Complementary coded apertures for 4-dimensional x-ray coherent scatter imaging.
X-ray scattering has played a key role in non-destructive materials characterization due to the material-specific coherent scattering signatures. In the current energy dispersive coherent scatter imaging systems, including selected volume tomography and coherent scatter computed tomography, each object voxel is measured at a single scatter angle, which suffers from slow acquisition time. The employment of coded apertures in x-ray scatter imaging systems improves the photon collection efficiency, making it promising for real time volumetric imaging and material identification. In this paper, we propose a volumetric x-ray scatter imaging system using a pair of complementary coded apertures: a coded aperture on the detector side introduces multiplexed measurement on an energy-sensitive detector array; a complementary source-side coded aperture selectively illuminates the object to decouple the ambiguity due to the increased parallelization for 4D imaging. The system yields the 1D coherent scattering form factor at each voxel in 3D. We demonstrate tomographic imaging and material identification with the system and achieve a spatial resolution ~1 cm and a normalized momentum transfer resolution, Δq/q, of 0.2.


Rapid Detection of Human Norovirus in Frozen Raspberries.
Raspberries have lately caused several human norovirus (HuNoV) outbreaks in Europe. In this study, we developed and evaluated for HuNoV reverse transcription (RT)-PCR detection in frozen raspberries extraction methods that have equal sensitivity but are less time-consuming than widely used methods based on polyethylene glycol (PEG) precipitation and chloroform-butanol purification. One method was applied to stored frozen raspberries linked to previous HuNoV outbreaks and berries on sale. In the virus elution-based Method 1, sparkling water eluted viruses most efficiently from the berries. Method 2, based on direct nucleic acid extraction with minor PEG supplement, yielded the highest number of positive findings (4 out of 9) at low virus concentration level of 100 genome copies HuNoV genogroup II per 25 g raspberries. Both methods showed approximately equal sensitivity to a method including PEG precipitation and chloroform-butanol purification. Two naturally contaminated berry samples linked to HuNoV outbreaks in 2006 and 2009 were still positive for HuNoV genogroup I, but all berry products purchased from a local store remained negative for HuNoV. In conclusion, this study presents two efficient and rapid methods which can be used in urgent HuNoV outbreak investigations, since the results of the virus analysis are available in a few hours.


Portable sequencing, genomic data, and scale in global emerging infectious disease surveillance.
Emerging infectious diseases (EIDs) occur when pathogens unpredictably spread into new contexts. EID surveillance systems seek to rapidly identify EID outbreaks to contain spread and improve public health outcomes. Sequencing data has historically not been integrated into real-time responses, but portable DNA sequencing technology has prompted optimism among epidemiologists. Specifically, attention has focused on the goal of a "sequencing singularity": the integration of portable sequencers in a worldwide event-based surveillance network with other digital data (Gardy & Loman, Nature Reviews Genetics, 19, 2018, p. 9). The sequencing singularity vision is a powerful socio-technical imaginary, shaping the discourse around the future of portable sequencing. Ethical and practical issues are bound by the vision in two ways: they are framed only as obstacles, and they are formulated only at the scales made visible by its implicit geography. This geography privileges two extremes of scale - the genomic and the global - and leaves intermediate scales comparatively unmapped. We explore how widespread portable sequencing could challenge this geography. Portable sequencers put the ability to produce genomic data in the hands of the individual. The explicit assertion of rights over data may therefore become a matter disputed more at an interpersonal scale than an international one. Portable sequencers also promise ubiquitous, indiscriminate sequencing of the total metagenomic content of samples, raising the question of what (or who) is under surveillance and inviting consideration of the human microbiome and more-than-human geographies. We call into question a conception of a globally integrated stream of sequencing data as composed mostly of "noise," within which signals of pathogen "emergence" are "hidden," considering it instead from the perspective of recent work into more-than-human geographies. Our work highlights a practical need for researchers to consider both the alternative possibilities they foreclose as well as the exciting opportunities they move towards when they deploy their visions of the future.


Effect of the exercise of seven consecutive days hill-walking on fluid homeostasis.
1. The effect of 7 consecutive days of strenuous exercise, hill-walking, on water balance and distribution was studied in five subjects. The exercise was preceded and followed by 3 control days. The diet was fixed throughout but water was allowed ad libitum. 2. Packed cell volume was measured daily. Serum electrolytes and arginine vasopressin were measured twice daily. Daily water, sodium and potassium balances were calculated. 3. During exercise there was a fall in packed cell volume, reaching a maximum of 11% by day 5 and a retention of sodium reaching a cumulative maximum of 358 mmol by day 6. During and immediately after exercise there was a retention of potassium, reaching a total of 120 mmol by day 3 after stopping exercise. 4. There was a loss of 650 ml of water on day 1 of exercise, followed by a modest retention reaching a cumulative maximum of 650 ml on day 5 of exercise. 5. Neither arginine vasopressin nor serum electrolyte concentrations were affected by exercise. 6. From the packed cell volume, sodium and water balances it was calculated that by day 5 of exercise there was an increase in plasma volume of .068 litre (22%), an increase in interstitial fluid volume of 2.0 litres (17%) and a decrease in intracellular fluid volume of 1.8 litres (8%). 7. These changes, together with the clinical observation of facial and ankle oedema during the experiemnt, suggest that continuous exercise may cause oedema and thus may be a factor in the aetiology of high-altitude oedema.


Effects of simvastatin on the lipid profile and attainment of low-density lipoprotein cholesterol goals when added to thiazolidinedione therapy in patients with type 2 diabetes mellitus: A multicenter, randomized, double-blind, placebo-controlled trial.
Coronary heart disease is the major cause of mortality in individuals with diabetes mellitus (DM). Given the increasingly aggressive low-density lipoprotein cholesterol (LDL-C) goals for patients with DM set by the National Cholesterol Education Program Adult Treatment Panel III and the American Diabetes Association, many patients remain above target. Treatment with thiazolidinediones (TZDs) improves glycemic control but does not lower (and may raise) LDL-C concentrations. This study assessed the lipid-modifying efficacy and tolerability of adding the hydroxymethylglutaryl coenzyme A-reductase inhibitor simvastatin to existing TZD therapy in patients with type 2 DM. This was a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial. Patients with type 2 DM who were taking a stable dose of pioglitazone or rosiglitazone and had a glycosylated hemoglobin (HbA1c) value < or =9.0% and an LDL-C concentration > 100 mg/dL were randomized to receive simvastatin 40 mg (the recommended initial dose for patients with DM) or placebo for 24 weeks. The primary end point was the effect of treatment on LDL-C concentrations. Other lipid, lipoprotein, and safety measures were also assessed. Two hundred fifty-three patients (127 [50.2%] men, 126 [49.8%] women; mean age, 56 years) were randomized to treatment (123 simvastatin, 130 placebo). At the end of the study, mean LDL-C concentrations were reduced 34.)% from baseline (from 134.3 to 89.5 mg/dL) in the simvastatin group and were unchanged in the placebo group (P<0.001). Simvastatin produced significant reductions in concentrations of total cholesterol, triglycerides (TG), non-high-density lipoprotein cholesterol, and apolipoprotein (apo) B compared with placebo (all, P<0.001 ) and significant increases in concentrations of high-density lipoprotein cholesterol (HDL-C) ( P=0.002 ) and apo A-I ( P=0.006 ). In patients who had not attained target concentrations of LDL-C (<100 mg/dL), TG (<150 mg/dL), or HDL-C (>45 mg/dL) at baseline, significantly more simvastatin recipients had achieved these goals at the end of the study compared with placebo recipients (LDL-C: 67.3% vs 5.2%, respectively, P<0.001; HDL-C: 95.3% vs 83.6%, P<0.05; TG: 40.8% vs 11.0%, P<0.001 ). Simvastatin was well tolerated, and no clinically meaningful differences in the incidence of serious adverse events, treatment-related adverse events, or discontinuations due to adverse events were observed between groups. There were no significant between-group differences in glycemic control (HbA1c) or concentrations of fasting insulin, creatine phosphokinase, or hepatic transaminases. Simvastatin was an effective and generally well tolerated treatment for hyperlipidemia when used in combination with TZD therapy in this population of patients with type 2 DM.


Functional analysis of the omega-6 fatty acid desaturase (CaFAD2) gene family of the oil seed crop Crambe abyssinica.
Crambe abyssinica produces high erucic acid (C22:1, 55-60%) in the seed oil, which can be further increased by reduction of polyunsaturated fatty acid (PUFA) levels. The omega-6 fatty acid desaturase enzyme (FAD2) is known to be involved in PUFA biosynthesis. In crambe, three CaFAD2 genes, CaFAD2-C1, CaFAD2-C2 and CaFAD2-C3 are expressed. The individual effect of each CaFAD2 gene on oil composition was investigated through studying transgenic lines (CaFAD2-RNAi) for differential expression levels in relation to the composition of seed-oil. Six first generation transgenic plants (T1) showed C18:1 increase (by 6% to 10.5%) and PUFA reduction (by 8.6% to 10.2%). The silencing effect in these T1-plants ranged from the moderate silencing (40% to 50% reduction) of all three CaFAD2 genes to strong silencing (95% reduction) of CaFAD2-C3 alone. The progeny of two T1-plants (WG4-4 and WG19-6) was further analysed. Four or five transgene insertions are characterized in the progeny (T2) of WG19-6 in contrast to a single insertion in the T2 progeny of WG4-4. For the individual T2-plants of both families (WG19-6 and WG4-4), seed-specific silencing of CaFAD2-C1 and CaFAD2-C2 was observed in several individual T2-plants but, on average in both families, the level of silencing of these genes was not significant. A significant reduction in expression level (P < 0.01) in both families was only observed for CaFAD2-C3 together with significantly different C18:1 and PUFA levels in oil. CaFAD2-C3 expression is highly correlated to levels of C18:1 (r = -0.78) and PUFA (r = 0.75), which suggests that CaFAD2-C3 is the most important one for changing the oil composition of crambe.


Integrin α3 mutations with kidney, lung, and skin disease.
Integrin α(3) is a transmembrane integrin receptor subunit that mediates signals between the cells and their microenvironment. We identified three patients with homozygous mutations in the integrin α(3) gene that were associated with disrupted basement-membrane structures and compromised barrier functions in kidney, lung, and skin. The patients had a multiorgan disorder that included congenital nephrotic syndrome, interstitial lung disease, and epidermolysis bullosa. The renal and respiratory features predominated, and the lung involvement accounted for the lethal course of the disease. Although skin fragility was mild, it provided clues to the diagnosis.


Policy change and health care research.
Explaining policy change is one of the most central tasks of contemporary policy analysis. Reacting to overly rigid institutionalist frameworks that emphasize stability rather than change, a growing number of scholars have formulated new theoretical models to shed light on policy change. Focusing on health care reform but drawing on the broader social science literature on policy and politics, this article offers critical perspectives on the institutionalist and ideational literatures on policy change while assessing their relevance for analyzing change in contemporary health care systems. The last section sketches a research agenda for studying policy change in health care.


Ultrafast static and diffusion-controlled electron transfer at Ag29 nanocluster/molecular acceptor interfaces.
Efficient absorption of visible light and a long-lived excited state lifetime of silver nanoclusters (Ag29 NCs) are integral properties for these new clusters to serve as light-harvesting materials. Upon optical excitation, electron injection at Ag29 NC/methyl viologen (MV(2+)) interfaces is very efficient and ultrafast. Interestingly, our femto- and nanosecond time-resolved results demonstrate clearly that both dynamic and static electron transfer mechanisms are involved in photoluminescence quenching of Ag29 NCs.


Patients' values and preferences of the expected efficacy of hip arthroscopy for osteoarthritis: a protocol for a multinational structured interview-based study combined with a randomised survey on the optimal amount of information to elicit preferences.
Symptomatic hip osteoarthritis (OA) is a disabling condition with up to a 25% cumulative lifetime risk. Total hip arthroplasty (THA) is effective in relieving patients' symptoms and improving function. It is, however, associated with substantial risk of complications, pain and major functional limitation before patients can return to full function. In contrast, hip arthroscopy (HA) is less invasive and can postpone THA. However, there is no evidence regarding the delay in the need for THA that patients would find acceptable to undergoing HA. Knowing patients' values and preferences (VP) on this expected delay is critical when making recommendations regarding the advisability of HA. Furthermore, little is known on the optimal amount of information regarding interventions and outcomes needed to present in order to optimally elicit patients' VP. We will perform a multinational, structured interview-based survey of preference in delay time for THA among patients with non-advanced OA who failed to respond to conservative therapy. We will combine these interviews with a randomised trial addressing the optimal amount of information regarding the interventions and outcomes required to elicit preferences. Eligible patients will be randomly assigned (1 : 1) to either a short or a long format of health scenarios of THA and HA. We will determine each patient's VP using a trade-off and anticipated regret exercises. Our primary outcomes for the combined surveys will be: (1) the minimal delay time in the need for THA surgery that patients would find acceptable to undertaking HA, (2) patients' satisfaction with the amount of information provided in the health scenarios used to elicit their VPs. The protocol has been approved by the Hamilton Integrated Research Ethics Board (HIREB13-506). We will disseminate our study findings through peer-reviewed publications and conference presentations, and make them available to guideline makers issuing recommendations addressing HA and THA.


Primitive adult hematopoietic stem cells can function as osteoblast precursors.
Osteoblasts are continually recruited from stem cell pools to maintain bone. Although their immediate precursor is a plastic-adherent mesenchymal stem cell able to generate tissues other than bone, increasing evidence suggests the existence of a more primitive cell that can differentiate to both hematopoietic and mesenchymal cells. We show here that the "side population" (SP) of marrow stem cells, defined by their ability to rapidly expel a DNA-binding dye and to regenerate the hematopoietic compartment, can differentiate to osteoblasts through a mesenchymal intermediate. When transplanted into lethally irradiated mice, single gene-marked murine SP cells reconstituted depleted osteoprogenitor pools, such that a large proportion of the osteogenic cells in the epiphysis of long bone carried the donor SP cell marker. These findings suggest that the developmental capacity of SP cells is not restricted to the hematopoietic lineages but extends to osteogenic differentiation. This property not only elucidates a previously unrecognized step in osteoblast development, but also has intriguing implications for the use of SP cells in clinical orthopedics and stem cell-based disorders of bone.


Identification by site-directed mutagenesis of amino acids contributing to ligand-binding specificity or signal transduction properties of the human FP prostanoid receptor.
Prostanoid receptors belong to the class of heptahelical plasma membrane receptors. For the five prostanoids, eight receptor subtypes have been identified. They display an overall sequence similarity of roughly 30%. Based on sequence comparison, single amino acids in different subtypes of different species have previously been identified by site-directed mutagenesis or in hybrid receptors that appear to be essential for ligand binding or G-protein coupling. Based on this information, a series of mutants of the human FP receptor was generated and characterized in ligand-binding and second-messenger-formation studies. It was found that mutation of His-81 to Ala in transmembrane domain 2 and of Arg-291 to Leu in transmembrane domain 7, which are putative interaction partners for the prostanoid's carboxyl group, abolished ligand binding. Mutants in which Ser-263 in transmembrane domain 6 or Asp-300 in transmembrane domain 7 had been replaced by Ala or Gln, respectively, no longer discriminated between prostaglandins PGF(2alpha) and PGD(2). Thus distortion of the topology of transmembrane domains 6 and 7 appears to interfere with the cyclopentane ring selectivity of the receptor. PGF(2alpha)-induced inositol formation was strongly reduced in the mutant Asp-300Gln, inferring a role for this residue in agonist-induced G-protein activation.


Improving the Accuracy of Registration-Based Biomechanical Analysis: A Finite Element Approach to Lung Regional Strain Quantification.
Tissue deformation plays an important role in lung physiology, as lung parenchyma largely deforms during spontaneous ventilation. However, excessive regional deformation may lead to lung injury, as observed in patients undergoing mechanical ventilation. Thus, the accurate estimation of regional strain has recently received great attention in the intensive care community. In this work, we assess the accuracy of regional strain maps computed from direct differentiation of B-Spline (BS) interpolations, a popular technique employed in non-rigid registration of lung computed tomography (CT) images. We show that, while BS-based registration methods give excellent results for the deformation transformation, the strain field directly computed from BS derivatives results in predictions that largely oscillate, thus introducing important errors that can even revert the sign of strain. To alleviate such spurious behavior, we present a novel finite-element (FE) method for the regional strain analysis of lung CT images. The method follows from a variational strain recovery formulation, and delivers a continuous approximation to the strain field in arbitrary domains. From analytical benchmarks, we show that the FE method results in errors that are a fraction of those found for the BS method, both in an average and pointwise sense. The application of the proposed FE method to human lung CT images results in 3D strain maps are heterogeneous and smooth, showing high consistency with specific ventilation maps reported in the literature. We envision that the proposed FE method will considerably improve the accuracy of image-based biomechanical analysis, making it reliable enough for routine medical applications.


Evidence for Dobzhansky-Muller incompatibilites contributing to the sterility of hybrids between Mimulus guttatus and M. nasutus.
Both chromosomal rearrangements and negative interactions among loci (Dobzhansky-Muller incompatibilities) have been advanced as the genetic mechanism underlying the sterility of interspecific hybrids. These alternatives invoke very different evolutionary histories during speciation and also predict different patterns of sterility in artificial hybrids. Chromosomal rearrangements require drift, inbreeding, or other special conditions for initial fixation and, because heterozygosity per se generates any problems with gamete formation, F1 hybrids will be most infertile. In contrast, Dobzhansky-Muller incompatibilities may arise as byproducts of adaptive evolution and often affect the segregating F2 generation most severely. To distinguish the effects of these two mechanisms early in divergence, we investigated the quantitative genetics of hybrid sterility in a line cross between two members of the Mimulus guttatus species complex (M. guttatus and M. nasutus). Hybrids showed partial male and female sterility, and the patterns of infertility were not consistent with the action of chromosomal rearrangements alone. F2 and F1 hybrids exhibited equal decreases in pollen viability (> 40%) relative to the highly fertile parental lines. A large excess of completely pollen-sterile F2 genotypes also pointed to the segregation of Dobzhansky-Muller incompatibility factors affecting male fertility. Female fertility showed a pattern similarly consistent with epistatic interactions: F2 hybrids produced far fewer seeds per flower than F1 hybrids (88.0 +/- 2.8 vs. 162.9 +/- 8.5 SE, respectively) and either parental line, and many F2 genotypes were completely female sterile. Dobzhansky-Muller interactions also resulted in the breakdown of several nonreproductive characters and appear to contribute to correlations between male and female fertility in the F2 generation. These results parallel and contrast with the genetics of postzygotic isolation in model animal systems and are a first step toward understanding the process of speciation in this well-studied group of flowering plants.


Expression of T-cell-associated serine proteinase 1 during murine Leishmania major infection correlates with susceptibility to disease.
The expression of T-cell-associated serine proteinase 1 (MTSP-1) in vivo during Leishmania major infection was analyzed in genetically resistant C57BL/6 mice and in genetically susceptible BALB/c mice. Using a monoclonal antibody as well as an RNA probe specific for MTSP-1 to stain tissue sections, we found T cells expressing MTSP-1 in skin lesions and spleens of mice of both strains. In skin lesions, MTSP-1-positive T cells could be detected as early as 3 days after infection. Most importantly, the frequency of T cells expressing MTSP-1 was significantly higher in susceptible BALB/c mice than in resistant C57BL/6 mice. These findings suggest that MTSP-1 is associated with disease-promoting T cells and that it may be an effector molecule involved in the pathogenesis of cutaneous leishmaniasis.


Band 6 protein, a major constituent of desmosomes from stratified epithelia, is a novel member of the armadillo multigene family.
Desmosomes are intercellular adhering junctions characteristic of epithelial cells. Several constitutive proteins--desmoplakin, plakoglobin and the transmembrane glycoproteins desmoglein and desmocollin--have been identified as fundamental constituents of desmosomes in all tissues. A number of additional and cell type-specific constituents also contribute to desmosomal plaque formation. Among these proteins is the band 6 polypeptide (B6P). This positively charged, non-glycosylated protein is a major constituent of the plaque in stratified and complex glandular epithelia. Using an overlay assay we show that purified keratins bind in vitro to B6P. Thus B6P may play a role in ordering intermediate filament networks of adjacent epithelial cells. To characterize the structure of B6P in the desmosome we have isolated cDNA clones representing the entire coding sequence. The predicted amino acid sequence of human B6P shows strong sequence homology with a murine p120 protein, which is a substrate of protein tyrosine kinase receptors and of p60v-src. P120 and B6P show amino-terminal domains differing distinctly in length and sequence. These are followed in both proteins by 460 residues that display a series of imperfect repeats corresponding to the repeats in the cadherin binding proteins armadillo, plakoglobin and beta-catenin. Over this repeat region B6P and p120 share 33% sequence identity (54% similarity). These sequence characteristics define B6P as a novel member of the armadillo multigene family and raise the question of whether the structural proteins B6P, plakoglobin, beta-catenin and armadillo share some function. Since armadillo, plakoglobin, beta-catenin and p120 seem involved in signal transduction this may also hold for B6P. The amino-terminal region of B6P (residues 1 to 263) shows no significant homology to any known protein sequence. It may therefore be involved in unique functions of B6P.


Memoryless control of boundary concentrations of diffusing particles.
Flux between regions of different concentration occurs in nearly every device involving diffusion, whether an electrochemical cell, a bipolar transistor, or a protein channel in a biological membrane. Diffusion theory has calculated that flux since the time of Fick (1855), and the flux has been known to arise from the stochastic behavior of Brownian trajectories since the time of Einstein (1905), yet the mathematical description of the behavior of trajectories corresponding to different types of boundaries is not complete. We consider the trajectories of noninteracting particles diffusing in a finite region connecting two baths of fixed concentrations. Inside the region, the trajectories of diffusing particles are governed by the Langevin equation. To maintain average concentrations at the boundaries of the region at their values in the baths, a control mechanism is needed to set the boundary dynamics of the trajectories. Different control mechanisms are used in Langevin and Brownian simulations of such systems. We analyze models of controllers and derive equations for the time evolution and spatial distribution of particles inside the domain. Our analysis shows a distinct difference between the time evolution and the steady state concentrations. While the time evolution of the density is governed by an integral operator, the spatial distribution is governed by the familiar Fokker-Planck operator. The boundary conditions for the time dependent density depend on the model of the controller; however, this dependence disappears in the steady state, if the controller is of a renewal type. Renewal-type controllers, however, produce spurious boundary layers that can be catastrophic in simulations of charged particles, because even a tiny net charge can have global effects. The design of a nonrenewal controller that maintains concentrations of noninteracting particles without creating spurious boundary layers at the interface requires the solution of the time-dependent Fokker-Planck equation with absorption of outgoing trajectories and a source of ingoing trajectories on the boundary (the so called albedo problem).


Ab initio resolution measurement for single particle structures.
A computational method is described that allows the measurement of the signal-to-noise ratio and resolution of a three-dimensional structure obtained by single particle electron microscopy and reconstruction. The method does not rely on the availability of the original image data or the calculation of several structures from different parts of the data that are needed for the commonly used Fourier Shell Correlation criterion. Instead, the correlation between neighboring Fourier pixels is calculated and used to distinguish signal from noise. The new method has been conveniently implemented in a computer program called RMEASURE and is available to the microscopy community.


The impact of Lean bundles on hospital performance: does size matter?
Purpose The purpose of this paper is to study the effect of the implementation of Lean bundles on hospital performance in private hospitals in Jordan and evaluate how much the size of organization can affect the relationship between Lean bundles implementation and hospital performance. Design/methodology/approach The research is considered as quantitative method (descriptive and hypothesis testing). Three statistical techniques were adopted to analyse the data. Structural equation modeling techniques and multi-group analysis were used to examine the research's hypothesis, and to perform the required statistical analysis of the data from the survey. Reliability analysis and confirmatory factor analysis were used to test the construct validity, reliability and measurement loadings that were performed. Findings Lean bundles have been identified as an effective approach that can dramatically improve the organizational performance of private hospitals in Jordan. Main Lean bundles - just in time, human resource management, and total quality management are applicable to large, small and medium hospitals without significant differences in advantages that depend on size. Originality/value According to the researchers' best knowledge, this is the first research that studies the impact of Lean bundles implementation in healthcare sector in Jordan. This research also makes a significant contribution for decision makers in healthcare to increase their awareness of Lean bundles.


Factors affecting IUCD discontinuation in Nepal: a nested case-control study.
Information related to contraception discontinuation, especially in the context of Nepal is very limited. A nested case-control study was carried out to determine the factors affecting discontinuation of intrauterine contraceptive devices (IUCDs). A total of 115 cases (IUCD discontinuers) and 115 controls (IUCD continuers) were randomly selected based on the data obtained from the user's record of a family planning center in Kathmandu. Matching criteria were age during insertion and date of insertion of IUCD. Logistic regression was used to analyze the data. When cases were compared with controls, the results showed that place of residence, sex of last child, reproductive intention, experience of side effects, and follow-up practice were associated with discontinuation of the IUCD. Experience of side effects has been seen as the major reason for discontinuation. The results suggest that side effects after IUCD insertion should be properly discussed and promptly treated to reduce the discontinuation rate.


A spiking neural network model of model-free reinforcement learning with high-dimensional sensory input and perceptual ambiguity.
A theoretical framework of reinforcement learning plays an important role in understanding action selection in animals. Spiking neural networks provide a theoretically grounded means to test computational hypotheses on neurally plausible algorithms of reinforcement learning through numerical simulation. However, most of these models cannot handle observations which are noisy, or occurred in the past, even though these are inevitable and constraining features of learning in real environments. This class of problem is formally known as partially observable reinforcement learning (PORL) problems. It provides a generalization of reinforcement learning to partially observable domains. In addition, observations in the real world tend to be rich and high-dimensional. In this work, we use a spiking neural network model to approximate the free energy of a restricted Boltzmann machine and apply it to the solution of PORL problems with high-dimensional observations. Our spiking network model solves maze tasks with perceptually ambiguous high-dimensional observations without knowledge of the true environment. An extended model with working memory also solves history-dependent tasks. The way spiking neural networks handle PORL problems may provide a glimpse into the underlying laws of neural information processing which can only be discovered through such a top-down approach.


Utility Values for Health States in Ireland: A Value Set for the EQ-5D-5L.
Our objective was to develop a value set based on Irish utility values for the EuroQol 5-Dimension, 5-Level instrument (EQ-5D-5L). The research design and data collection followed a protocol developed by the EuroQol Group. The EuroQol Valuation Technology (EQ-VT) software was administered using computer-assisted personal interviews to a representative sample of adults resident in Ireland between 2015 and 2016. Utility values were elicited using two stated-preference techniques: time trade-off (TTO) and discrete-choice experiment (DCE). Each respondent completed a valuation exercise in which the EQ-VT system randomly selected one block of ten TTO questions from ten blocks relating to a possible 86 health states. One block of seven DCE pairs from 28 blocks of a possible 196 pairs of health states were randomly selected to accompany this. The relationship between utility values and health states was analysed using a hybrid regression model that combined data from the TTO and DCE techniques and expressed these as a function of the health state presented to the individual. This model estimated coefficients for 20 dummy variables that characterised each health state in the EQ-5D-5L framework, with the lowest level of severity providing the reference category in each domain. The relationship between weighted and unweighted TTO and DCE analyses of main effects was analysed separately. Comparison of weighted and unweighted models revealed no substantive differences in results with respect to either DCE or TTO models. The unweighted hybrid model produced estimated effects, the ordering of which was intuitively consistent within each domain: lower levels of health were associated with lower utility values. Differences were evident between domains with respect to valuations; the disutility associated with conditions related to anxiety/depression and pain/discomfort was higher than for other domains. The decrement in utility associated with movement from the highest to the lowest level of health was 0.344 for mobility, 0.287 for self-care, 0.187 for usual activities, 0.510 for pain/discomfort and 0.646 for anxiety/depression. The results present the first value set based on the EQ-5D-5L framework for a representative sample of residents in Ireland. The set reveals a higher decrement in utility associated with anxiety/depression than with other domains of health. Caution is warranted in comparisons with other value sets. That said, those in England, the Netherlands, Uruguay and China reveal that, whereas Irish values are broadly consistent with respect to mobility, self-care and usual activities, residents of Ireland attach a higher decrement to pain/discomfort and anxiety/depression than do other populations.


Resourcing an evolution of roles in general-practice: a study to determine the validity and reliability of tools to assist nurses and patients to assess physical activity.
Traditionally, GPs have been responsible for physical activity (PA) assessment within the general practice setting. Multiple questionnaires are available to support uptake of PA assessment but less than 30% of patients are assessed. A range of barriers hamper uptake. Evidence indicates that practice nurses (PNs) and patients are resourceful members of the general practice team but have been underutilised. This study assessed the validity and reliability of two instruments for assessing PA, administered by PNs and patients. The study aimed to identify robust tool(s) to support the evolving role of PNs and patients in prevention and management strategies in general practice. A purposive sample of PNs and patients from general practices in Sydney was invited to participate. The results of the PN- or patient-administered general practice physical activity questionnaire (GPPAQ) and the three-question physical activity questionnaire (3Q) were compared against accelerometer activity. The study examined agreement in classification of PA levels according to Australian PA recommendations. Validity showed low-moderate correlations between accelerometer and GPPAQ (rho=0.26), 3Q (rho=0.45). Seven-day test-retest reliability intraclass correlation coefficients (ICCs) were 0.82-0.95 for GGPAQ and 0.94-0.98 for 3Q. Agreement with PA recommendations was moderate for GPPAQ (kappa 0.73, 95% CI, 0.56-0.85) and fair for 3Q (kappa 0.62, 95% CI, 0.47-0.78). Although 3Q demonstrated higher correlation with accelerometry, GPPAQ demonstrated higher agreement with PA guidelines. Given GPPAQ showed reasonable rigour, it may prove useful for PN and patient use.


Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor.
Two metabolites of the steroid hormones progesterone and deoxycorticosterone, 3 alpha-hydroxy-5 alpha-dihydroprogesterone and 3 alpha, 5 alpha-tetrahydrodeoxycorticosterone, are potent barbiturate-like ligands of the gamma-aminobutyric acid (GABA) receptor-chloride ion channel complex. At concentrations between 10(-7) and 10(-5)M both steroids inhibited binding of the convulsant t-butylbicyclophosphorothionate to the GABA-receptor complex and increased the binding of the benzodiazepine flunitrazepam; they also stimulated chloride uptake (as measured by uptake of 36Cl-) into isolated brain vesicles, and potentiated the inhibitory actions of GABA in cultured rat hippocampal and spinal cord neurons. These data may explain the ability of certain steroid hormones to rapidly alter neuronal excitability and may provide a mechanism for the anesthetic and hypnotic actions of naturally occurring and synthetic anesthetic steroids.


Resonant Tunneling Induced Enhancement of Electron Field Emission by Ultra-Thin Coatings.
The emission of electrons from the surface of a material into vacuum depends strongly on the material's work function, temperature, and the intensity of electric field. The combined effects of these give rise to a multitude of related phenomena, including Fowler-Nordheim tunneling and Schottky emission, which, in turn, enable several families of devices, ranging from vacuum tubes, to Schottky diodes, and thermionic energy converters. More recently, nanomembrane-based detectors have found applications in high-resolution mass spectrometry measurements in proteomics. Progress in all the aforementioned applications critically depends on discovering materials with effective low surface work functions. We show that a few atomic layer deposition (ALD) cycles of zinc oxide onto suspended diamond nanomembranes, strongly reduces the threshold voltage for the onset of electron field emission which is captured by resonant tunneling from the ZnO layer. Solving the Schroedinger equation, we obtain an electrical field- and thickness-dependent population of the lowest few subbands in the thin ZnO layer, which results in a minimum in the threshold voltage at a thickness of 1.08 nm being in agreement with the experimentally determined value. We conclude that resonant tunneling enables cost-effective ALD coatings that lower the effective work function and enhance field emission from the device.


The genetic impact of Aztec imperialism: ancient mitochondrial DNA evidence from Xaltocan, Mexico.
In AD 1428, the city-states of Tenochtitlan, Texcoco, and Tlacopan formed the Triple Alliance, laying the foundations of the Aztec empire. Although it is well documented that the Aztecs annexed numerous polities in the Basin of Mexico over the following years, the demographic consequences of this expansion remain unclear. At the city-state capital of Xaltocan, 16th century documents suggest that the site's conquest and subsequent incorporation into the Aztec empire led to a replacement of the original Otomí population, whereas archaeological evidence suggests that some of the original population may have remained at the town under Aztec rule. To help address questions about Xaltocan's demographic history during this period, we analyzed ancient DNA from 25 individuals recovered from three houses rebuilt over time and occupied between AD 1240 and 1521. These individuals were divided into two temporal groups that predate and postdate the site's conquest. We determined the mitochondrial DNA haplogroup of each individual and identified haplotypes based on 372 base pair sequences of first hypervariable region. Our results indicate that the residents of these houses before and after the Aztec conquest have distinct haplotypes that are not closely related, and the mitochondrial compositions of the temporal groups are statistically different. Altogether, these results suggest that the matrilines present in the households were replaced following the Aztec conquest. This study therefore indicates that the Aztec expansion may have been associated with significant demographic and genetic changes within Xaltocan.


Mediators of interpersonal violence and drug addiction severity among methamphetamine users in Cape Town, South Africa.
South Africa has high rates of interpersonal violence and a rapidly growing methamphetamine epidemic. Previous research has linked experiences of interpersonal violence to higher rates of substance use, and identified mental health constructs as potential mediators of this association. The aim of this study was to examine the relationship between interpersonal violence and addiction severity among active methamphetamine users in Cape Town, South Africa, and to explore symptoms of posttraumatic stress disorder (PTSD) and substance use coping as mediators of this relationship. A community sample of 360 methamphetamine users was recruited through respondent driven sampling and surveyed on their experiences of violence, mental health, coping, and drug use and severity. A series of one-way ANOVAs were conducted to examine the relationship of self-reported interpersonal violence with drug addiction severity, and multiple mediation analyses were used to determine if PTSD symptoms and substance use coping mediated this relationship. The majority (87%) of the sample reported experiencing at least one instance of interpersonal violence in their lifetime, and the number of violent experiences was associated with increased drug addiction severity. PTSD and substance use coping were significant mediators of this association. Only the indirect effect of substance use coping remained significant for the female sample when the mediation model was conducted separately for men and women. The findings point to the need for integrated treatments that address drug use and PTSD for methamphetamine users in South Africa and highlight the importance of coping interventions for women.


Patient-centered communication strategies for patients with aphasia: discrepancies between what patients want and what physicians do.
Communication during clinical encounters can be challenging with patients with communication disabilities. Physicians have the potential to positively affect the encounter by using communication strategies that engage the patient in patient-centered communication. We engaged patients and their physicians in defining their preferences for patient-centered communication strategies, then evaluated the use of the identified strategies during observed clinical encounters. We video-recorded 25 clinical encounters with persons with aphasia. All encounters were previously scheduled with community physicians and a companion was present. Following each encounter, physicians completed a brief questionnaire and the person with aphasia and his or her companion participated in a video elicitation interview. While many of the communication strategies identified and described by physicians, patients and companions were similar, patients and companions identified three additional key communication strategies. These strategies included (1) using visual aids, (2) writing down key words while speaking, and (3) using gestures. In the video recorded clinical encounters, no physicians wrote down key words while speaking and only one used a visual aid during the clinical encounter. The frequency with which physicians used gestures varied greatly, even within the same patient, suggesting the use of gestures was independent of patient or companion characteristics. To maximize patient-centered communication with patients with communication disabilities, physicians should use "disability-specific" communication strategies. Our study suggests that physicians should routinely ask patients and companions about communication preferences and then incorporate identified communication strategies into their communication style.


IROme, a new high-throughput molecular tool for the diagnosis of inherited retinal dystrophies.
The molecular diagnosis of retinal dystrophies is difficult because of the very important number of genes implicated and is rarely helped by genotype-phenotype correlations. This prompted us to develop IROme, a custom designed in solution-based targeted exon capture assay (SeqCap EZ Choice library, Roche NimbleGen) for 60 retinitis pigmentosa-linked genes and three candidate genes (942 exons). Pyrosequencing was performed on a Roche 454 GS Junior benchtop high-throughput sequencing platform. In total, 23 patients affected by retinitis pigmentosa were analyzed. Per patient, 39.6 Mb were generated, and 1111 sequence variants were detected on average, at a median coverage of 17-fold. After data filtering and sequence variant prioritization, disease-causing mutations were identified in ABCA4, CNGB1, GUCY2D, PROM1, PRPF8, PRPF31, PRPH2, RHO, RP2, and TULP1 for twelve patients (55%), ten mutations having never been reported previously. Potential mutations were identified in 5 additional patients, and in only 6 patients no molecular diagnosis could be established (26%). In conclusion, targeted exon capture and next-generation sequencing are a valuable and efficient approach to identify disease-causing sequence variants in retinal dystrophies.


Calcium handling in airway smooth muscle: mechanisms and therapeutic implications.
Calcium plays a central role in the activation of many cellular processes, including the most relevant end-point in airway smooth muscle physiology: contraction. For this reason, the cytosolic concentration of calcium is tightly controlled by an elaborate array of mechanisms. The latter include multiple entry pathways from the extracellular space, a pump on the membrane that extrudes calcium out of the cell, an internal pump that sequesters calcium into an intracellular pool and at least two types of release sites from which sequestered calcium can be released back into the cytosol; all of these mechanisms are tightly regulated by second messenger-signalling pathways. Understanding of the relationship between calcium handling and contraction ('excitation-contraction coupling') has progressed from a mechanism in which activation of voltage-dependent calcium channels plays a central role (as in skeletal muscle) to a mechanism in which a small localized signalling event triggers a massive release of internal calcium (as in cardiac muscle) to a more complicated model in which the internal calcium pool divides the cytosol into two physiologically distinct spaces where the cytosolic concentration of calcium is regulated independently (as in vascular smooth muscle). The changes that may occur in calcium-handling pathways in asthma and the opportunities for novel approaches to the treatment of asthma are also discussed.


A multi-centre, randomised controlled trial of cognitive therapy to prevent harmful compliance with command hallucinations.
Command hallucinations are among the most distressing, high risk and treatment resistant symptoms for people with psychosis; however, currently, there are no evidence-based treatment options available for this group. A cognitive therapy grounded in the principles of the Social Rank Theory, is being evaluated in terms of its effectiveness in reducing harmful compliance with command hallucinations. This is a single blind, intention-to-treat, multi-centre, randomized controlled trial comparing Cognitive Therapy for Command Hallucinations + Treatment as Usual with Treatment as Usual alone. Eligible participants have to fulfil the following inclusion criteria: i) ≥16 years; ii) ICD-10 diagnosis of schizophrenia or related disorder; iii) command hallucinations for at least 6 months leading to risk of harm to self or others. Following the completion of baseline assessments, eligible participants will be randomly allocated to either the Cognitive Therapy for Command Hallucinations + Treatment as Usual group or the Treatment as Usual group. Outcome will be assessed at 9 and 18 months post randomization with assessors blind to treatment allocation. The primary outcome is compliance behaviour and secondary outcomes include beliefs about voices' power, distress, psychotic symptoms together with a health economic evaluation. Qualitative interviews with services users will explore the acceptability of Cognitive Therapy for Command Hallucinations. Cognitive behaviour therapy is recommended for people with psychosis; however, its focus and evaluation has primarily revolved around the reduction of psychotic symptoms. In this trial, however, the focus of the cognitive behavioural intervention is on individuals' appraisals, behaviour and affect and not necessarily symptoms; this is also reflected in the outcome measures used. If successful, the results will mark a significant breakthrough in the evidence base for service users and clinicians and will provide a treatment option for this group where none currently exist. The trial will open the way for further breakthrough work with the 'high risk' population of individuals with psychosis, which we would intend to pursue. ISRCTN: ISRCTN62304114.


Durable effects of cognitive restructuring on conditioned fear.
Studies of cognitive reappraisal have demonstrated that reinterpreting a stimulus can alter emotional responding, yet few studies have examined the durable effects associated with reinterpretation-based emotion regulation strategies. Evidence for the enduring effects of emotion regulation may be found in clinical studies that use cognitive restructuring (CR) techniques in cognitive-behavioral therapy (CBT) to alleviate anxiety. These techniques are based on cognitive theories of anxiety that suggest these disorders arise from biased cognitions; therefore, changing a person's thoughts will elicit durable changes in an individual's emotional responses. Despite the considerable success of CBT for anxiety disorders, durable effects associated with emotion regulation have not been thoroughly examined in the context of a laboratory paradigm. The goal of this study was to determine whether CR, a technique used in CBT and similar to cognitive reappraisal, could attenuate conditioned fear responses, and whether the effect would persist over time (24 hr). We conditioned participants using images of snakes or spiders that were occasionally paired with a mild shock to the wrist while we obtained subjective fear reports and electrodermal activity (EDA). After conditioning, half of the participants were randomly assigned to CR training aimed at decreasing their emotional response to the shock and the conditioned stimuli, while the other half received no such training. All participants returned 24 hr later to repeat the conditioning session. Compared with control participants, CR participants demonstrated a reduction in fear and EDA across sessions. These findings suggest that CR has durable effects on fear responding.


Pathogenesis-related PR-1 proteins are antifungal. Isolation and characterization of three 14-kilodalton proteins of tomato and of a basic PR-1 of tobacco with inhibitory activity against Phytophthora infestans.
Three distinct basic 14-kD proteins, P14a, P14b, and P14c, were isolated from tomato (Lycopersicon esculentum Mill. cv Baby) leaves infected with Phytophthora infestans. They exhibited antifungal activity against P. infestans both in vitro (inhibition of zoospore germination) and in vivo with a tomato leaf disc assay (decrease in infected leaf surface). Serological cross-reactions and amino acid sequence comparisons showed that the three proteins are members of the PR-1 group of pathogenesis-related (PR) proteins. P14a and P14b showed high similarity to a previously characterized P14, whereas P14c was found to be very similar to a putative basic-type PR-1 from tobacco predicted from isolated DNA clones. This protein, named PR-1 g, was purified from virus-infected tobacco (Nicotiana tabacum Samsun NN) leaves and characterized by amino acid microsequencing, along with the well-known acidic tobacco PR-1a, PR-1b, and PR-1c. The various tomato and tobacco PR-1 proteins were compared for their biological activity and found to display differential fungicidal activity against P. infestans in both the in vitro and in vivo assays, the most efficient being the newly characterized tomato P14c and tobacco PR-1g.


Probing electric field control of magnetism using ferromagnetic resonance.
Exchange coupled CoFe/BiFeO3 thin-film heterostructures show great promise for power-efficient electric field-induced 180° magnetization switching. However, the coupling mechanism and precise qualification of the exchange coupling in CoFe/BiFeO3 heterostructures have been elusive. Here we show direct evidence for electric field control of the magnetic state in exchange coupled CoFe/BiFeO3 through electric field-dependent ferromagnetic resonance spectroscopy and nanoscale spatially resolved magnetic imaging. Scanning electron microscopy with polarization analysis images reveal the coupling of the magnetization in the CoFe layer to the canted moment in the BiFeO3 layer. Electric field-dependent ferromagnetic resonance measurements quantify the exchange coupling strength and reveal that the CoFe magnetization is directly and reversibly modulated by the applied electric field through a ~180° switching of the canted moment in BiFeO3. This constitutes an important step towards robust repeatable and non-volatile voltage-induced 180° magnetization switching in thin-film multiferroic heterostructures and tunable RF/microwave devices.


Could Beta blockade improve outcome after injury by modulating inflammatory profiles?
Cardioprotection with beta-receptor antagonists improves outcome in high risk patients undergoing elective surgery. Recent trials have demonstrated an association between beta blocker (BB) use and improved outcomes after injury. The mechanisms through which BB result in improved outcomes remain poorly elucidated. In vitro evidence supports that BB modulates the postinjury inflammatory response. The purpose of this study was to examine the effects of BB on inflammatory profiles in injured patients at increased risk for heart disease. A pseudo-randomized, controlled trial of injured patients over 55 admitted to the intensive care unit was conducted. Patients were randomized to receive continuous BB or standard of care. Patients with a reported history of prehospital BB use were enrolled into an observational arm of the trial, continued on BB, and analyzed with the continuous BB group. Plasma interleukin (IL)-6 and IL-1beta levels were measured by enzyme-linked immunosorbent assay at baseline and day 1, 2, and 4 after BB initiation. Cytokine data were log transformed for normality assumptions. Repeated measures analysis of variance was used to test for within-group differences in cytokine levels over time. Forty-two patients were enrolled. Seventeen patients were randomized to the control group and 25 patients received continuous BB (10 randomized/15 observational). There was no difference in gender, age, prior history of heart disease, or admission heart rate, systolic blood pressure or initial base deficit between groups. Baseline levels of IL-6 and IL-1beta did not differ between groups. Levels of IL-6, but not IL-1beta, decreased over time in patients receiving BB (p = 0.04), whereas levels in controls remained unchanged (p = 0.27). There were no BB related complications. Use of BB decreases serum IL-6 levels over time in injured patients at risk for heart disease. This may contribute to improved outcomes noted in trauma patients receiving BB. Additionally, BB use in this population of patients is safe after endpoints of resuscitation have been met.


Safety of long-term intrathecal methotrexate in progressive forms of MS.
There are few treatment options for multiple sclerosis (MS) patients with advanced disability [expanded disability status scale (EDSS) ⩾ 6.0]. In 2010, we reported initial results of using intrathecal methotrexate (ITMTX) in patients with progressive MS. We now report on long-term use of ITMTX. We performed a retrospective chart analysis of patients who have had 18 or more treatments to establish the ongoing safety and tolerability of ITMTX. Thus, the objective of this study was to establish the safety and tolerability of long-term therapy with (ITMTX) in patients with treatment-resistant, progressive forms of MS. We studied 83 patients (67 secondary and 16 primary progressive) who received ITMTX 12.5 mg every 8-11 weeks for 3-10 years (range: 18-57 treatments). All patients were evaluated neurologically, and their EDSS was assessed at every treatment. In addition, all adverse events, frequency of infections, and any hospitalizations, were noted. There were no deaths, hospitalizations, or other serious adverse effects related to ITMTX. Headaches occurred at least once in 12% of patients, and transient fatigue occurred in 53% of patients. As determined by EDSS, there was no significant change from baseline status to post-treatment scores in both primary progressive MS (PPMS) and secondary progressive (SPMS) patients. Pulsed ITMTX was well tolerated for up to 10 years in PPMS patients with no serious adverse effects. Although this was an open-label, retrospective analysis, and efficacy could not be studied, there was evidence of disease stabilization in many patients receiving ITMTX. It appears that long-term ITMTX is a safe therapeutic option in advanced progressive MS.


MUC16 expression in Sjogren's syndrome, KCS, and control subjects.
To investigate the expression of MUC16 protein in tears and conjunctival cell membranes and MUC16 mRNA in conjunctival cells of Sjogren's syndrome (SS), keratoconjunctivitus sicca (KCS) and non-dry eyed (NDE) subjects. The relationship of tear flow and soluble MUC16 concentration was also measured. Seventy-six subjects were recruited for this study: 25 SS (confirmed via American-European Consensus Criteria 2002), 25 KCS (confirmed by symptoms and Schirmer scores < or =10 mm) and 26 NDE. Tear flow was measured by the Schirmer test without anesthesia for 5 min. Tears were collected using an eye-wash technique. Protein and mRNA were isolated from conjunctival epithelial cells collected via impression cytology. Soluble and membrane bound MUC16 were quantified via western blotting and MUC16 mRNA was quantified by real time qPCR. The SS group demonstrated significantly higher concentrations of soluble MUC16 (7.28 [SS] +/- 3.97 versus 3.35 [KCS] +/- 4.54 [p=0.004] and versus 1.61 [NDE] +/- 1.22 [p<0.001]) and MUC16 mRNA (4.66 [SS] +/- 5.06 versus 1.84 [KCS] +/- 2.26 [p=0.01] and 1.52 [NDE] +/- 1.04 [p=0.003]) compared to both KCS and NDE groups, respectively. No differences in soluble MUC16 or MUC16 mRNA were found between the KCS and NDE groups. Membrane bound MUC16 was similar in all three groups. No significant correlation was found between mean Schirmer values and any measure of MUC16 expression. These results demonstrate that SS subjects display a significant increase in both soluble MUC16 and MUC16 mRNA concentrations compared to other forms of aqueous deficient dry eye and non dry-eyed individuals. There was no correlation between tear flow and soluble MUC16 concentration.


Evaluation of sister chromatid exchange and chromosome breaks in a cohort of untreated Hodgkin's disease patients.
Cytogenetic biomarkers, chromosomal breaks [spontaneous breaks (SB) and bleomycin-induced breaks (BIB)], and sister chromatid exchange (SCE) have been shown to be sensitive cytological assays to defect susceptibility to DNA-damaging effects. However, little information is available on how environmental factors and demographic and clinical characteristics influence variation among individuals. We sought to characterize interindividual variability in a cohort of 105 untreated adult Hodgkin's disease patients. SB, BIB, and SCE data were integrated with epidemiological data by using linear regression analysis. Age, sex, ethnicity, education, histology, history of mononucleosis, and family history of cancer showed no association with any biomarker. In univariate analysis, alcohol intake was significantly associated with high SCEs (P = 0.005) and SBs (P = 0.02). Current smoking was associated only with high frequencies of SCE (P = 0.05). Advanced stage of disease was related with high SBs (P = 0.01). BIBs were not associated with any of the variables studied. In multivariate modeling, current alcohol intake was associated with high SCEs (P = 0.04) and SBs (P = 0.01). Former smokers had higher SBs than nonsmokers did (P = 0.02). A small positive correlation was found among each pair of markers. The higher SCEs and SBs in patients who smoke and consume alcohol indicate the need for evaluating these exposures when interpreting these biomarkers.


Overlapping spectra of SMAD4 mutations in juvenile polyposis (JP) and JP-HHT syndrome.
Juvenile polyposis (JP) and hereditary hemorrhagic telangiectasia (HHT) are clinically distinct diseases caused by mutations in SMAD4 and BMPR1A (for JP) and endoglin and ALK1 (for HHT). Recently, a combined syndrome of JP-HHT was described that is also caused by mutations in SMAD4. Although both JP and JP-HHT are caused by SMAD4 mutations, a possible genotype:phenotype correlation was noted as all of the SMAD4 mutations in the JP-HHT patients were clustered in the COOH-terminal MH2 domain of the protein. If valid, this correlation would provide a molecular explanation for the phenotypic differences, as well as a pre-symptomatic diagnostic test to distinguish patients at risk for the overlapping but different clinical features of the disorders. In this study, we collected 19 new JP-HHT patients from which we identified 15 additional SMAD4 mutations. We also reviewed the literature for other reports of JP patients with HHT symptoms with confirmed SMAD4 mutations. Our combined results show that although the SMAD4 mutations in JP-HHT patients do show a tendency to cluster in the MH2 domain, mutations in other parts of the gene also cause the combined syndrome. Thus, any mutation in SMAD4 can cause JP-HHT. Any JP patient with a SMAD4 mutation is, therefore, at risk for the visceral manifestations of HHT and any HHT patient with SMAD4 mutation is at risk for early onset gastrointestinal cancer. In conclusion, a patient who tests positive for any SMAD4 mutation must be considered at risk for the combined syndrome of JP-HHT and monitored accordingly.


Structural brain changes in patients with recurrent major depressive disorder presenting with anxiety symptoms.
Major depressive disorder (MDD) presents with extensive clinical heterogeneity. In particular, overlap with anxiety symptoms is common during depressive episodes and as a comorbid disorder. The aim of this study was to test for morphological brain differences between patients having a history of recurrent MDD with, and without, anxiety symptoms (MDD+A and MDD-A). T1-weighted magnetic resonance images of age-, gender- and ethnically matched groups of MDD+A (n= 49) and MDD-A (n= 96) patients were available for voxel-based morphometry analysis of regional gray matter (GM) volume differences. Brain structural images were also contrasted with 183 age-, gender-, and ethnicity-matched healthy controls. MDD+A patients had greater GM volume (P(FWE) = .002) than MDD-A patients in the right temporal cortex extending from the mid-posterior superior temporal gyrus into the posterior middle and inferior temporal gyrus. The MDD patients together showed lower GM volume than healthy controls in the superior parietal lobe. Regional volume differences in patients are consistent with altered neuronal or glial microstructure. The temporolateral cortical differences distinguishing the 2 MDD groups suggest neurobiological differences related to the expression of anxiety symptoms in depression and provide further rationale for considering these groups independently for therapeutic outcomes studies.


Advanced thin film technology for ultrahigh resolution X-ray microscopy.
Further progress in the spatial resolution of X-ray microscopes is currently impaired by fundamental limitations in the production of X-ray diffractive lenses. Here, we demonstrate how advanced thin film technologies can be applied to boost the fabrication and characterization of ultrahigh resolution X-ray optics. Specifically, Fresnel zone plates were fabricated by combining electron-beam lithography with atomic layer deposition and focused ion beam induced deposition. They were tested in a scanning transmission X-ray microscope at 1.2 keV photon energy using line pair structures of a sample prepared by metal organic vapor phase epitaxy. For the first time in X-ray microscopy, features below 10nm in width were resolved.


ICD-11 and SNOMED CT Common Ontology: circulatory system.
The improvement of semantic interoperability between data in electronic health records and aggregated data for health statistics requires efforts to carefully align the two domain terminologies ICD and SNOMED CT. Both represent a new generation of ontology-based terminologies and classifications. The proposed alignment of these two systems and, in consequence, the validity of their cross-utilisation, requires a specific resource, named Common Ontology. We present the ICD-11 SNOMED CT Common Ontology building process including: a) the principles proposed for aligning the two systems with the help of a common model of meaning, b) the design of this common ontology, and c) preliminary results of the application to the diseases of the circulatory system.


Enhanced mosquito vectorial capacity underlies the Cape Verde Zika epidemic.
The explosive emergence of Zika virus (ZIKV) across the Pacific and Americas since 2007 was associated with hundreds of thousands of human cases and severe outcomes, including congenital microcephaly caused by ZIKV infection during pregnancy. Although ZIKV was first isolated in Uganda, Africa has so far been exempt from large-scale ZIKV epidemics, despite widespread susceptibility among African human populations. A possible explanation for this pattern is natural variation among populations of the primary vector of ZIKV, the mosquito Aedes aegypti. Globally invasive populations of Ae. aegypti outside of Africa are considered effective ZIKV vectors because they are human specialists with high intrinsic ZIKV susceptibility, whereas African populations of Ae. aegypti across the species' native range are predominantly generalists with low intrinsic ZIKV susceptibility, making them less likely to spread viruses in the human population. We test this idea by studying a notable exception to the patterns observed across most of Africa: Cape Verde experienced a large ZIKV outbreak in 2015 to 2016. We find that local Ae. aegypti in Cape Verde have substantial human-specialist ancestry, show a robust behavioral preference for human hosts, and exhibit increased susceptibility to ZIKV infection, consistent with a key role for variation among mosquito populations in ZIKV epidemiology. These findings suggest that similar human-specialist populations of Ae. aegypti in the nearby Sahel region of West Africa, which may be expanding in response to rapid urbanization, could serve as effective vectors for ZIKV in the future.


A methodological protocol for selecting and quantifying low-value prescribing practices in routinely collected data: an Australian case study.
Growing imperatives for safety, quality and responsible resource allocation have prompted renewed efforts to identify and quantify harmful or wasteful (low-value) medical practices such as test ordering, procedures and prescribing. Quantifying these practices at a population level using routinely collected health data allows us to understand the scale of low-value medical practices, measure practice change following specific interventions and prioritise policy decisions. To date, almost all research examining health care through the low-value lens has focused on medical services (tests and procedures) rather than on prescribing. The protocol described herein outlines a program of research funded by Australia's National Health and Medical Research Council to select and quantify low-value prescribing practices within Australian routinely collected health data. We start by describing our process for identifying and cataloguing international low-value prescribing practices. We then outline our approach to translate these prescribing practices into indicators that can be applied to Australian routinely collected health data. Next, we detail methods of using Australian health data to quantify these prescribing practices (e.g. prevalence of low-value prescribing and related costs) and their downstream health consequences. We have approval from the necessary Australian state and commonwealth human research ethics and data access committees to undertake this work. The lack of systematic and transparent approaches to quantification of low-value practices in routinely collected data has been noted in recent reviews. Here, we present a methodology applied in the Australian context with the aim of demonstrating principles that can be applied across jurisdictions in order to harmonise international efforts to measure low-value prescribing. The outcomes of this research will be submitted to international peer-reviewed journals. Results will also be presented at national and international pharmacoepidemiology and health policy forums such that other jurisdictions have guidance to adapt this methodology.


The Argonautes.
RNA interference (RNAi) has been greatly exploited in recent years as an increasingly effective tool to study gene function by gene silencing. The introduction of exogenous double-stranded RNA (dsRNA) into a cell can trigger this gene silencing process. An RNase III family enzyme, Dicer, initiates silencing by releasing approximately 20 base duplexes, with 2- nucleotide 3' overhangs called siRNAs. The RNAi pathway also mediates the function of endogenous, noncoding regulatory RNAs called miRNAs. Both miRNAs and siRNAs guide substrate selection by similar if not identical effector complexes called RISCs. These contain single-stranded versions of the small RNA and additional protein components. Of those, the signature element, at the heart of all RISCs, is a member of the Argonaute family of proteins. Our structural and biochemical studies on Argonaute identified this protein as Slicer, the enzyme in RISC that cleaves the mRNA as directed by the siRNA. The role of the Argonautes as Slicers and non-Slicers is discussed.


Epidemiology, Risk Factors and Measures for Preventing Drowning in Africa: A Systematic Review.
: Background: Drowning is a leading cause of unintentional injury related mortality worldwide, and accounts for roughly 320,000 deaths yearly. Over 90% of these deaths occur in low- and middle-income countries with inadequate prevention measures. The highest rates of drowning are observed in Africa. The aim of this review is to describe the epidemiology of drowning and identify the risk factors and strategies for prevention of drowning in Africa. Methods: A review of multiple databases (MEDLINE, CINAHL, PsycINFO, Scopus and Emcare) was conducted from inception of the databases to the 1st of April 2019 to identify studies investigating drowning in Africa. The preferred reporting items for systematic review and meta-analysis (PRISMA) was utilised. Results: Forty-two articles from 15 countries were included. Twelve articles explored drowning, while in 30 articles, drowning was reported as part of a wider study. The data sources were coronial, central registry, hospital record, sea rescue and self-generated data. Measures used to describe drowning were proportions and rates. There was a huge variation in the proportion and incidence rate of drowning reported by the studies included in the review. The potential risk factors for drowning included young age, male gender, ethnicity, alcohol, access to bodies of water, age and carrying capacity of the boat, weather and summer season. No study evaluated prevention strategies, however, strategies proposed were education, increased supervision and community awareness. Conclusions: There is a need to address the high rate of drowning in Africa. Good epidemiological studies across all African countries are needed to describe the patterns of drowning and understand risk factors. Further research is needed to investigate the risk factors and to evaluate prevention strategies.


Distribution of potassium conductance in mammalian Müller (glial) cells: a comparative study.
The distribution of K+ conductance across the surface of retinal Müller cells was determined in 5 mammalian species--rabbit, guinea pig, mouse, owl monkey, and cat--and in tiger salamander. Potassium conductance was measured by monitoring cell depolarizations evoked by focal ejections of a high-K+ solution onto the surface of freshly dissociated cells. This technique measured the total K+ conductance of a given cell region (regional conductance), i.e., the specific K+ conductance times the total surface area in that region. In mammalian species with avascular retinas (rabbit, guinea pig), the regional K+ conductance within the middle portion of the cell was only a fraction (10.6-28.9%) of the endfoot conductance, while the conductance of the distal (photo-receptor) end of the cell was approximately half (41.2-49.8%) the endfoot conductance. In 2 species with vascularized retinas (mouse and owl monkey), by contrast, the regional K+ conductance within the middle portion of the cell was as large as 125.5-129.8% of the endfoot conductance. In these cells the K+ conductance of the distal end was 68.3-82.9% of the endfoot value. In cat, a third vascularized species, the K+ conductance was highest (187.1% of the endfoot value) at the distal end of the cell. In tiger salamander, which has an avascular retina, the regional K+ conductance of all regions distal to the endfoot was only 2.4-15.7% of the endfoot value. Differences in the distributions of regional K+ conductance observed in the 6 species raise the possibility that in vascularized mammalian retinas, the high-K+ conductance of the middle portion of Müller cells is associated with retinal blood vessels. The results are consistent with the hypothesis that, in avascular species, Müller cells aid in regulating extracellular K+ levels by transferring (siphoning) excess K+ principally into the vitreous humor, while in at least some vascularized species (mouse, monkey), excess K+ is transferred by Müller cells into retinal capillaries, as well as into the vitreous.


Adsorption and detection of some phenolic compounds by rice husk ash of Kenyan origin.
Rice husk ash (RHA) obtained from a rice mill in Kenya has been used as an inexpensive and effective adsorbent (and reagent) for the removal (and detection) of some phenolic compounds in water. The abundantly available rice mill waste was used in dual laboratory-scale batch experiments to evaluate its potential in: (i) the removal of phenol, 1,3-dihydroxybenzene (resorcinol) and 2-chlorophenol from water; and (ii) the detection of 1,2-dihydroxybenzene (pyrocatechol) and 1,2,3-trihydroxybenzene (pyrogallol) present in an aqueous medium. The studies were conducted using synthetic water with different initial concentrations of the phenolic compounds. The effects of different operating conditions (such as contact time, concentration of the phenolic compounds, adsorbent quantity, temperature, and pH) were assessed by evaluating the phenolic compound removal efficiency as well as the extent of their color formation reactions (where applicable). RHA exhibits reasonable adsorption capacity for the phenolic compounds and follows both Langmuir and Freundlich isotherm models. Adsorption capacities of 1.53 x 10(-4), 8.07 x 10(-5), and 1.63 x 10(-6) mol g(-1) were determined for phenol, resorcinol and 2-chlorophenol, respectively. Nearly 100% adsorption of the phenolic compounds was possible and this depended on the weight of RHA employed. For the detection experiments, pyrocatechol and pyrogallol present in water formed coloured complexes with RHA, with the rate of colour formation increasing with temperature, weight of RHA, concentration of the phenolic compounds and sonication. This study has proven that RHA is a useful agricultural waste product for the removal and detection of some phenolic compounds.


Chromatographically purified vancomycin: therapy of serious infections caused by Staphylococcus aureus and other gram-positive bacteria.
Fourteen patients with serious infections caused by Staphylococcus aureus and other gram-positive bacteria were prospectively treated with chromatographically purified vancomycin in an open-label, nonrandomized study, between December 1986 and June 1987. Five patients were excluded from the evaluation of efficacy. Among the nine evaluable patients, cure was achieved in six patients--a success rate of 67%. One patient had a relapse of osteomyelitis, and cultures of draining pus were positive for oxacillin-resistant S aureus within three weeks after the discontinuation of vancomycin therapy. One patient failed to respond to vancomycin therapy for S aureus-induced endocarditis, meningitis, and osteomyelitis; in another patient, the treatment failed to reverse the course of S aureus septicemia. No serious drug toxicity, for example, nephrotoxicity, was encountered in any patient. One patient (7%) experienced mild ototoxicity. Four patients (29%) had mild phlebitis, two patients (14%) had a transiently positive Coombs' test, and one patient (7%) had a "red neck syndrome" and "pain and spasm syndrome." Chromatographically purified vancomycin is an effective antibiotic in the treatment of serious infections caused by susceptible gram-positive bacteria. Some minor side effects of vancomycin may not be due to impurities in the preparation but rather to the vancomycin itself.


Jack of all trades, master of all: a positive association between habitat niche breadth and foraging performance in pit-building antlion larvae.
Species utilizing a wide range of resources are intuitively expected to be less efficient in exploiting each resource type compared to species which have developed an optimal phenotype for utilizing only one or a few resources. We report here the results of an empirical study whose aim was to test for a negative association between habitat niche breadth and foraging performance. As a model system to address this question, we used two highly abundant species of pit-building antlions varying in their habitat niche breadth: the habitat generalist Myrmeleon hyalinus, which inhabits a variety of soil types but occurs mainly in sandy soils, and the habitat specialist Cueta lineosa, which is restricted to light soils such as loess. Both species were able to discriminate between the two soils, with each showing a distinct and higher preference to the soil type providing higher prey capture success and characterizing its primary habitat-of-origin. As expected, only small differences in the foraging performances of the habitat generalist were evident between the two soils, while the performance of the habitat specialist was markedly reduced in the alternative sandy soil. Remarkably, in both soil types, the habitat generalist constructed pits and responded to prey faster than the habitat specialist, at least under the temperature range of this study. Furthermore, prey capture success of the habitat generalist was higher than that of the habitat specialist irrespective of the soil type or prey ant species encountered, implying a positive association between habitat niche-breadth and foraging performance. Alternatively, C. lineosa specialization to light soils does not necessarily confer upon its superiority in utilizing such habitats. We thus suggest that habitat specialization in C. lineosa is either an evolutionary dead-end, or, more likely, that this species' superiority in light soils can only be evident when considering additional niche axes.


Di-copper(ii) DNA G-quadruplexes as EPR distance rulers.
Artificial metal-base tetrads composed of square-planar CuII(pyridine)4 complexes were covalently attached to both the 3' and 5' ends of tetramolecular DNA G-quadruplexes [Ld(G3-5)LdT]4 (L = pyridine ligand) of different lengths. Owing to the planar four-point attachment of the metal complexes, the magnetic orbitals (dx2-y2) of the d9-configured CuII cations are placed in a coplanar fashion, separated by the stacked guanine tetrads. Pulsed EPR-derived CuII-CuII distances and angles were found to be in agreement with those obtained from molecular dynamics simulations. DNA-confined transition metal spin labels open new ways to study oligonucleotide structure and DNA-protein complexes.


Ukrain treatment in a patient with stage IV neuroblastoma. A case report.
A 22-month-old boy with stage IV neuroblastoma underwent laparotomy with tumor removal and nephrectomy, followed by treatment with Ukrain. Two months later, a remaining abdominal tumor, a retroperitoneal tumor (approximately 2 x 1 cm), and lung, brain, pelvis, kidney, and distal femur metastases were found. Growth of the neuroblastoma around the spinal cord and growth into the spinal canal was also found. Ukrain was administered in 3-week therapy series with 3-week pauses between each series. Some tumors disappeared, others were smaller, and growth stopped in the remaining tumors. Various metastases were no longer detectable.


Hyper-generalized-gradient functionals constructed from the Lieb-Oxford bound: implementation via local hybrids and thermochemical assessment.
In 2009 Odashima and Capelle (OC) showed a way to design a correlation-only density functional that satisfies a Lieb-Oxford bound on the correlation energy, without empirical parameters and even without additional theoretical parameters. However, they were only able to test a size-inconsistent version of it that employs total energies. Here, we show that their alternative size-consistent form that employs energy densities, when combined with exact or semilocal exchange, is a local hybrid (lh) functional. We test several variants of this nonempirical OC-lh functional on standard molecular test sets. Although no variant yields enthalpies of formation with the accuracy of the semilocal Tao-Perdew-Staroverov-Scuseria (TPSS) exchange-correlation, OC-lh correlation with exact exchange yields rather accurate energy barriers for chemical reactions. Our purpose here is not to advocate for a new density functional, but to explore a previously published idea. We also discuss the importance of near-self-consistency for fully nonlocal functionals.


Prolonged survival of rat renal allografts after multiple allogeneic pregnancies: strain specificity and role of erythrocyte antibody rosette inhibiting antibodies.
The influence of allogeneic pregnancies on the survival of subsequent rat renal allografts was investigated in three rat strain combinations. Multiple but not single pregnancies produced significantly more long-term surviving kidney grafts than were found in virgin animals; the effect was specific for paternal antigens, as multiple pregnancies by an unrelated strain did not prolong kidney graft survival. In the multiparous groups, those animals with long-surviving grafts had significantly higher levels of non-cytotoxic antibodies against paternal strain B-lymphocytes (detected by the erythrocyte antibody rosette inhibition assay) than did animals which rejected their grafts. The results show that multiple pregnancies may produce a state of specific unresponsiveness to paternal antigens, similar to enhancement, which is marked by the presence of non-cytotoxic antibodies against paternal B-lymphocytes. It is suggested, therefore, that enhancement may be one of the protective mechanisms which prevent rejection of the fetus during pregnancy.


Uptake of purines in Plasmodium falciparum-infected human erythrocytes is mostly mediated by the human equilibrative nucleoside transporter and the human facilitative nucleobase transporter.
Plasmodium parasites are unable to synthesize purines de novo and have to salvage them from the host. Due to this limitation in the parasite, purine transporters have been an area of focus in the search for anti-malarial drugs. Although the uptake of purines through the human equilibrative nucleoside transporter (hENT1), the human facilitative nucleobase transporter (hFNT1) and the parasite-induced new permeation pathway (NPP) has been studied, no information appears to exist on the relative contribution of these three transporters to the uptake of adenosine and hypoxanthine. Using the appropriate transporter inhibitors, the role of each of these salvage pathways to the overall purine transport in intraerythrocytic Plasmodium falciparum was systematically investigated. The transport of adenosine, hypoxanthine and adenine into uninfected and P. falciparum-infected human erythrocytes was investigated in the presence or absence of classical inhibitors of the hFNT1, hENT1 and NPP. The effective inhibition of the various transporters by the classical inhibitors was verified using appropriate known substrates. The ability of high concentration of unlabelled substrates to saturate these transporters was also studied. Transport of exogenous purine into infected or uninfected erythrocytes occurred primarily through saturable transporters rather than through the NPP. Hypoxanthine and adenine appeared to enter erythrocytes mainly through the hFNT1 nucleobase transporter whereas adenosine entered predominantly through the hENT1 nucleoside transporter. The rate of purine uptake was approximately doubled in infected cells compared to uninfected erythrocytes. In addition, it was found that the rate of adenosine uptake was considerably higher than the rate of hypoxanthine uptake in infected human red blood cells (RBC). It was also demonstrated that furosemide inhibited the transport of purine bases through hFNT1. Collectively, the data obtained in this study clearly show that the endogenous host erythrocyte transporters hENT1 and hFNT1, rather than the NPP, are the major route of entry of purine into parasitized RBC. Inhibitors of hENT1 and hFNT1, as well as the NPP, should be considered in the development of anti-malarials targeted to purine transport.


Selection for territory acquisition is modulated by social network structure in a wild songbird.
The social environment may be a key mediator of selection that operates on animals. In many cases, individuals may experience selection not only as a function of their phenotype, but also as a function of the interaction between their phenotype and the phenotypes of the conspecifics they associate with. For example, when animals settle after dispersal, individuals may benefit from arriving early, but, in many cases, these benefits will be affected by the arrival times of other individuals in their local environment. We integrated a recently described method for calculating assortativity on weighted networks, which is the correlation between an individual's phenotype and that of its associates, into an existing framework for measuring the magnitude of social selection operating on phenotypes. We applied this approach to large-scale data on social network structure and the timing of arrival into the breeding area over three years. We found that late-arriving individuals had a reduced probability of breeding. However, the probability of breeding was also influenced by individuals' social networks. Associating with late-arriving conspecifics increased the probability of successfully acquiring a breeding territory. Hence, social selection could offset the effects of nonsocial selection. Given parallel theoretical developments of the importance of local network structure on population processes, and increasing data being collected on social networks in free-living populations, the integration of these concepts could yield significant insights into social evolution.


Activity of closantel against experimentally induced Fascioloides magna infection in sheep.
The efficacy of closantel against experimentally induced Fascioloides magna infection in sheep was studied. In each of 3 experiments, closantel was administered 8 weeks after the sheep were given (oral inoculation) 100 metacercariae of F magna. In the 1st experiment, closantel was given orally to 5 groups of 6 sheep each at dosages of 0 (nontreated control), 5, 7.5, 10, and 15 mg/kg of body weight. In the 2nd and 3rd experiments, groups of 10 or 12 sheep were treated to confirm the efficacy of the previously determined optimal dosage of 15 mg/kg. An additional group of sheep (n = 10) was used in the 3rd experiment to evaluate the efficacy of closantel given IM at a dosage of 7.5 mg/kg. Closantel given orally at a dosage level of 15 mg/kg was highly effective (94.6% to 97.7%) in reducing F magna burdens. Also, pathologic scores associated with the F magna infection were reduced by 81.3% to 92.6% in sheep given this dosage of closantel. Efficacy of the IM administered dosage of 7.5 mg of drug/kg was equivalent to that of the 15 mg/kg oral dosage. Other than mild, transient lameness of the limbs which were injected with the drug (group 10), side effects were not observed.


The effects of curvature on haptic judgments of extent in sighted and blind people.
A series of experiments was carried out to examine the effect of curvature on haptic judgments of extent in sighted and blind individuals. Experiment 1 showed that diameters connecting the endpoints of semicircular lines were underestimated with respect to straight lines, but failed to show an effect of visual experience on length judgments. In experiment 2 we tested are lengths. The effects of curvature on perceived path length were weaker, but were still present in this experiment. Visual experience had no effect on path length judgments. Another experiment was performed to examine the effect of repeated tracing (1, 5, 9, or unlimited number of traces) on judgments of the lengths of straight lines and diameters of semicircles. Judgments of extent were more accurate when subjects engaged in larger numbers of traces. There was no effect of number of traces on curve-height judgments, suggesting that subjects were not using height estimates to judge diameters of semicircles. In a further experiment we tested the effect of number of traces on curves that varied in height. Restricting subjects to a single trace magnified the effect of path length on judgments of the distance between the endpoints of curves. Additional experiments showed that curvature effects on diameter judgments were not eliminated when stimuli were in the frontal plane or when the curves were explored with the use of two hands. Arm support had no effect on judged length in experiment 7. A final experiment showed a robust horizontal vertical illusion in haptic perception of convex curves, with overestimation of the heights of the curves compared with their widths. The practical and theoretical implications of the results are discussed.


EARS-DM: Efficient Auto Correction Retrieval Scheme for Data Management in Edge Computing.
Edge computing is an extension of cloud computing that enables messages to be acquired and processed at low cost. Many terminal devices are being deployed in the edge network to sense and deal with the massive data. By migrating part of the computing tasks from the original cloud computing model to the edge device, the message is running on computing resources close to the data source. The edge computing model can effectively reduce the pressure on the cloud computing center and lower the network bandwidth consumption. However, the security and privacy issues in edge computing are worth noting. In this paper, we propose an efficient auto-correction retrieval scheme for data management in edge computing, named EARS-DM. With automatic error correction for the query keywords instead of similar words extension, EARS-DM can tolerate spelling mistakes and reduce the complexity of index storage space. By the combination of TF-IDF value of keywords and the syntactic weight of query keywords, keywords who are more important will obtain higher relevance scores. We construct an R-tree index building with the encrypted keywords and the children nodes of which are the encrypted identifier FID and Bloom filter BF of files who contain this keyword. The secure index will be uploaded to the edge computing and the search phrase will be performed by the edge computing which is close to the data source. Then EDs sort the matching encrypted file identifier FID by relevance scores and upload them to the cloud server (CS). Performance analysis with actual data indicated that our scheme is efficient and accurate.


The DNA-binding domain in the Bacillus subtilis transition-state regulator AbrB employs significant motion for promiscuous DNA recognition.
AbrB is a Bacillus subtilis protein responsible for regulating a diverse array of unrelated genes during periods of sub-optimal growth conditions. DNA binding by AbrB is unique in that sequence recognition is specific, yet no obvious consensus sequence of bound promoter regions is apparent. The N-terminal domain is a recently characterized representative of a novel class of DNA-binding proteins that possess a looped-hinge helix DNA-binding topology. Although the structural characterization of this DNA-binding topology contributed to an understanding of the architectural basis for recognition of DNA target sequences, specific mechanisms responsible for promiscuity in DNA sequence recognition still were not apparent. Analysis of (15)N backbone relaxation parameters shows that dynamic motion of regions directly linked to DNA binding show concerted motion on the microsecond-millisecond timescale. Furthermore, dynamic motion of the hinge region suggests that the DNA-binding region is capable of conformational orientations that allow it to accommodate DNA sequence variability in the cognate binding sites.


Bacterial Synthesis of Unusual Sulfonamide and Sulfone Antibiotics by Flavoenzyme-Mediated Sulfur Dioxide Capture.
Sulfa drugs, such as sulfonilamide and dapsone, are classical antibiotics that have been in clinical use worldwide. Despite the relatively simple architectures, practically no natural products are known to feature such aromatic sulfonamide or diarylsulfone substructures. We report the unexpected discovery of three fully unprecedented, sulfonyl-bridged alkaloid dimers (sulfadixiamycins A-C) from recombinant Streptomyces species harboring the entire xiamycin biosynthesis gene cluster. Sulfadixiamycins exhibit moderate antimycobacterial activities and potent antibiotic activities even against multidrug-resistant bacteria. Gene inactivation, complementation, and biotransformation experiments revealed that a flavin-dependent enzyme (XiaH) plays a key role in sulfadixiamycin biosynthesis. XiaH mediates a radical-based, three-component reaction involving two equivalents of xiamycin and sulfur dioxide, which is reminiscent of radical styrene/SO2 copolymerization.


Changes in inositol 1,4,5-trisphosphate and inositol 1,3,4,5- tetrakisphosphate mass accumulations in cultured adrenal chromaffin cells in response to bradykinin and histamine.
In previous studies it has been shown that both bradykinin and histamine increase the formation of 3H-labeled inositol phosphates in adrenal chromaffin cells prelabelled with [3H]inositol and that both these agonists stimulate release of catecholamines by a mechanism dependent on extracellular calcium. Here, we have used mass assays of inositol 1,4,5-trisphosphate [Ins(1,4,5)P3] and inositol 1,3,4,5-tetrakisphosphate [Ins(1,3,4,5)P4] to investigate changes in levels of these two candidates as second messengers in response to stimulation with bradykinin and histamine. Bradykinin increased the mass of Ins(1,3,4,5)P4 despite the failure in earlier studies with [3H]inositol-labelled cells to observe a bradykinin-mediated increase in content of [3H]InsP4. Bradykinin elicited a very rapid increase in level of Ins(1,4,5)P3, which was maximal at 5-10 s and then rapidly decreased to a small but sustained elevation at 2 min. The bradykinin-elicited Ins(1,3,4,5)P4 response increased to a maximum at 30-60 s and at 2 min was still elevated severalfold above basal levels. Histamine, which produced a larger overall total inositol phosphate response in [3H]inositol-loaded cells, produced significantly smaller Ins(1,4,5)P3 and Ins(1,3,4,5)P4 responses compared with bradykinin. The bradykinin stimulation of Ins(1,4,5)P3 accumulation was partially dependent on a high (1.8 mM) extracellular Ca2+ concentration, whereas the Ins(1,3,4,5)P4 response was almost completely lost when the extracellular Ca2+ concentration was reduced to 100 nM. Changes in the inositol polyphosphate second messengers are compared with the time course of bradykinin-stimulated increases in free intracellular Ca2+ concentrations and noradrenaline release.