Post-puff respiration measures on smokers of different tar yield cigarettes

The purpose of this study was to determine the effect of different tar yield cigarette brands on the post-puff inhalation/exhalation depth and duration for established smokers of the brands. The study was conducted with 74 established smokers of 1–17 mg Federal Trade Commission (FTC) tar products. The subjects were participating in a five-day inpatient clinical biomarker study during which time they were allowed to smoke their own brand of cigarette whenever they wished. On two separate days, the subjects' breathing pattern was measured using respiratory inductive plethysmography while they smoked one cigarette. This enabled the measurement of the post-puff inhalation volume, exhalation volume, inhalation duration, and exhalation duration for each subject after each puff on two of their own brand of cigarettes

Reconsidering Association Testing Methods Using Single-Variant Test Statistics as Alternatives to Pooling Tests for Sequence Data with Rare Variants

Association tests that pool minor alleles into a measure of burden at a locus have been proposed for case-control studies using sequence data containing rare variants. However, such pooling tests are not robust to the inclusion of neutral and protective variants, which can mask the association signal from risk variants. Early studies proposing pooling tests dismissed methods for locus-wide inference using nonnegative single-variant test statistics based on unrealistic comparisons. However, such methods are robust to the inclusion of neutral and protective variants and therefore may be more useful than previously appreciated. In fact, some recently proposed methods derived within different frameworks are equivalent to performing inference on weighted sums of squared single-variant score statistics. In this study, we compared two existing methods for locus-wide inference using nonnegative single-variant test statistics to two widely cited pooling tests under more realistic conditions. We established analytic results for a simple model with one rare risk and one rare neutral variant, which demonstrated that pooling tests were less powerful than even Bonferroni-corrected single-variant tests in most realistic situations. We also performed simulations using variants with realistic minor allele frequency and linkage disequilibrium spectra, disease models with multiple rare risk variants and extensive neutral variation, and varying rates of missing genotypes. In all scenarios considered, existing methods using nonnegative single-variant test statistics had power comparable to or greater than two widely cited pooling tests. Moreover, in disease models with only rare risk variants, an existing method based on the maximum single-variant Cochran-Armitage trend chi-square statistic in the locus had power comparable to or greater than another existing method closely related to some recently proposed methods. We conclude that efficient locus-wide inference using single-variant test statistics should be reconsidered as a useful framework for devising powerful association tests in sequence data with rare variants

Recruitment Potential of a Green Alga Ulva flexuosa Wulfen Dark Preserved Zoospore and Its Development

The recruitment potential and the ability of Ulva flexuosa Wulfen zoospores to survive darkness were tested under different conditions in the present study. The dark preserved zoospore was cultured under a two-factor experimental design to test the effect of salinity and nitrate, effect of salinity and phosphate, effect of light and salinity, and effect of light and phosphate. The recruitment (germination and growth) of zoospores was significantly affected by light and salinity. The nitrate concentration of 20 µmol.l−1 was found to initiate the process of germination and its subsequent growth and, its effect appeared greatest under 25 psu condition. While nitrate enhances the growth of biomass more than phosphate, both show a positive interactive effect on biomass increase when crossed with salinity. The combined effect of 25 psu salinity and 8 µmol.l−1 phosphate exhibited higher biomass growth. There was a significant effect of light and salinity on the biomass of zoospore, though there was no significant interaction between the two factors. There was an increase in biomass of growing zoospores to increase in light intensity and 80 µmol.m−2.s−1 of light intensity was considered optimal. Similarly, high light intensity condition favored higher biomass growth and there was significant interaction between light (80 µmol. m−2. s−1) and phosphate (4 µmol. l−1) in high salinity (35 psu) condition. The result of this study showed that dark preserved zoospores of U. flexuosa have the potential for recruitment and it gives us an understanding how different factors play a role in the process of recruitment

In Silico Simulation of Corticosteroids Effect on an NFkB- Dependent Physicochemical Model of Systemic Inflammation

During the onset of an inflammatory response signaling pathways are activated for "translating" extracellular signals into intracellular responses converging to the activation of nuclear factor (NF)-kB, a central transcription factor in driving the inflammatory response. An inadequate control of its transcriptional activity is associated with the culmination of a hyper-inflammatory response making it a desired therapeutic target. Predicated upon the nature of the response, a systems level analysis might provide rational leads for the development of strategies that promote the resolution of the response.A physicochemical host response model is proposed to integrate biological information in the form of kinetic rules and signaling cascades with pharmacokinetic models of drug action for the modulation of the response. The unifying hypothesis is that the response is triggered by the activation of the NFkB signaling module and corticosteroids serve as a template for assessing anti-inflammatory strategies. The proposed in silico model is evaluated through its ability to predict and modulate uncontrolled responses. The pre-exposure of the system to hypercortisolemia, i.e. 6 hr before or simultaneously with the infectious challenge "reprograms" the dynamics of the host towards a balanced inflammatory response. However, if such an intervention occurs long before the inflammatory insult a symptomatic effect is observed instead of a protective relief while a steroid infusion after inducing inflammation requires much higher drug doses.We propose a reversed engineered inflammation model that seeks to describe how the system responds to a multitude of external signals. Timing of intervention and dosage regimes appears to be key determinants for the protective or symptomatic effect of exogenous corticosteroids. Such results lie in qualitative agreement with in vivo human studies exposed both to LPS and corticosteroids under various time intervals thus improving our understanding of how interacting modules generate a behavior

Streptococcus pneumoniae induced c-Jun-N-terminal kinase- and AP-1 -dependent IL-8 release by lung epithelial BEAS-2B cells

BACKGROUND: Although pneumococcal pneumonia is one of the most common causes of death due to infectious diseases, little is known about pneumococci-lung cell interaction. Herein we tested the hypothesis that pneumococci activated pulmonary epithelial cell cytokine release by c-Jun-NH(2)-terminal kinase (JNK) METHODS: Human bronchial epithelial cells (BEAS-2B) or epithelial HEK293 cells were infected with S. pneumoniae R6x and cytokine induction was measured by RT-PCR, ELISA and Bioplex assay. JNK-phosphorylation was detected by Western blot and nuclear signaling was assessed by electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP). JNK was modulated by the small molecule inhibitor SP600125 and AP1 by transfection of a dominant negative mutant. RESULTS: S. pneumoniae induced the release of distinct CC and CXC, as well as Th1 and Th2 cytokines and growth factors by human lung epithelial cell line BEAS-2B. Furthermore, pneumococci infection resulted in JNK phosphorylation in BEAS-2B cells. Inhibition of JNK by small molecule inhibitor SP600125 reduced pneumococci-induced IL-8 mRNA expression and release of IL-8 and IL-6. One regulator of the il8 promoter is JNK-phosphorylated activator protein 1 (AP-1). We showed that S. pneumoniae time-dependently induced DNA binding of AP-1 and its phosphorylated subunit c-Jun with a maximum at 3 to 5 h after infection. Recruitment of Ser(63/73)-phosphorylated c-Jun and RNA polymerase II to the endogenous il8 promoter was found 2 h after S. pneumoniae infection by chromatin immunoprecipitation. AP-1 repressor A-Fos reduced IL-8 release by TLR2-overexpressing HEK293 cells induced by pneumococci but not by TNFα. Antisense-constructs targeting the AP-1 subunits Fra1 and Fra2 had no inhibitory effect on pneumococci-induced IL-8 release. CONCLUSION: S. pneumoniae-induced IL-8 expression by human epithelial BEAS-2B cells depended on activation of JNK and recruitment of phosphorylated c-Jun to the il8 promoter

Variations in the Hemagglutinin of the 2009 H1N1 Pandemic Virus: Potential for Strains with Altered Virulence Phenotype?

A novel, swine-origin influenza H1N1 virus (H1N1pdm) caused the first pandemic of the 21st century. This pandemic, although efficient in transmission, is mild in virulence. This atypical mild pandemic season has raised concerns regarding the potential of this virus to acquire additional virulence markers either through further adaptation or possibly by immune pressure in the human host. Using the mouse model we generated, within a single round of infection with A/California/04/09/H1N1 (Ca/04), a virus lethal in mice—herein referred to as mouse-adapted Ca/04 (ma-Ca/04). Five amino acid substitutions were found in the genome of ma-Ca/04: 3 in HA (D131E, S186P and A198E), 1 in PA (E298K) and 1 in NP (D101G). Reverse genetics analyses of these mutations indicate that all five mutations from ma-Ca/04 contributed to the lethal phenotype; however, the D131E and S186P mutations—which are also found in the 1918 and seasonal H1N1 viruses—in HA alone were sufficient to confer virulence of Ca/04 in mice. HI assays against H1N1pdm demonstrate that the D131E and S186P mutations caused minor antigenic changes and, likely, affected receptor binding. The rapid selection of ma-Ca/04 in mice suggests that a virus containing this constellation of amino acids might have already been present in Ca/04, likely as minor quasispecies

Predictors and correlates for weight changes in patients co-treated with olanzapine and weight mitigating agents; a post-hoc analysis

<p>Abstract</p> <p>Background</p> <p>This study focuses on exploring the relationship between changes in appetite or eating behaviors and subsequent weight change for adult patients with schizophrenia or bipolar disorder treated with olanzapine and adjunctive potential weight mitigating pharmacotherapy. The aim is not to compare different weight mitigating agents, but to evaluate patients' characteristics and changes in their eating behaviors during treatment. Identification of patient subgroups with different degrees of susceptibility to the effect of weight mitigating agents during olanzapine treatment may aid clinicians in treatment decisions.</p> <p>Methods</p> <p>Data were obtained from 3 randomized, double-blind, placebo-controlled, 16-week clinical trials. Included were 158 patients with schizophrenia or bipolar disorder and a body mass index (BMI) ≥ 25 kg/m²who had received olanzapine treatment in combination with nizatidine (n = 68), sibutramine (n = 42), or amantadine (n = 48). Individual patients were analyzed for categorical weight loss ≥ 2 kg and weight gain ≥ 1 kg. Variables that were evaluated as potential predictors of weight outcomes included baseline patient characteristics, factors of the Eating Inventory, individual items of the Eating Behavior Assessment, and the Visual Analog Scale.</p> <p>Results</p> <p>Predictors/correlates of weight loss ≥ 2 kg included: high baseline BMI, low baseline interest in food, and a decrease from baseline to endpoint in appetite, hunger, or cravings for carbohydrates. Reduced cognitive restraint, increase in hunger, and increased overeating were associated with a higher probability of weight gain ≥ 1 kg.</p> <p>Conclusion</p> <p>The association between weight gain and lack of cognitive restraint in the presence of increased appetite suggests potential benefit of psychoeducational counseling in conjunction with adjunctive pharmacotherapeutic agents in limiting weight gain during antipsychotic drug therapy.</p> <p>Trial Registration</p> <p>This analysis was not a clinical trial and did not involve any medical intervention.</p

Insect Repellents: Modulators of Mosquito Odorant Receptor Activity

Background: DEET, 2-undecanone (2-U), IR3535 and Picaridin are widely used as insect repellents to prevent interactions between humans and many arthropods including mosquitoes. Their molecular action has only recently been studied, yielding seemingly contradictory theories including odorant-dependent inhibitory and odorant-independent excitatory activities on insect olfactory sensory neurons (OSNs) and odorant receptor proteins (ORs). Methodology/Principal Findings: Here we characterize the action of these repellents on two Aedes aegypti ORs, AaOR2 and AaOR8, individually co-expressed with the common co-receptor AaOR7 in Xenopus oocytes; these ORs are respectively activated by the odors indole (AaOR2) and (R)-(2)-1-octen3-ol (AaOR8), odorants used to locate oviposition sites and host animals. In the absence of odorants, DEET activates AaOR2 but not AaOR8, while 2-U activates AaOR8 but not AaOR2; IR3535 and Picaridin do not activate these ORs. In the presence of odors, DEET strongly inhibits AaOR8 but not AaOR2, while 2-U strongly inhibits AaOR2 but not AaOR8; IR3535 and Picaridin strongly inhibit both ORs. Conclusions/Significance: These data demonstrate that repellents can act as olfactory agonists or antagonists, thus modulating OR activity, bringing concordance to conflicting models

Physical and land-cover variables influence ant functional groups and species diversity along elevational gradients

Of particular importance in shaping species assemblages is the spatial heterogeneity of the environment. The aim of our study was to investigate the influence of spatial heterogeneity and environmental complexity on the distribution of ant functional groups and species diversity along altitudinal gradients in a temperate ecosystem (Pyrenees Mountains). During three summers, we sampled 20 sites distributed across two Pyrenean valleys ranging in altitude from 1,009 to 2,339 m by using pitfall traps and hand collection. The environment around each sampling points was characterized by using both physical and land-cover variables. We then used a self-organizing map algorithm (SOM, neural network) to detect and characterize the relationship between the spatial distribution of ant functional groups, species diversity, and the variables measured. The use of SOM allowed us to reduce the apparent complexity of the environment to five clusters that highlighted two main gradients: an altitudinal gradient and a gradient of environmental closure. The composition of ant functional groups and species diversity changed along both of these gradients and was differently affected by environmental variables. The SOM also allowed us to validate the contours of most ant functional groups by highlighting the response of these groups to the environmental and land-cover variables

X-ray emission from the Sombrero galaxy: discrete sources

We present a study of discrete X-ray sources in and around the bulge-dominated, massive Sa galaxy, Sombrero (M104), based on new and archival Chandra observations with a total exposure of ~200 ks. With a detection limit of L_X = 1E37 erg/s and a field of view covering a galactocentric radius of ~30 kpc (11.5 arcminute), 383 sources are detected. Cross-correlation with Spitler et al.'s catalogue of Sombrero globular clusters (GCs) identified from HST/ACS observations reveals 41 X-rays sources in GCs, presumably low-mass X-ray binaries (LMXBs). We quantify the differential luminosity functions (LFs) for both the detected GC and field LMXBs, whose power-low indices (~1.1 for the GC-LF and ~1.6 for field-LF) are consistent with previous studies for elliptical galaxies. With precise sky positions of the GCs without a detected X-ray source, we further quantify, through a fluctuation analysis, the GC LF at fainter luminosities down to 1E35 erg/s. The derived index rules out a faint-end slope flatter than 1.1 at a 2 sigma significance, contrary to recent findings in several elliptical galaxies and the bulge of M31. On the other hand, the 2-6 keV unresolved emission places a tight constraint on the field LF, implying a flattened index of ~1.0 below 1E37 erg/s. We also detect 101 sources in the halo of Sombrero. The presence of these sources cannot be interpreted as galactic LMXBs whose spatial distribution empirically follows the starlight. Their number is also higher than the expected number of cosmic AGNs (52+/-11 [1 sigma]) whose surface density is constrained by deep X-ray surveys. We suggest that either the cosmic X-ray background is unusually high in the direction of Sombrero, or a distinct population of X-ray sources is present in the halo of Sombrero.Comment: 11 figures, 5 tables, ApJ in pres