Evaluation of exposure-specific risks from two independent samples: A simulation study

<p>Abstract</p> <p>Background</p> <p>Previous studies have proposed a simple product-based estimator for calculating exposure-specific risks (ESR), but the methodology has not been rigorously evaluated. The goal of our study was to evaluate the existing methodology for calculating the ESR, propose an improved point estimator, and propose variance estimates that will allow the calculation of confidence intervals (CIs).</p> <p>Methods</p> <p>We conducted a simulation study to test the performance of two estimators and their associated confidence intervals: 1) current (simple product-based estimator) and 2) proposed revision (revised product-based estimator). The first method for ESR estimation was based on multiplying a relative risk (RR) of disease given a certain exposure by an overall risk of disease. The second method, which is proposed in this paper, was based on estimates of the risk of disease in the unexposed. We then multiply the updated risk by the RR to get the revised product-based estimator. A log-based variance was calculated for both estimators. Also, a binomial-based variance was calculated for the revised product-based estimator. 95% CIs were calculated based on these variance estimates. Accuracy of point estimators was evaluated by comparing observed relative bias (percent deviation from the true estimate). Interval estimators were evaluated by coverage probabilities and expected length of the 95% CI, given coverage. We evaluated these estimators across a wide range of exposure probabilities, disease probabilities, relative risks, and sample sizes.</p> <p>Results</p> <p>We observed more bias and lower coverage probability when using the existing methodology. The revised product-based point estimator exhibited little observed relative bias (max: 4.0%) compared to the simple product-based estimator (max: 93.9%). Because the simple product-based estimator was biased, 95% CIs around this estimate exhibited small coverage probabilities. The 95% CI around the revised product-based estimator from the log-based variance provided better coverage in most situations.</p> <p>Conclusion</p> <p>The currently accepted simple product-based method was only a reasonable approach when the exposure probability is small (< 0.05) and the RR is ≤ 3.0. The revised product-based estimator provides much improved accuracy.</p

A novel approach to improve cardiac performance: cardiac myosin activators

Decreased systolic function is a central factor in the pathogenesis of heart failure, yet there are no safe medical therapies to improve cardiac function in patients. Currently available inotropes, such as dobutamine and milrinone, increase cardiac contractility at the expense of increased intracellular concentrations of calcium and cAMP, contributing to increased heart rate, hypotension, arrhythmias, and mortality. These adverse effects are inextricably linked to their inotropic mechanism of action. A new class of pharmacologic agents, cardiac myosin activators, directly targets the kinetics of the myosin head. In vitro studies have demonstrated that these agents increase the rate of effective myosin cross-bridge formation, increasing the duration and amount of myocyte contraction, and inhibit non-productive consumption of ATP, potentially improving myocyte energy utilization, with no effect on intracellular calcium or cAMP. Animal models have shown that this novel mechanism increases the systolic ejection time, resulting in improved stroke volume, fractional shortening, and hemodynamics with no effect on myocardial oxygen demand, culminating in significant increases in cardiac efficiency. A first-in-human study in healthy volunteers with the lead cardiac myosin activator, CK-1827452, as well as preliminary results from a study in patients with stable chronic heart failure, have extended these findings to humans, demonstrating significant increases in systolic ejection time, fractional shortening, stroke volume, and cardiac output. These studies suggest that cardiac myosin activators offer the promise of a safe and effective treatment for heart failure. A program of clinical studies are being planned to test whether CK-1827452 will fulfill that promise

A facile chemical conversion synthesis of Sb2S3 nanotubes and the visible light-driven photocatalytic activities

We report a simple chemical conversion and cation exchange technique to realize the synthesis of Sb2S3 nanotubes at a low temperature of 90°C. The successful chemical conversion from ZnS nanotubes to Sb2S3 ones benefits from the large difference in solubility between ZnS and Sb2S3. The as-grown Sb2S3 nanotubes have been transformed from a weak crystallization to a polycrystalline structure via successive annealing. In addition to the detailed structural, morphological, and optical investigation of the yielded Sb2S3 nanotubes before and after annealing, we have shown high photocatalytic activities of Sb2S3 nanotubes for methyl orange degradation under visible light irradiation. This approach offers an effective control of the composition and structure of Sb2S3 nanomaterials, facilitates the production at a relatively low reaction temperature without the need of organics, templates, or crystal seeds, and can be extended to the synthesis of hollow structures with various compositions and shapes for unique properties

TNF-α induced endothelial MAdCAM-1 expression is regulated by exogenous, not endogenous nitric oxide

BACKGROUND: MAdCAM-1 is an adhesion molecule expressed in Peyer's patches and lymphoid tissues which is mobilized by cytokines like TNF-α and is a major determinant of lymphocyte trafficking to the gut in human inflammatory bowel disease (IBD). It has been suggested that both reactive oxygen and nitrogen metabolites participate in regulating adhesion molecule expression in response to TNF-α. METHODS: To examine how exogenous and endogenous sources of NO modulate MAdCAM-1 induction by TNF-α, we pre-treated mouse lymphatic endothelial cells with either long or short acting NO donors prior to TNF-α-stimulation, and measured MAdCAM-1 induction at 24 h. RESULTS AND DISCUSSION: DETA-NO, a long-acting NO donor, and SperNO, a rapid releasing NO donor both inhibited TNF-α-stimulated MAdCAM-1 expression in a concentration dependent manner. Both NO donors also reduced a4b7-dependent lymphocyte endothelial adhesion. Inhibition of endogenous NO production by either L-NAME, a non-selective NOS inhibitor, or by 1400 w, a selective iNOS inhibitor failed to induce, or potentiate TNF-α regulated MAdCAM-1 expression. CONCLUSIONS: Exogenous NO donors may be beneficial in the treatment of IBD, while endogenous nitric oxide synthases may be less effective in controlling adhesion molecule expression in response to cytokines

Effects of Increased Nitrogen Deposition and Precipitation on Seed and Seedling Production of Potentilla tanacetifolia in a Temperate Steppe Ecosystem

The responses of plant seeds and seedlings to changing atmospheric nitrogen (N) deposition and precipitation regimes determine plant population dynamics and community composition under global change.In a temperate steppe in northern China, seeds of P. tanacetifolia were collected from a field-based experiment with N addition and increased precipitation to measure changes in their traits (production, mass, germination). Seedlings germinated from those seeds were grown in a greenhouse to examine the effects of improved N and water availability in maternal and offspring environments on seedling growth. Maternal N-addition stimulated seed production, but it suppressed seed mass, germination rate and seedling biomass of P. tanacetifolia. Maternal N-addition also enhanced responses of seedlings to N and water addition in the offspring environment. Maternal increased-precipitation stimulated seed production, but it had no effect on seed mass and germination rate. Maternal increased-precipitation enhanced seedling growth when grown under similar conditions, whereas seedling responses to offspring N- and water-addition were suppressed by maternal increased-precipitation. Both offspring N-addition and increased-precipitation stimulated growth of seedlings germinated from seeds collected from the maternal control environment without either N or water addition. Our observations indicate that both maternal and offspring environments can influence seedling growth of P. tanacetifolia with consequent impacts on the future population dynamics of this species in the study area.The findings highlight the importance of the maternal effects on seed and seedling production as well as responses of offspring to changing environmental drivers in mechanistic understanding and projecting of plant population dynamics under global change

The genomes of two key bumblebee species with primitive eusocial organization

Background: The shift from solitary to social behavior is one of the major evolutionary transitions. Primitively eusocial bumblebees are uniquely placed to illuminate the evolution of highly eusocial insect societies. Bumblebees are also invaluable natural and agricultural pollinators, and there is widespread concern over recent population declines in some species. High-quality genomic data will inform key aspects of bumblebee biology, including susceptibility to implicated population viability threats. Results: We report the high quality draft genome sequences of Bombus terrestris and Bombus impatiens, two ecologically dominant bumblebees and widely utilized study species. Comparing these new genomes to those of the highly eusocial honeybee Apis mellifera and other Hymenoptera, we identify deeply conserved similarities, as well as novelties key to the biology of these organisms. Some honeybee genome features thought to underpin advanced eusociality are also present in bumblebees, indicating an earlier evolution in the bee lineage. Xenobiotic detoxification and immune genes are similarly depauperate in bumblebees and honeybees, and multiple categories of genes linked to social organization, including development and behavior, show high conservation. Key differences identified include a bias in bumblebee chemoreception towards gustation from olfaction, and striking differences in microRNAs, potentially responsible for gene regulation underlying social and other traits. Conclusions: These two bumblebee genomes provide a foundation for post-genomic research on these key pollinators and insect societies. Overall, gene repertoires suggest that the route to advanced eusociality in bees was mediated by many small changes in many genes and processes, and not by notable expansion or depauperation

GA-based multi-objective optimization of active nonlinear quarter car suspension system—PID and fuzzy logic control

Background The primary function of a suspension system is to isolate the vehicle body from road irregularities thus providing the ride comfort and to support the vehicle and provide stability. The suspension system has to perform conflicting requirements; hence, a passive suspension system is replaced by the active suspension system which can supply force to the system. Active suspension supplies energy to respond dynamically and achieve relative motion between body and wheel and thus improves the performance of suspension system. Methods This study presents modelling and control optimization of a nonlinear quarter car suspension system. A mathematical model of nonlinear quarter car is developed and simulated for control and optimization in Matlab/Simulink® environment. Class C road is selected as input road condition with the vehicle traveling at 80 kmph. Active control of the suspension system is achieved using FLC and PID control actions. Instead of guessing and or trial and error method, genetic algorithm (GA)-based optimization algorithm is implemented to tune PID parameters and FLC membership functions’ range and scaling factors. The optimization function is modeled as a multi-objective problem comprising of frequency weighted RMS seat acceleration, Vibration dose value (VDV), RMS suspension space, and RMS tyre deflection. ISO 2631-1 standard is adopted to assess the ride and health criterion. Results The nonlinear quarter model along with the controller is modeled and simulated and optimized in a Matlab/Simulink environment. It is observed that GA-optimized FLC gives better control as compared to PID and passive suspension system. Further simulations are validated on suspension system with seat and human model. Parameters under observation are frequency-weighted RMS head acceleration, VDV at the head, crest factor, and amplitude ratios at the head and upper torso (AR_h and AR_ut). Simulation results are presented in time and frequency domain. Conclusion Simulation results show that GA-based FLC and PID controller gives better ride comfort and health criterion by reducing RMS head acceleration, VDV at the head, CF, and AR_h and AR_ut over passive suspension system

A Powerful Test of Parent-of-Origin Effects for Quantitative Traits Using Haplotypes

Imprinting is an epigenetic phenomenon where the same alleles have unequal transcriptions and thus contribute differently to a trait depending on their parent of origin. This mechanism has been found to affect a variety of human disorders. Although various methods for testing parent-of-origin effects have been proposed in linkage analysis settings, only a few are available for association analysis and they are usually restricted to small families and particular study designs. In this study, we develop a powerful maximum likelihood test to evaluate the parent-of-origin effects of SNPs on quantitative phenotypes in general family studies. Our method incorporates haplotype distribution to take advantage of inter-marker LD information in genome-wide association studies (GWAS). Our method also accommodates missing genotypes that often occur in genetic studies. Our simulation studies with various minor allele frequencies, LD structures, family sizes, and missing schemes have uniformly shown that using the new method significantly improves the power of detecting imprinted genes compared with the method using the SNP at the testing locus only. Our simulations suggest that the most efficient strategy to investigate parent-of-origin effects is to recruit one parent and as many offspring as possible under practical constraints. As a demonstration, we applied our method to a dataset from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN) to test the parent-of-origin effects of the SNPs within the PPARGC1A, MTP and FABP2 genes on diabetes-related phenotypes, and found that several SNPs in the MTP gene show parent-of-origin effects on insulin and glucose levels

Temporal and Spatial Profiling of Root Growth Revealed Novel Response of Maize Roots under Various Nitrogen Supplies in the Field

A challenge for Chinese agriculture is to limit the overapplication of nitrogen (N) without reducing grain yield. Roots take up N and participate in N assimilation, facilitating dry matter accumulation in grains. However, little is known about how the root system in soil profile responds to various N supplies. In the present study, N uptake, temporal and spatial distributions of maize roots, and soil mineral N (Nmin) were thoroughly studied under field conditions in three consecutive years. The results showed that in spite of transient stimulation of growth of early initiated nodal roots, N deficiency completely suppressed growth of the later-initiated nodal roots and accelerated root death, causing an early decrease in the total root length at the rapid vegetative growth stage of maize plants. Early N excess, deficiency, or delayed N topdressing reduced plant N content, resulting in a significant decrease in dry matter accumulation and grain yield. Notably, N overapplication led to N leaching that stimulated root growth in the 40–50 cm soil layer. It was concluded that the temporal and spatial growth patterns of maize roots were controlled by shoot growth and local soil Nmin, respectively. Improving N management involves not only controlling the total amount of chemical N fertilizer applied, but also synchronizing crop N demand and soil N supply by split N applications

Stanniocalcin-1 Regulates Re-Epithelialization in Human Keratinocytes

Stanniocalcin-1 (STC1), a glycoprotein hormone, is believed to be involved in various biological processes such as inflammation, oxidative responses and cell migration. Riding on these emerging evidences, we hypothesized that STC1 may participate in the re-epithelialization during wound healing. Re-epithelialization is a critical step that involves keratinocyte lamellipodia (e-lam) formation, followed by cell migration. In this study, staurosporine (STS) treatment induced human keratinocyte (HaCaT) e-lam formation on fibronectin matrix and migration via the activation of focal adhesion kinase (FAK), the surge of intracellular calcium level [Ca2+]i and the inactivation of Akt. In accompanied with these migratory features, a time- and dose-dependent increase in STC1 expression was detected. STC1 gene expression was found not the downstream target of FAK-signaling as illustrated by FAK inhibition using PF573228. The reduction of [Ca2+]i by BAPTA/AM blocked the STS-mediated keratinocyte migration and STC1 gene expression. Alternatively the increase of [Ca2+]i by ionomycin exerted promotional effect on STS-induced STC1 gene expression. The inhibition of Akt by SH6 and GSK3β by lithium chloride (LiCl) could respectively induce and inhibit the STS-mediated e-lam formation, cell migration and STC1 gene expression. The STS-mediated e-lam formation and cell migration were notably hindered or induced respectively by STC1 knockdown or overexpression. This notion was further supported by the scratched wound assay. Collectively the findings provide the first evidence that STC1 promotes re-epithelialization in wound healing