. We resampled a unique, nested permanent vegetation plot data set in the longleaf pine ecosystem of the southeastern USA after 20 years to determine how environmental context and fire frequency jointly influence vegetation change across multiple spatial scales (0.01–1000 m2).

The magnitude of vegetation change was quantified using two different, yet complementary metrics of beta‐diversity (beta turnover measured as the proportion of species turning over and Bray–Curtis dissimilarity) and by documenting changes in species richness. We used null model analysis to explore whether communities were more dynamic over time at small spatial scales relative to larger scales.

Changes in species richness, beta turnover and Bray–Curtis dissimilarity were greatest on silty, frequently burned sites, whereas sandy, less frequently burned sites remained relatively stable. The amount of change detected was scale dependent: species richness increased at larger spatial scales over time, but decreased at the two smallest spatial scales. Null model analysis revealed that beta turnover standardized effect sizes (SES) were negative and significantly different from random expectation at all spatial scales except the smallest. Thus, the magnitude of compositional change across most scales was small, despite substantial changes in species richness across time. We attribute this initial contradiction to the turnover of infrequent, low‐abundance species amidst a matrix of dominant grasses.

Synthesis. In contrast to previous longleaf pine studies, we found fire frequency to be less important than environmental site conditions in predicting vegetation change. Thus, future work in this ecosystem and in other fire‐dependent grasslands and woodlands should consider not only disturbance, but also environmental context. Since species richness and beta‐diversity patterns were scale dependent, we recommend sampling vegetation across multiple spatial scales in order to comprehensively quantify changes in community structure over time. We believe this study lays the groundwork for understanding how fire and environmental filtering jointly influence vegetation dynamics across space and time in fire‐dependent grasslands and woodlands.
Scotland's Future Political System
Authors: Cairney Paul
Published: April 2015

Debates on Scottish constitutional reform go hand in hand with discussions of political reform. Its reformers use the image of ‘old Westminster’ to describe ‘control freakery’ within government and an adversarial political system. Many thought that the Scottish political system could diverge from the UK, to strengthen the parliamentary system, introduce consensus politics and further Scotland's alleged social and democratic tradition. Yet the experience of devolution suggests that Holyrood and Westminster politics share key features. Both systems are driven by government, making policy in ‘communities’ involving interest groups and governing bodies, with parliaments performing a limited role and public participation limited largely to elections. The Scottish government's style of policy‐making is distinctive, but new reforms are in their infancy and their effects have not been examined in depth. In this context, the article identifies Scotland's ability to make and implement policy in a new way, based on its current trajectory rather than the hopes of reformers.
Eptifibatide in Post‐infarction Angina Patients who refused Intervention: Ajmer Postmyocardial Infarction Angina Eptifibatide Research (AJMER) Study: A Pilot Study
Authors: Gokhroo Rajendra , Kishor Kamal , Ranwa Bhanwar , Bisht Devendra Singh , Gupta Sajal , Anantharaj Avinash
Published: April 2015

Background

Early intervention is certainly a preferred strategy over conservative management in patients with post‐infarction angina (PIA). But at times, it may not be feasible to intervene, especially if patient refuses for intervention. In a pilot study, we analyzed whether the addition of eptifibatide to intensified antianginal therapy would be of added benefit, in patients with PIA not willing to undergo intervention.

Methods

A total of 461 patients with PIA who refused intervention were randomized in a 1:1 manner to receive either eptifibatide along with intensification of antianginal therapy (group A; n = 229) or intensified antianginal therapy alone (group B; n = 232). The primary endpoints were composite of all‐cause death and nonfatal myocardial infarction at 30 days.

Results

Primary composite endpoint did not differ between the two groups (16.2% vs. 18.9% in group A and group B, odds ratio [OR], 0.82; 95% CI, 0.5–1.30; P‐value = 0.43). Significant earlier relief of angina (complete relief of angina within 12 h: 76% of patients in group A vs. 40.5% in group B; P‐value <0.0001) was achieved in group A compared to group B. Although on Bleeding Academic Research Consortium (BARC) scale, type 1 and 2 bleeding was higher in group A (OR, 3.18; 95% CI, 1.76–5.74; P‐value = 0.0001), the more serious (composite of type 3 and 5) bleeds did not show any difference (OR, 1.73; 95% CI, 0.7–4.08; P‐value = 0.21).

Conclusion

In patients with PIA who refused intervention, eptifibatide infusion resulted in earlier relief of angina albeit at the cost of increased non–life‐threatening bleeding. Further, this effect was achieved in significantly higher number of patients receiving eptifibatide infusion when compared to patients not receiving it. Primary composite endpoints, however, did not differ in two groups, but being a pilot study, this needs to be confirmed by larger study of adequate sample size.
No silver bullets in correlative ecological niche modelling: insights from testing among many potential algorithms for niche estimation
Authors: Qiao Huijie , Soberón Jorge , Peterson Andrew Townsend
Published: April 2015

The field of ecological niche modelling or species distribution modelling has seen enormous activity and attention in recent years, in the light of exciting biological inferences that can be drawn from correlational models of species' environmental requirements (i.e. ecological niches) and inferences of potential geographic distributions. Among the many methods used in the field, one or two are in practice assumed to be ‘best’ and are used commonly, often without explicit testing.

We explore herein implications of the ‘no free lunch’ theorem, which suggests that no single optimization approach will prove to be best under all circumstances: we developed diverse virtual species with known niche and dispersal properties to test a suite of niche modelling algorithms designed to estimate potential areas of distribution.

The result was that (i) indeed, no single ‘best’ algorithm was found and (ii) different algorithms performing very different manners depending on the particularities of the virtual species.

The conclusion is that niche or distribution modelling studies should begin by testing a suite of algorithms for predictive ability under the particular circumstances of the study and choose an algorithm for a particular challenge based on the results of those tests. Studies that do not take this step may use algorithms that are not optimal for that particular challenge.
Light therapy and serotonin transporter binding in the anterior cingulate and prefrontal cortex
Authors: Harrison S. J. , Tyrer A. E. , Levitan R. D. , Xu X. , Houle S. , Wilson A. A. , Nobrega J. N. , Rusjan P. M. , Meyer J. H.
Published: April 2015

Objective

To investigate the effects of light therapy on serotonin transporter binding (5‐HTT BPND), an index of 5‐HTT levels, in the anterior cingulate and prefrontal cortices (ACC and PFC) of healthy individuals during the fall and winter. Twenty‐five per cent of healthy individuals experience seasonal mood changes that affect functioning. 5‐HTT BPND has been found to be higher across multiple brain regions in the fall and winter relative to spring and summer, and elevated 5‐HTT BPND may lead to extracellular serotonin loss and low mood. We hypothesized that, during the fall and winter, light therapy would reduce 5‐HTT BPND in the ACC and PFC, which sample brain regions involved in mood regulation.

Method

In a single‐blind, placebo‐controlled, counterbalanced, crossover design, [11C]DASB positron emission tomography was used measure 5‐HTT BPND following light therapy and placebo conditions during fall and winter.

Results

In winter, light therapy significantly decreased 5‐HTT BPND by 12% in the ACC relative to placebo (F1,9 = 18.04, P = 0.002). In the fall, no significant change in 5‐HTT BPND was found in any region across conditions.

Conclusion

These results identify, for the first time, a central biomarker associated with the intervention of light therapy in humans which may be applied to further develop this treatment for prevention of seasonal depression.
Paediatric Off‐Label Use of Melatonin – A Register Linkage Study between the Norwegian Prescription Database and Patient Register
Authors: Hartz Ingeborg , Handal Marte , Tverdal Aage , Skurtveit Svetlana
Published: April 2015

The aims were, for the entire Norwegian population aged 4–17 years, to study the prevalence of melatonin use during 2004–2012, recurrent use in incident users and psychiatric and neurological morbidity in recurrent users. Data on dispensed melatonin were retrieved from the Norwegian Prescription Database and linked to diagnostic data from the Norwegian Patient Register. Outcome measures were the following: 1‐year prevalence of use, proportion of recurrent use (use over three consecutive 365‐day periods among incident users in 2009) and annual number of milligrams and number of prescriptions dispensed in recurrent users. The prevalence of registered ICD‐10 diagnoses during the period of 2008–2012 was given for the recurrent users. The prevalence of melatonin use increased annually in both genders during 2004–2012 (boys: 3.4–11.0 per 1000; girls: 1.5–7.7 per 1000). Twenty‐nine per cent of boys and 23% of girls were recurrent melatonin users, with highest level of recurrent use among the youngest (aged 4–8 years; boys: 47%, girls: 42%). In the third year, the median annual amount of melatonin dispensed was 1080 (IQR 586–1800) milligrams in boys and 900 (IQR 402–1620) milligrams in girls. Among recurrent users, 91% had a diagnosis of either psychiatric (84%) or neurological (32%) disorder. Off‐label recurrent use of melatonin seems to have acquired a role mainly in treating secondary sleep problems in children and adolescents with psychiatric and neurological disorders. Once melatonin has been started, a large proportion of patients continue for at least 3 years, in doses corresponding to daily use in the majority.
Celastrol induces proteasomal degradation of FANCD2 to sensitize lung cancer cells to DNA crosslinking agents
Authors: Wang Gui‐Zhen , Liu Yong‐Qiang , Cheng Xin , Zhou Guang‐Biao
Published: April 2015

The Fanconi anemia (FA) pathway plays a key role in interstrand crosslink (ICL) repair and maintenance of the genomic stability, while inhibition of this pathway may sensitize cancer cells to DNA ICL agents and ionizing radiation (IR). The active FA core complex acts as an E3 ligase to monoubiquitinate FANCD2, which is a functional readout of an activated FA pathway. In the present study, we aimed to identify FANCD2‐targeting agents, and found that the natural compound celastrol induced degradation of FANCD2 through the ubiquitin–proteasome pathway. We demonstrated that celastrol downregulated the basal and DNA damaging agent‐induced monoubiquitination of FANCD2, followed by proteolytic degradation of the substrate. Furthermore, celastrol treatment abrogated the G2 checkpoint induced by IR, and enhanced the ICL agent‐induced DNA damage and inhibitory effects on lung cancer cells through depletion of FANCD2. These results indicate that celastrol is a FANCD2 inhibitor that could interfere with the monoubiquitination and protein stability of FANCD2, providing a novel opportunity to develop FA pathway inhibitor and combinational therapy for malignant neoplasms.
Nucleus accumbens associated 1 is recruited within the promyelocytic leukemia nuclear body through SUMO modification
Authors: Tatemichi Yoshinori , Shibazaki Masahiko , Yasuhira Shinji , Kasai Shuya , Tada Hiroshi , Oikawa Hiroki , Suzuki Yuji , Takikawa Yasuhiro , Masuda Tomoyuki , Maesawa Chihaya
Published: April 2015

Nucleus accumbens associated 1 (NACC1) is a cancer‐associated BTB/POZ (pox virus and zinc finger/bric‐a‐brac tramtrack broad complex) gene, and is involved in several cellular functions in neurons, cancer and stem cells. Some of the BTB/POZ proteins associated with cancer biology are SUMOylated, which appears to play an important role in transcription regulation. We show that NACC1 is SUMOylated on a phylogenetically conserved lysine (K167) out of three consensus SUMOylation motif sites. Amino acid substitution in the SIM sequence (SIM/M) within the BTB/POZ domain partially reduced K167 SUMOylation activity of NACC1. Overexpression of GFP‐NACC1 fusion protein leads to formation of discrete nuclear foci similar to promyelocytic leukemia nuclear bodies (PML‐NB), which colocalized with SUMO paralogues (SUMO1/2/3). Both NACC1 nuclear body formation and colocalization with SUMO paralogues were completely suppressed in the GFP‐NACC1‐SIM/M mutant, whereas they were partially maintained in the NACC1 K167R mutant. Confocal immunofluorescence analysis showed that endogenous and exogenous NACC1 proteins colocalized with endogenous PML protein. A pull‐down assay revealed that the consensus motifs of the SUMO acceptor site at K167 and the SIM within the BTB/POZ domain were both necessary for efficient binding to PML protein. Our study demonstrates that NACC1 can be modified by SUMO paralogues, and cooperates with PML protein.
Time to take notice: what about fatigue?
Authors: Bjornson Kristie
Published: April 2015

This commentary is on the original article by Maher et al. on pages 742–747 of this issue.
A cost‐effectiveness analysis of real‐world treatment for elderly patients with multiple myeloma using a full disease model
Authors: Blommestein Hedwig M. , Verelst Silvia G. R. , de Groot Saskia , Huijgens Peter C. , Sonneveld Pieter , Uyl‐de Groot Carin A.
Published: April 2015

Objectives

To study the impact of novel treatments for elderly (≥66 yr) patients with multiple myeloma (MM) in daily practice by comparing real‐world effects [overall survival (OS) and quality‐adjusted life years (QALYs)] and costs over time. Also, we calculate cost‐effectiveness of treatment sequences commonly prescribed to predict effects and costs if patients had received a different treatment sequence.

Methods

Real‐world data including patient and disease characteristics, treatment information and resource use were collected from 1054 elderly patients with MM. Patients received first‐line treatment during 2004–2007 (cohort 1) and 2008–2013 (cohort 2). The two cohorts were compared using a patient‐level simulation (PLS) model comprising regression models which used patient and disease characteristics to estimate time to next treatment and death. Effects and costs from cohort 2 were compared to 4 commonly prescribed real‐world sequences.

Results

Utilisation of novel agents was higher for cohort 2 compared to cohort 1. Modelled average OS for cohort 1 was 38 months (median 25) and total costs €44 200. OS for cohort 2 was 42 months (median 28) and total costs €69 017. The model identified potential OS gains if all patients were to be treated using combinations containing thalidomide, lenalidomide and bortezomib in that particular order. This sequence had, compared to real‐world treatment, the most favourable incremental cost‐effectiveness ratio, €24 618 per life year gained and €34 875 per QALY.

Conclusions

Our patient‐level model enabled to study the effects and costs of entire treatment sequences and to compare real‐world treatment patterns over time. Increased utilisation of novel agents improved survival and increased costs for real‐world patients with MM in the Netherlands.
Differentiating neural systems mediating the acquisition vs. expression of goal‐directed and habitual behavioral control
Authors: Liljeholm Mimi , Dunne Simon , O'Doherty John P.
Published: April 2015

Considerable behavioral data indicate that operant actions can become habitual, as demonstrated by insensitivity to changes in the action–outcome contingency and in subjective outcome values. Notably, although several studies have investigated the neural substrates of habits, none has clearly differentiated the areas of the human brain that support habit formation from those that implement habitual control. We scanned participants with functional magnetic resonance imaging as they learned and performed an operant task in which the conditional structure of the environment encouraged either goal‐directed encoding of the consequences of actions, or a habit‐like mapping of actions to antecedent cues. Participants were also scanned during a subsequent assessment of insensitivity to outcome devaluation. We identified dissociable roles of the cerebellum and ventral striatum, across learning and test performance, in behavioral insensitivity to outcome devaluation. We also showed that the inferior parietal lobule (an area previously implicated in several aspects of goal‐directed action selection, including the attribution of intent and awareness of agency) predicted sensitivity to outcome devaluation. Finally, we revealed a potential functional homology between the human subgenual cortex and rodent infralimbic cortex in the implementation of habitual control. In summary, our findings suggested a broad systems division, at the cortical and subcortical levels, between brain areas mediating the encoding and expression of action–outcome and stimulus–response associations.
The effect of acute unilateral inflammation of the equine temporomandibular joint on the kinematics of mastication
Authors: Smyth T. T. , Carmalt J. L. , Treen T. T. , Lanovaz J. L.
Published: April 2015

Reasons for performing study

Diseases of the temporomandibular joint (TMJ) are well reported in man and some domestic animals other than the horse. The pathophysiology of equine TMJ disease and the effects of disease on the kinematics of mastication are unknown.

Objectives

To determine whether transient unilateral inflammation of the equine TMJ results in alterations in the masticatory cycle.

Study design

An experimental controlled study utilising 6 horses of various ages with normal dentition.

Methods

Each horse was equipped with an optical motion tracking (kinematic) system. Horses were observed chewing grass hay over 3 min intervals. Regardless of the initial side of the power stroke in the masticatory cycle, lipopolysaccharide (LPS) was injected in the left TMJ in each horse and the horses were reassessed after 6 h.

Results

Four horses developed effusion of the injected TMJs; 2 of these also began quidding. All horses injected on the original side of the power stroke switched sides while the 2 injected on the contralateral side did not. All horses developed reduced vertical pitch (vertical opening) of the mandible. Overall, rostrocaudal movement of the mandible did not change; however, the timing of this movement relative to the phase of the masticatory cycle did. Injection with LPS did not affect the amount of lateral movement of the mandible.

Conclusions

Injection of LPS into the TMJ significantly altered the masticatory cycle compared with baseline values representing avoidance behaviour due to inflammation of the joint, despite which the horses continued to eat using the contralateral mandible. Lipopolysaccharide administration also led to quidding and a loss of feed efficiency (in some individuals).