bluuebunny/crossref_metadata_2025 huggingface dataset:
Reduced dimensional Gaussian process emulators of parametrized partial differential equations based on Isomap
Authors: Xing Wei , Shah Akeel A. , Nair Prasanth B.
Published: December 2014

In this paper, Isomap and kernel Isomap are used to dramatically reduce the dimensionality of the output space to efficiently construct a Gaussian process emulator of parametrized partial differential equations. The output space consists of spatial or spatio-temporal fields that are functions of multiple input variables. For such problems, standard multi-output Gaussian process emulation strategies are computationally impractical and/or make restrictive assumptions regarding the correlation structure. The method we develop can be applied without modification to any problem involving vector-valued targets and vector-valued inputs. It also extends a method based on linear dimensionality reduction to response surfaces that cannot be described accurately by a linear subspace of the high dimensional output space. Comparisons to the linear method are made through examples that clearly demonstrate the advantages of nonlinear dimensionality reduction.
Genomic evidence for rod monochromacy in sloths and armadillos suggests early subterranean history for Xenarthra
Authors: Emerling Christopher A. , Springer Mark S.
Published: December 2014

Rod monochromacy is a rare condition in vertebrates characterized by the absence of cone photoreceptor cells. The resulting phenotype is colourblindness and low acuity vision in dim-light and blindness in bright-light conditions. Early reports of xenarthrans (armadillos, sloths and anteaters) suggest that they are rod monochromats, but this has not been tested with genomic data. We searched the genomes ofDasypus novemcinctus(nine-banded armadillo),Choloepus hoffmanni(Hoffmann's two-toed sloth) andMylodon darwinii(extinct ground sloth) for retinal photoreceptor genes and examined them for inactivating mutations. We performed PCR and Sanger sequencing on cone phototransduction genes of 10 additional xenarthrans to test for shared inactivating mutations and estimated the timing of inactivation for photoreceptor pseudogenes. We concluded that a stem xenarthran became an long-wavelength sensitive-cone monochromat following a missense mutation at a critical residue inSWS1, and a stem cingulate (armadillos, glyptodonts and pampatheres) and stem pilosan (sloths and anteaters) independently acquired rod monochromacy early in their evolutionary history following the inactivation ofLWSandPDE6C, respectively. We hypothesize that rod monochromacy in armadillos and pilosans evolved as an adaptation to a subterranean habitat in the early history of Xenarthra. The presence of rod monochromacy has major implications for understanding xenarthran behavioural ecology and evolution.
Antibacterial toxin colicin N and phage protein G3p compete with TolB for a binding site on TolA
Authors: Ridley Helen , Lakey Jeremy H.
Published: December 2014

Most colicins kill Escherichia coli cells by membrane pore formation or nuclease activity and, superficially, the mechanisms are similar: receptor binding, translocon recruitment, periplasmic receptor binding and membrane insertion. However, in detail, they employ a wide variety of molecular interactions that reveal a high degree of evolutionary diversification. Group A colicins bind to members of the TolQRAB complex in the periplasm and heterotrimeric complexes of colicin–TolA–TolB have been observed for both ColA and ColE9. ColN, the smallest and simplest pore-forming colicin, binds only to TolA and we show here that it uses the binding site normally used by TolB, effectively preventing formation of the larger complex used by other colicins. ColN binding to TolA was by β-strand addition with a K
D of 1 µM compared with 40 µM for the TolA–TolB interaction. The β-strand addition and ColN activity could be abolished by single proline point mutations in TolA, which each removed one backbone hydrogen bond. By also blocking TolA–TolB binding these point mutations conferred a complete tol phenotype which destabilized the outer membrane, prevented both ColA and ColE9 activity, and abolished phage protein binding to TolA. These are the only point mutations known to have such pleiotropic effects and showed that the TolA–TolB β-strand addition is essential for Tol function. The formation of this simple binary ColN–TolA complex provided yet more evidence of a distinct translocation route for ColN and may help to explain the unique toxicity of its N-terminal domain.
Experimental phasing for structure determination using membrane-protein crystals grown by the lipid cubic phase method
Authors: Li Dianfan , Pye Valerie E. , Caffrey Martin
Published: December 2014

Despite the marked increase in the number of membrane-protein structures solved using crystals grown by the lipid cubic phase orin mesomethod, only ten have been determined by SAD/MAD. This is likely to be a consequence of the technical difficulties associated with handling proteins and crystals in the sticky and viscous hosting mesophase that is usually incubated in glass sandwich plates for the purposes of crystallization. Here, a four-year campaign aimed at phasing thein mesostructure of the integral membrane diacylglycerol kinase (DgkA) fromEscherichia coliis reported. Heavy-atom labelling of this small hydrophobic enzyme was attempted by pre-labelling, co-crystallization, soaking, site-specific mercury binding to genetically engineered single-cysteine mutants and selenomethionine incorporation. Strategies and techniques for special handling are reported, as well as the typical results and the lessons learned for each of these approaches. In addition, an assay to assess the accessibility of cysteine residues in membrane proteins for mercury labelling is introduced. The various techniques and strategies described will provide a valuable reference for future experimental phasing of membrane proteins where crystals are grown by the lipid cubic phase method.
Combining biophysical methods for the analysis of protein complex stoichiometry and affinity inSEDPHAT
Authors: Zhao Huaying , Schuck Peter
Published: December 2014

Reversible macromolecular interactions are ubiquitous in signal transduction pathways, often forming dynamic multi-protein complexes with three or more components. Multivalent binding and cooperativity in these complexes are often key motifs of their biological mechanisms. Traditional solution biophysical techniques for characterizing the binding and cooperativity are very limited in the number of states that can be resolved. A global multi-method analysis (GMMA) approach has recently been introduced that can leverage the strengths and the different observables of different techniques to improve the accuracy of the resulting binding parameters and to facilitate the study of multi-component systems and multi-site interactions. Here, GMMA is described in the softwareSEDPHATfor the analysis of data from isothermal titration calorimetry, surface plasmon resonance or other biosensing, analytical ultracentrifugation, fluorescence anisotropy and various other spectroscopic and thermodynamic techniques. The basic principles of these techniques are reviewed and recent advances in view of their particular strengths in the context of GMMA are described. Furthermore, a new feature inSEDPHATis introduced for the simulation of multi-method data. In combination with specific statistical tools for GMMA inSEDPHAT, simulations can be a valuable step in the experimental design.
Challenges and solutions for the analysis ofin situ,in crystallomicro-spectrophotometric data
Authors: Dworkowski Florian S. N. , Hough Michael A. , Pompidor Guillaume , Fuchs Martin R.
Published: December 2014

Combining macromolecular crystallography within crystallomicro-spectrophotometry yields valuable complementary information on the sample, including the redox states of metal cofactors, the identification of bound ligands and the onset and strength of undesired photochemistry, also known as radiation damage. However, the analysis and processing of the resulting data differs significantly from the approaches used for solution spectrophotometric data. The varying size and shape of the sample, together with the suboptimal sample environment, the lack of proper reference signals and the general influence of the X-ray beam on the sample have to be considered and carefully corrected for. In the present article, how to characterize and treat these sample-dependent artefacts in a reproducible manner is discussed and theSLS-APEin situ,in crystallooptical spectroscopy data-analysis toolbox is demonstrated.
Protein–ligand interactions investigated by thermal shift assays (TSA) and dual polarization interferometry (DPI)
Authors: Grøftehauge Morten K. , Hajizadeh Nelly R. , Swann Marcus J. , Pohl Ehmke
Published: December 2014

Over the last decades, a wide range of biophysical techniques investigating protein–ligand interactions have become indispensable tools to complement high-resolution crystal structure determinations. Current approaches in solution range from high-throughput-capable methods such as thermal shift assays (TSA) to highly accurate techniques including microscale thermophoresis (MST) and isothermal titration calorimetry (ITC) that can provide a full thermodynamic description of binding events. Surface-based methods such as surface plasmon resonance (SPR) and dual polarization interferometry (DPI) allow real-time measurements and can provide kinetic parameters as well as binding constants. DPI provides additional spatial information about the binding event. Here, an account is presented of new developments and recent applications of TSA and DPI connected to crystallography.
A national facility for biological cryo-electron microscopy
Authors: Saibil Helen R. , Grünewald Kay , Stuart David I.
Published: December 2014

Three-dimensional electron microscopy is an enormously powerful tool for structural biologists. It is now able to provide an understanding of the molecular machinery of cells, disease processes and the actions of pathogenic organisms from atomic detail through to the cellular context. However, cutting-edge research in this field requires very substantial resources for equipment, infrastructure and expertise. Here, a brief overview is provided of the plans for a UK national three-dimensional electron-microscopy facility for integrated structural biology to enable internationally leading research on the machinery of life. State-of-the-art equipment operated with expert support will be provided, optimized for both atomic-level single-particle analysis of purified macromolecules and complexes and for tomography of cell sections. The access to and organization of the facility will be modelled on the highly successful macromolecular crystallography (MX) synchrotron beamlines, and will be embedded at the Diamond Light Source, facilitating the development of user-friendly workflows providing near-real-time experimental feedback.
Structure calculation, refinement and validation usingCcpNmr Analysis
Authors: Skinner Simon P. , Goult Benjamin T. , Fogh Rasmus H. , Boucher Wayne , Stevens Tim J. , Laue Ernest D. , Vuister Geerten W.
Published: December 2014

CcpNmr Analysisprovides a streamlined pipeline for both NMR chemical shift assignment and structure determination of biological macromolecules. In addition, it encompasses tools to analyse the many additional experiments that make NMR such a pivotal technique for research into complex biological questions. This report describes howCcpNmr Analysiscan seamlessly link together all of the tasks in the NMR structure-determination process. It details each of the stages from generating NMR restraints [distance, dihedral, hydrogen bonds and residual dipolar couplings (RDCs)], exporting these to and subsequently re-importing them from structure-calculation software (such as the programsCYANAorARIA) and analysing and validating the results obtained from the structure calculation to, ultimately, the streamlined deposition of the completed assignments and the refined ensemble of structures into the PDBe repository. Until recently, such solution-structure determination by NMR has been quite a laborious task, requiring multiple stages and programs. However, with the new enhancements toCcpNmr Analysisdescribed here, this process is now much more intuitive and efficient and less error-prone.
BioSAXS Sample Changer: a robotic sample changer for rapid and reliable high-throughput X-ray solution scattering experiments
Authors: Round Adam , Felisaz Franck , Fodinger Lukas , Gobbo Alexandre , Huet Julien , Villard Cyril , Blanchet Clement E. , Pernot Petra , McSweeney Sean , Roessle Manfred , Svergun Dmitri I. , Cipriani Florent
Published: December 2014

Small-angle X-ray scattering (SAXS) of macromolecules in solution is in increasing demand by an ever more diverse research community, both academic and industrial. To better serve user needs, and to allow automated and high-throughput operation, a sample changer (BioSAXS Sample Changer) that is able to perform unattended measurements of up to several hundred samples per day has been developed. The Sample Changer is able to handle and expose sample volumes of down to 5 µl with a measurement/cleaning cycle of under 1 min. The samples are stored in standard 96-well plates and the data are collected in a vacuum-mounted capillary with automated positioning of the solution in the X-ray beam. Fast and efficient capillary cleaning avoids cross-contamination and ensures reproducibility of the measurements. Independent temperature control for the well storage and for the measurement capillary allows the samples to be kept cool while still collecting data at physiological temperatures. The Sample Changer has been installed at three major third-generation synchrotrons: on the BM29 beamline at the European Synchrotron Radiation Facility (ESRF), the P12 beamline at the PETRA-III synchrotron (EMBL@PETRA-III) and the I22/B21 beamlines at Diamond Light Source, with the latter being the first commercial unit supplied by Bruker ASC.
Leaf litter nutrient uptake in an intermittent blackwater river: influence of tree species and associated biotic and abiotic drivers
Authors: Mehring Andrew S. , Kuehn Kevin A. , Thompson Aaron , Pringle Catherine M. , Rosemond Amy D. , First Matthew R. , Lowrance R Richard , Vellidis George
Published: December 2014

Organic matter may sequester nutrients as it decomposes, increasing in total N and P mass via multiple uptake pathways. During leaf litter decomposition, microbial biomass and accumulated inorganic materials immobilize and retain nutrients, and therefore, both biotic and abiotic drivers may influence detrital nutrient content. We examined the relative importance of these types of nutrient immobilization and compared patterns of nutrient retention in recalcitrant and labile leaf litter.

Leaf packs of water oak (Quercus nigra), red maple (Acer rubrum) and Ogeechee tupelo (Nyssa ogeche) were incubated for 431 days in an intermittent blackwater stream and periodically analysed for mass loss, nutrient and metal content, and microbial biomass. These data informed regression models explaining temporal changes in detrital nutrient content. Informal exploratory models compared estimated biologically associated nutrient stocks (fungal, bacterial, leaf tissue) to observed total detrital nutrient stocks. We predicted that (i) labile and recalcitrant leaf litter would act as sinks at different points in the breakdown process, (ii) plant and microbial biomass would not account for the entire mass of retained nutrients, and (iii) total N content would be more closely approximated than total P content solely from nutrients stored in leaf tissue and microbial biomass, due to stronger binding of P to inorganic matter.

Labile litter had higher nutrient concentrations throughout the study. However, lower mass loss of recalcitrant litter facilitated greater nutrient retention over longer incubations, suggesting that it may be an important long‐term sink. N and P content were significantly related to both microbial biomass and metal content, with slightly stronger correlation with metal content over longer incubations.

Exploratory models demonstrated that a substantial portion of detrital nutrients was not accounted for by living or dead plant and microbial biomass, especially in the case of N. This suggests increased importance of both N and P sorption to inorganic matter over time, with possible additional storage of N complexed with lignin. A better understanding of the influence of these mechanisms may improve our understanding of detrital nutrient uptake, basal resource quality and retention and transport of nutrients in aquatic ecosystems.
Highway to the danger zone: exposure‐dependent costs of immunity in a vertebrate ectotherm
Authors: Brace Amber J. , Sheikali Sam , Martin Lynn B.
Published: December 2014

Parasite exposure often causes innate immune activation, resulting in trade‐offs among physiological processes and strong selection on the parasite. Costs of immune activation vary widely among and within host populations though, likely dependent on the evolutionary history of host–parasite interactions and the environments in which they occur. For hosts, degree of exposure may drive the magnitude of costs incurred and subsequently whether hosts resist or tolerate infections.

If costs increase concomitantly with exposure, a threshold may exist where the expense of parasite resistance becomes prohibitive and parasite tolerance becomes favourable. Here, we characterized exposure‐dependent costs of an innate immune response in brown anoles (Anolis sagrei) by tracking allocation of an isotopically labelled essential amino acid (13C‐leucine), to the liver and gonads. To elicit immune responses, we used lipopolysaccharide (LPS), a strongly immunogenic molecule from Salmonella spp.

We found that both sexes paid dose‐dependent costs of SalmonellaLPS‐induced immune activation, but costs were experienced differently by the sexes, likely due to differences in life history. Males allocated more leucine to their livers in response to higher LPS doses. In females, a tendency for increased costs in response to dose was only revealed when leucine allocation ratios between lymphoid and reproductive organs were considered. We also found that regardless of dose, males always allocated more leucine to their gonads than females. Lastly, and perhaps most interestingly, cost functions in both sexes were linear, but with shallow slopes, indicating modest costs of immune activation in response to SalmonellaLPS in this species.

Altogether, our results demonstrate that costs of immunity are dose dependent in this introduced lizard species, sexes experience costs differently. Characterization of relationships between host exposure and costs of immune activation such as these can facilitate predictions about how parasites might circulate through communities.
Experiences of paraprofessionals in US preschool special education and general education classrooms
Authors: Brown Tiara Saufley , Stanton‐Chapman Tina L.
Published: December 2014

A substantial challenge confronting public education systems across the world is the employment and retention of high‐quality paraprofessionals (also known as teaching assistants and educational assistants). The current study expands upon previous research by employing a mixed methods design to examine the relationship between paraprofessionals' perceptions of their responsibilities and the corresponding satisfaction and issues relating to their job in the USA. Analytic induction through the generation of themes was used to analyse the qualitative data and revealed that paraprofessionals perceive or demonstrate issues relating to three primary domains: confusion of responsibilities in different contexts, relational power dynamics between paraprofessionals and teachers, and satisfaction based on both monetary compensation and recognition. In addition to the qualitative findings, researchers designed the paraprofessional perception survey, a quantitative survey measuring the concept of paraprofessional perceptions relating to their job. Results from the survey analysis revealed similar findings across domains. Additional results, practice implications and directions for future research are discussed.
Discovery and microbial content of the driest site of the hyperarid Atacama Desert, Chile
Authors: Azua‐Bustos Armando , Caro‐Lara Luis , Vicuña Rafael
Published: December 2014

The Atacama Desert is the driest and oldest desert on Earth. Eleven years ago, the Yungay region was established as the driest site of this hyperarid desert and also close to the dry limit for life on Earth. Since then, much has been published about the extraordinary characteristics of this site and its pertinence as a Mars analogue model. However, as a result of a more systematic search in the Atacama here, we describe a new site, María Elena South (MES), which is much drier than Yungay. The mean atmospheric relative humidity (RH) at MES was 17.3%, with the RH of its soils remaining at a constant 14% at the depth of 1 m, a value that matches the lowest RH measurements taken by the Mars Science Laboratory at Gale Crater. Remarkably, we found a number of viable bacterial species in the soil profile at MES using a combination of molecular dependent and independent methods, unveiling the presence of life in the driest place on the Atacama Desert reported to date.
Basic fibroblast growth factor shows prognostic impact on survival in operable non‐small cell lung cancer patients
Authors: Hu Ming‐ming , Hu Ying , Gao Guang‐kuo , Han Yi , Shi Guang‐li , Li Bao‐lan
Published: December 2014

Background

The important role of angiogenesis displaying in tumor development and metastasis has been generally realized. Vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and endostatin (ES) are critical members of angiogenesis modulating the balance between pro‐angiogenenic and anti‐angiogenenic factors. The aim of this study was to evaluate the circulating level of these factors in serum and explore their prognostic significance in 96 operable non‐small cell lung cancer (NSCLC) patients.

Methods

Pre‐operational serum VEGF, bFGF, and ES were determined by commercially available enzyme‐link immunosorbent assay for 96 NSCLC patients and compared to a cohort of healthy controls (n = 51). Values were correlated with clinicopathological features and overall survival (OS).

Results

The pretreatment serum levels of VEGF, bFGF and ES in NSCLC were significantly higher than in the healthy control (P < 0.001, P = 0.009 and P = 0.016, respectively). Univariate survival analysis showed that a high bFGF level correlated with shorter OS and remained an independent factor in multivariate analysis (hazard ratio [HR] = 1.918, 95% confidence interval [CI], 1.061–3.464). In the squamous subtype, a high bFGF indicated a particularly poor prognosis (HR = 2.609, 95% CI, 1.188–5.729).

Conclusions

bFGF is an independent predictor of poor survival in patients with NSCLC. For patients with high serum bFGF, aggressive antitumor treatments should be given after surgery. Approaches targeting the bFGF signaling pathway should be considered as potentially promising therapeutic strategies in NSCLC, especially for the squamous subtype.
Emergency Department Visits Related to Clostridium difficile Infection: Results From the Nationwide Emergency Department Sample, 2006 Through 2010
Authors: Pant Chaitanya , Sferra Thomas J. , Olyaee Mojtaba , Gilroy Richard , Anderson Michael P. , Rastogi Amit , Pandya Prashant K. , Deshpande Abhishek
Published: December 2014

Objectives

The objective was to estimate emergency department (ED) visits for Clostridium difficile infection in the United States for the years 2006 through 2010.

Methods

Estimates of ED visits for C. difficile infection were calculated in patients 18 years and older using the Nationwide Emergency Department Sample.

Results

During the calendar years 2006 through 2010, there were an estimated total of 491,406,018 ED visits. Of these, 462,160 ED visits were associated with a primary International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis of C. difficile. The C. difficile infection ED visit rate (visits/100,000 census population) increased from 34.1 in 2006 to 42.3 in 2010, an increase of 24% (p < 0.01). There was also a significant overall increased trend in the number of ED visits for C. difficile from 2006 through 2010 (p < 0.01). The highest ED visit rate for C. difficile was observed for patients 65 years and older (163.18 per 100,000), while the lowest visit rate was for patients aged 18 to 24 years (5.10 per 100,000). The greatest increase in C. difficile infection visits occurred in the age group 18 to 24 years.

Conclusions

These results indicate an increased trend of ED visits for C. difficile in the period 2006 through 2010 with an overall population‐adjusted increase of 24%. This represents important complementary data to previous studies reporting an increase in the rate of C. difficile infections in the U.S. hospitalized population.
You've Got Mail … and Need Follow‐up: The Effect and Patient Perception of E‐mail Follow‐up Reminders After Emergency Department Discharge
Authors: Sharp Brian , Singal Bonita , Pulia Michael , Fowler Jennifer , Simmons Stefanie
Published: December 2014

Objectives

The hypothesis was that a reminder about recommended primary care physician (PCP) follow‐up, sent via e‐mail to patients discharged from the emergency department (ED), would increase the proportion of patients who followed up with their PCPs within the recommended time frame. Patient receptiveness to e‐mail follow‐up reminders was also assessed.

Methods

This was a mixed methods clinical intervention study with subjects randomized either to receive the usual care discharge instructions only or to also receive a reminder e‐mail message the day after the ED visit. The reminder e‐mail contained the subject's PCP's name and address and the recommended PCP follow‐up time interval. A blinded review of outpatient PCP medical records was conducted to determine whether and when follow‐up occurred. Researchers attempted to contact patients with a telephone survey 2 weeks after their ED visits. The primary outcomes between groups were compared using chi‐square tests and relative risks (RRs) with 95% confidence intervals (CIs).

Results

Thirty‐three percent of the intervention group and 32% of the control group followed‐up as recommended (RR = 1.04, 95% CI = 0.81 to 1.33); 52% of the intervention group and 48% of the control group followed‐up within 10 days of the recommended time (RR = 1.08, 95% CI = 0.91 to 1.29). The 334 patients (57%) successfully contacted via telephone demonstrated a high interest in receiving future e‐mail reminders (75%), with the group that received e‐mail reminders more likely to want one in the future than those who did not receive e‐mail reminders (82.5% vs. 69.76%; p = 0.04).

Conclusions

E‐mail reminders sent after ED visits did not improve patients' adherence to the recommended timing of primary care follow‐up contained in discharge instructions. Subjects in both the control and the intervention groups favorably viewed the concept of e‐mail reminders, suggesting that the value of e‐mail reminders after ED discharge may be in areas such as patient satisfaction that were not specifically targeted for measurement in this study.
Correlation between ethanol behavioral sensitization and midbrain dopamine neuron reactivity to ethanol
Authors: Didone Vincent , Masson Sébastien , Quoilin Caroline , Seutin Vincent , Quertemont Etienne
Published: December 2014

Repeated ethanol injections lead to a sensitization of its stimulant effects in mice. Some recent results argue against a role for ventral tegmental area (VTA) dopamine neurons in ethanol behavioral sensitization. The aim of the present study was to test whether in vivo ethanol locomotor sensitization correlates with changes in either basal‐ or ethanol‐evoked firing rates of dopamine neurons in vitro. Female Swiss mice were daily injected with 2.5 g/kg ethanol (or saline in the control group) for 7 days and their locomotor activity was recorded. At the end of the sensitization procedure, extracellular recordings were made from dopaminergic neurons in midbrain slices from these mice. Significantly higher spontaneous basal firing rates of dopamine neurons were recorded in ethanol‐sensitized mice relative to control mice, but without correlations with the behavioral effects. The superfusion of sulpiride, a dopamine D2 antagonist, induced a stronger increase of dopamine neuron firing rates in ethanol‐sensitized mice. This shows that the D2 feedback in dopamine neurons is preserved after chronic ethanol administration and argues against a reduced D2 feedback as an explanation for the increased dopamine neuron basal firing rates in ethanol‐sensitized mice. Finally, ethanol superfusion (10–100 mM) significantly increased the firing rates of dopamine neurons and this effect was of higher magnitude in ethanol‐sensitized mice. Furthermore, there were significant correlations between such a sensitization of dopamine neuron activity and ethanol behavioral sensitization. These results support the hypothesis that changes in brain dopamine neuron activity contribute to the behavioral sensitization of the stimulant effects of ethanol.
Tracking the evolution of drug abuse in China, 2003–10: a retrospective, self‐controlled study
Authors: Jia Zhongwei , Liu Zhiming , Chu Ping , McGoogan Jennifer M. , Cong Minchao , Shi Jie , Lu Lin
Published: December 2014

Aim

To characterize trends in drug abuse in China before and after the 2005 initiation of the ‘People's War on Drugs’.

Design

Retrospective self‐controlled study.

Setting

Annual, nation‐wide surveillance from 2003 to 2010 of all registered drug users in China's National Surveillance System on Drug Abuse (NSSDA).

Participants

A total of 1 184 124 drug users registered in NSSDA were involved in this study and were classified into three groups based on registered dates—pre‐war group (n = 230 278) registered 2003–04, phase I group (n = 518 651) registered 2005–07 and phase II group (n = 435 195) registered 2008–10.

Measurements

Indicators included proportions of:(i) new and relapsed drug users, (ii) heroin and synthetic drug users among new users, (iii) people aged 35 years or younger and (iv) women. Comparisons were made across groups using annual data to describe temporal trends.

Findings

Between 2003 and 2010 the proportion of heroin users decreased by 52.3% and synthetic drugs use increased 860.7% among new users, while a 12.8% decrease in the proportion of heroin users and a 918.8% increase in synthetic drug use in all users was detected. Compared with the pre‐war group, the proportion of relapsed users decreased 2.6% and 29.1% in the phase I and phase II groups, respectively, but a significant increase in the proportion of new users was found in phase I (OR = 1.24, CI = 1.15‐1.35, p < 0.0001), followed by an apparent decrease in phase II compared with phase I (OR = 0.75, CI = 0.70‐0.80, p < 0.0001). Similarly, the proportion of heroin users decreased 15.1 and 24.2% among new drug users in phase I and phase II in comparison with the pre‐war group.

Conclusion

The decrease in proportions of drug users in China between 2003/4 and 2008/10 may suggest some positive influence of the ‘People's War on Drugs’, especially in the decreased proportion of relapsed users. In contrast, there was a rapid increase in new synthetic drug use over the same period.
Needle and syringe exchange programmes and prevalence of HIV infection among intravenous drug users in China
Authors: Luo Wei , Wu Zunyou , Poundstone Katharine , McGoogan Jennifer M. , Dong Willa , Pang Lin , Rou Keming , Wang Changhe , Cao Xiaobin
Published: December 2014

Aim

To examine the association between needle and syringe exchange programme (NSEP) participation and human immunodeficiency virus (HIV) infection among intravenous drug users (IDUs) in China.

Design

Cross‐sectional survey study design.

Setting

Six counties with active NSEP were selected from each of the seven provinces with active NSEP sampled, resulting in a sample of 42 counties in China.

Participants

Subjects were aged more than 18 years and had injected drugs in the past month before the survey, but were excluded if they were currently enrolled in methadone maintenance treatment in order to avoid mixed effects.

Measurements

HIV prevalence was the primary measure. Odds ratios (ORs), 95% confidence intervals (CIs) and P‐values were calculated to evaluate associations between HIV infection and NSEP participation.

Findings

A total of 3494 IDUs were interviewed, of whom 1928 (55.2%) were NSEP attendees (meaning they had attended NSEP at least once in their life‐time). The unadjusted HIV prevalence was 13.9% among NSEP attendees and 16.5% among NSEP non‐attendees (meaning IDUs who had never used NSEP services). After adjusting for potential confounders and taking into account the variation between counties, NSEP non‐attendees were 1.67 times more likely to be HIV‐positive compared to NSEP attendees (OR = 1.67, CI = 1.19–2.32, P = 0.0031).

Conclusions

Participation in needle and syringe exchange programmes was associated with a substantially lower risk of HIV infection among intravenous drug users in China. Needle and syringe exchange programmes should be expanded to include those who are needle and syringe exchange programme non‐attendees.
Full‐term newborn after repeated ovarian tissue transplants in a patient treated for Ewing sarcoma by sterilizing pelvic irradiation and chemotherapy
Authors: Rodriguez‐Wallberg Kenny A. , Karlström Per‐Olof , Rezapour Masoumeh , Castellanos Enrique , Hreinsson Julius , Rasmussen Carsten , Sheikhi Mona , Ouvrier Bettina , Bozóky Béla , Olofsson Jan I. , Lundqvist Monalill , Hovatta Outi
Published: December 2014

We report the first successful transplantation of cryopreserved ovarian cortical tissue into heavily irradiated tissues in a patient who had received sterilizing pelvic radiotherapy (54 Gy) and 40 weeks of intensive high‐dose chemotherapy for the treatment of Ewing's sarcoma 14 years earlier. Repeated transplantation procedures were required to obtain fully functional follicular development. Enlargement of the transplants over time and increase of the size of the uterus were demonstrated on sequential ultrasonographic examinations. Eggs of good quality that could be fertilized in vitro were obtained only after a substantial incremental increase of the amount of ovarian tissue transplanted. Single embryo replacement resulted in a normal pregnancy and the birth of a healthy child by cesarean section at full‐term. No neonatal or maternal postoperative complications occurred. Women facing high‐dose pelvic radiotherapy should not be systematically excluded from fertility preservation options, as is currently the trend.
Can inter‐professional simulation training influence the frequency of blood transfusions after birth?
Authors: Egenberg Signe , Øian Pål , Bru Lars Edvin , Sautter Michael , Kristoffersen Gunn , Eggebø Torbjørn Moe
Published: December 2014

Objective

To investigate whether inter‐professional simulation training influenced the rate of red blood cell (RBC) transfusions after birth.

Design

Two cohorts were compared retrospectively using a pre–post design.

Setting

Norwegian university hospital with 4800 deliveries annually.

Population

Women with estimated blood loss >500 mL within 24 h after birth in 2009 and 2011.

Methods

In 2010, all maternity staff attended a 6‐h, scenario‐based training on emergency obstetrics including postpartum hemorrhage, using a birthing simulator. The simulation focused on prevention, identification, and treatment of postpartum hemorrhage and on communication and leadership. Debrief immediately after the scenarios involved reflection and self‐assessment.

Main outcome measures

The frequency of women receiving RBC transfusions as a marker for blood loss. Secondary outcome was the frequency of surgical procedures in the management of postpartum hemorrhage.

Results

In 2009, 111/534 (20.8%) women with estimated blood loss >500 mL after birth received RBC transfusions vs. 67/546 (12.3%) in 2011 (p < 0.01). The adjusted odds ratio for women receiving RBC transfusions in 2011 vs. 2009 was 0.53 (95% CI 0.38–0.74). Parity, oxytocin augmentation, duration of second stage, episiotomy, operative vaginal delivery, and sphincter injury were included in the final model. The odds ratio was stable in all combinations of possible confounders. We observed a significant reduction in the frequencies of curettage (p < 0.01) and uterine artery embolizations (p = 0.01).

Conclusion

We found a significant reduction in RBC transfusions after birth, which might be associated with mandatory simulation training. A causal link cannot be documented because of complex interactions of several variables.
Contrast‐enhanced MRI in preoperative assessment of myometrial and cervical invasion, and lymph node metastasis: diagnostic value and error analysis in endometrial carcinoma
Authors: Teng Fei , Zhang Yan‐Fang , Wang Ying‐Mei , Yu Jing , Lang Xu , Tian Wen‐Yan , Jiang Chang‐Xin , Xue Feng‐Xia
Published: December 2014

Objective

To determine the ability of contrast‐enhanced magnetic resonance imaging to predict myometrial invasion, cervical invasion, and pelvic lymph node metastasis in endometrial carcinoma and to analyze factors that lead to errors in this identification.

Design

A retrospective study.

Setting

University general hospital.

Population

A total of 167 women diagnosed with endometrial carcinoma.

Methods

All patients received a preoperative contrast‐enhanced magnetic resonance imaging scan. Histopathological findings were used as the definitive diagnosis.

Main outcome measures

The results were compared with histopathological findings, factors that make accurate assessment of myometrial invasion, cervical invasion, and pelvic lymph node metastasis difficult by contrast‐enhanced magnetic resonance imaging were analyzed.

Results

The sensitivity, specificity, diagnostic accuracy, positive predictive values, and negative predictive values of contrast‐enhanced magnetic resonance imaging were 90.9, 91.8, 91.6, 73.2 and 97.6%, respectively, for identifying deep myometrial invasion; 84.2, 96.0, 94.6, 72.7 and 97.9%, respectively, for identifying cervical invasion; and 45.0, 91.2, 85.6, 40.9 and 92.4%, respectively, for identifying pelvic lymph node metastasis. The main causes of error in contrast‐enhanced magnetic resonance imaging were myomas, cornual lesions, deep myometrial invasion, large tumor size, non‐endometrioid tumor type, and lower tumor grade.

Conclusion

Contrast‐enhanced magnetic resonance imaging has a high accuracy and a low tendency to produce false‐negative predictive values. Gynecological oncologists should combine the imaging data and clinical information to make therapeutic decisions and avoid diagnostic errors.
Human legacies differentially organize functional and phylogenetic diversity of urban herbaceous plant communities at multiple spatial scales
Authors: Johnson Anna L. , Tauzer Erica C. , Swan Christopher M.
Published: December 2014

Questions

Patterns of functional and phylogenetic homogenization of plant diversity at the scale of entire cities are well established. However, fewer studies have investigated how shifts in the composition of urban species pools may alter spatial variation in community assembly across patches within a city. We compared plant diversity both within and between vacant lots in a single urban neighborhood and asked: (1) how do heterogeneous human legacies of land use within vacant lots structure plant community diversity and composition and (2) what is the importance of human legacies for structuring community composition, relative to spatial and environmental variation?

Location

Urban residential neighbourhood in Baltimore, MD, US (39°17′ N, 76°38′ W).

Methods

We surveyed herbaceous plant species identity and abundance in 24 unmanaged vacant lots. We constructed functional and phylogenetic diversity metrics from databases and the literature and compared taxonomic, functional and phylogenetic diversity between sections of the lot where a residential building was once located (building footprint), and the area that was originally the garden or backyard (remnant garden). We term these different ‘human legacy’ groups. We partitioned variation in plant community composition between human legacy groups as well as across measured environmental and spatial gradients.

Results

We report significant plant community compositional divergence between human legacy groups. Beta‐diversity, in particular, was significantly higher in remnant garden sections compared to building footprint sections for all metrics of biodiversity. Plant community compositional variation was primarily explained by differences in human legacies. We found no measurable effects of selected metrics of local environmental variation (abiotic soil characteristics) or environmental context (lot area, proximity to other vacant lots and tree canopy) on compositional variation. Geographic distance between sites, however, did interact with human legacy variation to structure phylogenetic composition.

Conclusions

Our findings suggest that human land‐use legacies have complex but measurable effects on both the patterns and the processes by which species co‐existence is maintained across the urban landscape. Within a single habitat type (here, residential vacant lots), variation in legacies of land use may have a stronger plant community structuring effect than contemporary environmental variation.
The effect of tafamidis on the QTc interval in healthy subjects
Authors: Klamerus Karen J. , Watsky Eric , Moller Robert , Wang Ronnie , Riley Steve
Published: December 2014

Aims

The transthyretin (TTR) stabilizer, tafamidis, has demonstrated efficacy and safety in the treatment of TTR familial amyloid polyneuropathy (20 mg day−1). Tafamidis use in TTR cardiomyopathy led to the study of the potential effect of tafamidis on the QTc interval in healthy subjects.

Methods

This randomized, three treatment, three period, six sequence crossover study with placebo, a positive control (moxifloxacin 400 mg) and tafamidis (400 mg, to achieve a supra‐therapeutic Cmax of ~20 µg ml−1) was conducted in healthy volunteers at three clinical research units. Oral dosing in each of the three treatment periods was separated by a washout period of  ≥ 14 days. Serial triplicate 12‐lead electrocardiograms were performed. QTc intervals were derived using the Fridericia correction method. Safety and tolerability were assessed by physical examination, vital signs measurement, laboratory analyses and monitoring of adverse events (AEs).

Results

A total of 42 subjects completed the study. The upper limit of the two‐sided 90% confidence intervals (CIs) for the difference in baseline‐adjusted QTcF between tafamidis 400 mg and placebo was <10 ms (non‐inferiority criterion) for all time points. The lower limit of the two‐sided 90% CI between moxifloxacin 400 mg and placebo exceeded 5 ms at the pre‐specified moxifloxacin tmax of 3 h post‐dose, confirming assay sensitivity. Cmax and AUC(0,24 h) for tafamidis were 20.36 µg ml−1 and 305.4 µg ml−1 h, respectively. There were no serious/severe AEs or treatment discontinuations due to AEs.

Conclusions

This thorough QTc study suggests that a supra‐therapeutic single 400 mg oral dose of tafamidis does not prolong the QTc interval and is well‐tolerated in healthy volunteers.
Autophagy: an emerging therapeutic target in vascular diseases
Authors: Vindis Cécile
Published: December 2014

Autophagy is a cellular catabolic process responsible for the destruction of long‐lived proteins and organelles via lysosome‐dependent pathway. This process is of great importance in maintaining cellular homeostasis, and deregulated autophagy has been implicated in the pathogenesis of a wide range of diseases. A growing body of evidence suggests that autophagy can be activated in vascular disorders such as atherosclerosis. Autophagy occurs under basal conditions and mediates homeostatic functions in cells but in the setting of pathological states up‐regulated autophagy can exert both protective and detrimental functions. Therefore, the precise role of autophagy and its relationship with the progression of the disease need to be clarified. This review highlights recent findings regarding autophagy activity in vascular cells and its potential contribution to vascular disorders with a focus on atherogenesis. Finally, whether the manipulation of autophagy represents a new therapeutic approach to treat or prevent vascular diseases is also discussed.
‘Partial’ competition of heterobivalent ligand binding may be mistaken for allosteric interactions: a comparison of different target interaction models
Authors: Vauquelin Georges , Hall David , Charlton Steven J
Published: December 2014

Background and Purpose

Non‐competitive drugs that confer allosteric modulation of orthosteric ligand binding are of increasing interest as therapeutic agents. Sought‐after advantages include a ceiling level to drug effect and greater receptor‐subtype selectivity. It is thus important to determine the mode of interaction of newly identified receptor ligands early in the drug discovery process and binding studies with labelled orthosteric ligands constitute a traditional approach for this. According to the general allosteric ternary complex model, allosteric ligands that exhibit negative cooperativity may generate distinctive ‘competition’ curves: they will not reach baseline levels and their nadir will increase in par with the orthosteric ligand concentration. This behaviour is often considered a key hallmark of allosteric interactions.

Experimental Approach

The present study is based on differential equation‐based simulations.

Key Results

The differential equation‐based simulations revealed that the same ‘competition binding’ pattern was also obtained when a monovalent ligand binds to one of the target sites of a heterobivalent ligand, even if this process is exempt of allosteric interactions. This pattern was not strictly reciprocal when the binding of each of the ligands was recorded. The prominence of this phenomenon may vary from one heterobivalent ligand to another and we suggest that this phenomenon may take place with ligands that have been proposed to bind according to ‘two‐domain’ and ‘charnière’ models.

Conclusions and Implications

The present findings indicate a familiar experimental situation where bivalency may give rise to observations that could inadvertently be interpreted as allosteric binding. Yet, both mechanisms could be differentiated based on alternative experiments and structural considerations.
The New Logics of Homeless Seclusion:Homeless Encampments in America's West Coast Cities
Authors: Herring Chris
Published: December 2014

Since the late 1990s, scores of American cities have witnessed the re–emergence of large–scale homeless encampments for the first time since the Great Depression. Commonly portrayed as rooted in the national economic downturn and functionally undifferentiated, this paper demonstrates that large–scale encampments are rather shaped by urban policies and serve varied and even contradictory roles in different localities. Drawing on interviews and observations in 12 encampments in eight municipalities, this study reveals four distinctive socio–spatial functions of encampments shaped by administrative strategies of city officials and adaptive strategies of campers. I demonstrate how large–scale encampments paradoxically serve as both tools of containing homeless populations for the local state and preferred safe grounds for those experiencing homelessness. The paper concludes with a discussion on the implications of homeless seclusion for social analysis and policy, arguing that exclusion and seclusion are two sides of the same coin of the management of marginality in the American city.