Data collection, handling and fitting strategies to optimize accuracy and precision of oxygen uptake kinetics estimation from breath-by-breath measurements.

Phase 2 pulmonary oxygen uptake kinetics (ϕ2 τVO2P) reflect muscle oxygen consumption dynamics and are sensitive to changes in state of training or health. This study identified an unbiased method for data collection, handling and fitting to optimize VO2P kinetics estimation. A validated computational model of VO2P kinetics and a Monte Carlo approach simulated 2 x 10(5) moderate intensity transitions using a distribution of metabolic and circulatory parameters spanning normal health. Effects of averaging (interpolation, binning, stacking or separate fitting of up to 10 transitions) and fitting procedures (bi-exponential fitting, or ϕ2 isolation by time removal, statistical or derivative methods followed by mono-exponential fitting) on accuracy and precision of ϕ2 τVO2P estimation were assessed. The optimal strategy to maximize accuracy and precision of τVO2P estimation was 1-s interpolation of 4 bouts, ensemble averaged, with the first 20 s of exercise data removed. Contradictory to previous advice, we found optimal fitting procedures removed no more than 20 s of ϕ1 data. Averaging method was less critical: interpolation, bin averaging and stacking gave similar results, each with greater accuracy compared to analyzing repeated bouts separately. The optimal procedure resulted in ϕ2 τVO2P estimates for transitions from an unloaded or loaded baseline that averaged 1.97±2.08 and 1.04±2.30 s from true, but were within 2 s of true in only 47-62% of simulations. Optimized 95% confidence intervals for τVO2P ranged from 4.08-4.51 s, suggesting a minimally important difference of ~5 s to determine significant changes in τVO2P during interventional and comparative studies

Cooperative coupling of ultracold atoms and surface plasmons

Cooperative coupling between optical emitters and light fields is one of the outstanding goals in quantum technology. It is both fundamentally interesting for the extraordinary radiation properties of the participating emitters and has many potential applications in photonics. While this goal has been achieved using high-finesse optical cavities, cavity-free approaches that are broadband and easy to build have attracted much attention recently. Here we demonstrate cooperative coupling of ultracold atoms with surface plasmons propagating on a plane gold surface. While the atoms are moving towards the surface they are excited by an external laser pulse. Excited surface plasmons are detected via leakage radiation into the substrate of the gold layer. A maximum Purcell factor of $\eta_\mathrm{P}=4.9$ is reached at an optimum distance of $z=250~\mathrm{nm}$ from the surface. The coupling leads to the observation of a Fano-like resonance in the spectrum.Comment: 9 pages, 4 figure

Temperature dependent CO2 behavior in microporous 1-D channels of a metal-organic framework with multiple interaction sites

The MOF with the encapsulated CO2 molecule shows that the CO2 molecule is ligated to the unsaturated Cu(II) sites in the cage using its Lewis basic oxygen atom via an angular eta(1)-(O-A) coordination mode and also interacts with Lewis basic nitrogen atoms of the tetrazole ligands using its Lewis acidic carbon atom. Temperature dependent structure analyses indicate the simultaneous weakening of both interactions as temperature increases. Infrared spectroscopy of the MOF confirmed that the CO2 interaction with the framework is temperature dependent. The strength of the interaction is correlated to the separation of the two bending peaks of the bound CO2 rather than the frequency shift of the asymmetric stretching peak from that of free CO2. The encapsulated CO2 in the cage is weakly interacting with the framework at around ambient temperatures and can have proper orientation for wiggling out of the cage through the narrow portals so that the reversible uptake can take place. On the other hand, the CO2 in the cage is restrained at a specific orientation at 195 K since it interacts with the framework strong enough using the multiple interaction sites so that adsorption process is slightly restricted and desorption process is almost clogged.ope

Optimisation and molecular signalling of apoptosis in sequential cryotherapy and chemotherapy combination in human A549 lung cancer xenografts in SCID mice

We define the optimal parameters for combination of cryotherapy (nitrous oxide) with chemotherapy (vinorelbine ditartrate, VNB) treatment and characterise some of the signals involved for apoptosis activation. No advantage appeared when cryotherapy and VNB were combined simultaneously compared to cryosurgery alone. In contrast, tumour volumes were reduced after a sequential treatment schedule, where each individual treatment was separated by 48 h. No significant benefit appeared when the sequential treatment was separated by 24 h, although some individual mice showed a good response. The sequence of treatment had no impact on the observed tumour growth inhibition in mice. The number of apoptotic cells was significantly augmented in the sequential treatment schedule where VNB was administered 48 h before cryotherapy. In this sequential treatment, the number of apoptotic cells correlated with heightened expression of the BH3-only Puma, Noxa and Bim-EL, at both the mRNA and protein levels. No significant change in Bax, Bcl-xL and Bcl-2 mRNA expression was apparent, whereas Mcl-1 expression increased only slightly to a much lower level than BH3-only mRNAs. Our data indicate that 48 h sequential rather than simultaneous cryotherapy with VNB in future cancer cryochemotherapy schedules will enhance the tumour response, and argue that VNB administration, 48 h before cryotherapy, will provoke apoptosis more efficiently

Biochemical, Structural and Molecular Dynamics Analyses of the Potential Virulence Factor RipA from Yersinia pestis

Human diseases are attributed in part to the ability of pathogens to evade the eukaryotic immune systems. A subset of these pathogens has developed mechanisms to survive in human macrophages. Yersinia pestis, the causative agent of the bubonic plague, is a predominately extracellular pathogen with the ability to survive and replicate intracellularly. A previous study has shown that a novel rip (required for intracellular proliferation) operon (ripA, ripB and ripC) is essential for replication and survival of Y. pestis in postactivated macrophages, by playing a role in lowering macrophage-produced nitric oxide (NO) levels. A bioinformatics analysis indicates that the rip operon is conserved among a distally related subset of macrophage-residing pathogens, including Burkholderia and Salmonella species, and suggests that this previously uncharacterized pathway is also required for intracellular survival of these pathogens. The focus of this study is ripA, which encodes for a protein highly homologous to 4-hydroxybutyrate-CoA transferase; however, biochemical analysis suggests that RipA functions as a butyryl-CoA transferase. The 1.9 Å X-ray crystal structure reveals that RipA belongs to the class of Family I CoA transferases and exhibits a unique tetrameric state. Molecular dynamics simulations are consistent with RipA tetramer formation and suggest a possible gating mechanism for CoA binding mediated by Val227. Together, our structural characterization and molecular dynamic simulations offer insights into acyl-CoA specificity within the active site binding pocket, and support biochemical results that RipA is a butyryl-CoA transferase. We hypothesize that the end product of the rip operon is butyrate, a known anti-inflammatory, which has been shown to lower NO levels in macrophages. Thus, the results of this molecular study of Y. pestis RipA provide a structural platform for rational inhibitor design, which may lead to a greater understanding of the role of RipA in this unique virulence pathway

Rare Exonic Minisatellite Alleles in MUC2 Influence Susceptibility to Gastric Carcinoma

BACKGROUND: Mucins are the major components of mucus and their genes share a common, centrally-located region of sequence that encodes tandem repeats. Mucins are well known genes with respect to their specific expression levels; however, their genomic levels are unclear because of complex genomic properties. In this study, we identified eight novel minisatellites from the entire MUC2 region and investigated how allelic variation in these minisatellites may affect susceptibility to gastrointestinal cancer. METHODOLOGY/PRINCIPLE FINDINGS: We analyzed genomic DNA from the blood of normal healthy individuals and multi-generational family groups. Six of the eight minisatellites exhibited polymorphism and were transmitted meiotically in seven families, following Mendelian inheritance. Furthermore, a case-control study was performed that compared genomic DNA from 457 cancer-free controls with DNA from individuals with gastric (455), colon (192) and rectal (271) cancers. A statistically significant association was identified between rare exonic MUC2-MS6 alleles and the occurrence of gastric cancer: odds ratio (OR), 2.56; 95% confidence interval (CI), 1.31-5.04; and p = 0.0047. We focused on an association between rare alleles and gastric cancer. Rare alleles were divided into short (40, 43 and 44) and long (47, 50 and 54), according to their TR (tandem repeats) lengths. Interestingly, short rare alleles were associated with gastric cancer (OR = 5.6, 95% CI: 1.93-16.42; p = 0.00036). Moreover, hypervariable MUC2 minisatellites were analyzed in matched blood and cancer tissue from 28 patients with gastric cancer and in 4 cases of MUC2-MS2, minisatellites were found to have undergone rearrangement. CONCLUSIONS/SIGNIFICANCE: Our observations suggest that the short rare MUC2-MS6 alleles could function as identifiers for risk of gastric cancer. Additionally, we suggest that minisatellite instability might be associated with MUC2 function in cancer cells

Apilimod Inhibits the Production of IL-12 and IL-23 and Reduces Dendritic Cell Infiltration in Psoriasis

Psoriasis is characterized by hyperplasia of the epidermis and infiltration of leukocytes into both the dermis and epidermis. IL-23, a key cytokine that induces TH17 cells, has been found to play a critical role in the pathogenesis of psoriasis. Apilimod is a small-molecule compound that selectively suppresses synthesis of IL-12 and IL-23. An open-label clinical study of oral administration of apilimod was conducted in patients with psoriasis. Substantial improvements in histology and clinical measurements were observed in patients receiving 70mg QD. The expression of IL-23p19 and IL-12/IL-23p40 in skin lesions was significantly reduced in this dose group, with a simultaneous increase in IL-10 observed. A decrease in the levels of TH1 and TH17 cytokines/chemokines in skin lesions followed these p19 and p40 changes. In parallel, a reduction in skin-infiltrating CD11c+ dendritic cells and CD3+ T cells was seen, with a greater decrease in the CD11c+ population. This was accompanied by increases in T and B cells, and decreases in neutrophils and eosinophils in the periphery. This study demonstrates the immunomodulatory activity of apilimod and provides clinical evidence supporting the inhibition of IL-12/IL-23 synthesis for the treatment of TH1- and TH17-mediated inflammatory diseases