Chronic urticaria (CU) is a mast cell (MC)‐dependent disease with limited therapeutic options. Current management strategies are directed at inhibiting IgE‐mediated activation of MCs and antagonizing ...effects of released mediators. Due to the complexity and heterogeneity of CU and other MC diseases and mechanisms of MC activation—including multiple activating receptors and ligands, diverse signaling pathways, and a menagerie of mediators—strategies of MC depletion or MC silencing (i.e., inhibition of MC activation via binding of inhibitory receptors) have been developed to overcome limitations of singularly targeted agents. MC silencers, such as agonist monoclonal antibodies that engage inhibitory receptors (e.g., sialic acid‐binding immunoglobulin‐like lectin8 ‐Siglec‐8 lirentelimab/AK002, Siglec‐6 AK006, and CD200R LY3454738), have reached preclinical and clinical stages of development. In this review, we (1) describe the role of MCs in the pathogenesis of CU, highlighting similarities with other MC diseases in disease mechanisms and response to treatment; (2) explore current therapeutic strategies, categorized by nonspecific immunosuppression, targeted inhibition of MC activation or mediators, and targeted modulation of MC activity; and (3) introduce the concept of MC silencing as an emerging strategy that could selectively block activation of MCs without eliciting or exacerbating on‐ or off‐target, immunosuppressive adverse effects.
Test compounds used on in vitro model systems are conventionally delivered to cell culture wells as fixed concentration bolus doses; however, this poorly replicates the pharmacokinetic (PK) ...concentration changes seen in vivo and reduces the predictive value of the data. Herein, proof-of-concept experiments were performed using a novel microfluidic device, the Microformulator, which allows in vivo like PK profiles to be applied to cells cultured in microtiter plates and facilitates the investigation of the impact of PK on biological responses. We demonstrate the utility of the device in its ability to reproduce in vivo PK profiles of different oncology compounds over multiweek experiments, both as monotherapy and drug combinations, comparing the effects on tumour cell efficacy in vitro with efficacy seen in in vivo xenograft models. In the first example, an ERK1/2 inhibitor was tested using fixed bolus dosing and Microformulator-replicated PK profiles, in 2 cell lines with different in vivo sensitivities. The Microformulator-replicated PK profiles were able to discriminate between cell line sensitivities, unlike the conventional fixed bolus dosing. In a second study, murine in vivo PK profiles of multiple Poly(ADP-Ribose) Polymerase 1/2 (PARP) and DNA-dependent protein kinase (DNA-PK) inhibitor combinations were replicated in a FaDu cell line resulting in a reduction in cell growth in vitro with similar rank ordering to the in vivo xenograft model. Additional PK/efficacy insight into theoretical changes to drug exposure profiles was gained by using the Microformulator to expose FaDu cells to the DNA-PK inhibitor for different target coverage levels and periods of time. We demonstrate that the Microformulator enables incorporating PK exposures into cellular assays to improve in vitro-in vivo translation understanding for early therapeutic insight.
Morphology engineering is of prime significance in designing semiconductor photoelectrodes for efficient photoelectrochemical (PEC) fuel generation. Herein, we report a strategy to fabricate ...nanostructured tungsten oxide films using anodic oxidation of tungsten and their performance as photoanodes for PEC water splitting. A solution of an organic compound, dimethyl sulfoxide, with hydrofluoric acid was used as the electrolyte. The anodization parameters such as voltage and electrolyte temperature were found to have a critical influence in determining the porous nature and dimensions of the resulting oxide film. Anodization conducted at a voltage ~10 V and a temperature ~40 °C led to the formation of compact tungsten oxide films due to the low strength of the electric field partially responsible for the porous morphology development. The surface of the film became porous at elevated temperatures. At higher voltages, a thin nanoporous film atop a thicker compact layer was formed; however, the structure became more disordered and less porous when the electrolyte temperature was increased. The study demonstrated that by adjusting the voltage and temperature, the oxide film morphology could be varied from a compact layer to a porous structure resembling nanotubes. The films heat treated at 500 °C attained the monoclinic phase of WO3. The PEC performance was influenced strongly by the morphology of the films. The films with nanotube like morphology yielded incident photon to current conversion efficiency values of over 40%. This study would provide a practical basis for developing optimal WO3 nanostructures for efficient PEC fuel generation.
Abstract
The Cucurbitaceae family (cucurbit) includes several economically important crops, such as melon, cucumber, watermelon, pumpkin, squash and gourds. During the past several years, genomic and ...genetic data have been rapidly accumulated for cucurbits. To store, mine, analyze, integrate and disseminate these large-scale datasets and to provide a central portal for the cucurbit research and breeding community, we have developed the Cucurbit Genomics Database (CuGenDB; http://cucurbitgenomics.org) using the Tripal toolkit. The database currently contains all available genome and expressed sequence tag (EST) sequences, genetic maps, and transcriptome profiles for cucurbit species, as well as sequence annotations, biochemical pathways and comparative genomic analysis results such as synteny blocks and homologous gene pairs between different cucurbit species. A set of analysis and visualization tools and user-friendly query interfaces have been implemented in the database to facilitate the usage of these large-scale data by the community. In particular, two new tools have been developed in the database, a ‘SyntenyViewer’ to view genome synteny between different cucurbit species and an ‘RNA-Seq’ module to analyze and visualize gene expression profiles. Both tools have been packed as Tripal extension modules that can be adopted in other genomics databases developed using the Tripal system.
We present a catalog of galaxy cluster candidates, selected through their Sunyaev-Zel'dovich (SZ) effect signature in the first 720 deg2 of the South Pole Telescope (SPT) survey. This area was mapped ...with the SPT in the 2008 and 2009 austral winters to a depth of ~18 mu KCMB-arcmin at 150 GHz; 550 deg2 of it was also mapped to ~44 mu KCMB-arcmin at 95 GHz. We report photometrically derived redshifts for confirmed clusters and redshift lower limits for the remaining candidates. The catalog extends to high redshift with a median redshift of z = 0.55 and maximum confirmed redshift of z = 1.37. Forty-five of the clusters have counterparts in the ROSAT bright or faint source catalogs from which we estimate X-ray fluxes. A multi-wavelength observation program to improve the cluster mass calibration will make it possible to realize the full potential of the final 2500 deg2 SPT cluster catalog to constrain cosmology.
(ProQuest: ... denotes formulae and/or non-USASCII text omitted) We present measurements of secondary cosmic microwave background (CMB) anisotropies and cosmic infrared background (CIB) fluctuations ...using data from the South Pole Telescope (SPT) covering the complete 2540 deg super(2) SPT-SZ survey area. Data in the three SPT-SZ frequency bands centered at 95, 150, and 220 GHz, are used to produce six angular power spectra (three single-frequency auto-spectra and three cross-spectra) covering the multipole range 2000 < l < 11,000 (angular scales 5' > ~ straighttheta > ~ 1'). These are the most precise measurements of the angular power spectra at l > 2500 at these frequencies. The main contributors to the power spectra at these angular scales and frequencies are the primary CMB, CIB, thermal and kinematic Sunyaev-Zel'dovich effects (tSZ and kSZ), and radio galaxies. We include a constraint on the tSZ power from a measurement of the tSZ bispectrum from 800 deg super(2) of the SPT-SZ survey. We measure the tSZ power at 143 GHz to be ... mu K super(2) and the kSZ power to be ... mu K super(2). The data prefer positive kSZ power at 98.1% CL. We measure a correlation coefficient of ... between sources of tSZ and CIB power, with xi < 0 disfavored at a confidence level of 99.0%. The constraint on kSZ power can be interpreted as an upper limit on the duration of reionization. When the post-reionization homogeneous kSZ signal is accounted for, we find an upper limit on the duration Delta z < 5.4 at 95% CL.
Taurine (aminoethane sulfonic acid) is an ubiquitous compound, found in very high concentrations in heart and muscle. Although taurine is classified as an amino acid, it does not participate in ...peptide bond formation. Nonetheless, the amino group of taurine is involved in a number of important conjugation reactions as well as in the scavenging of hypochlorous acid. Because taurine is a fairly inert compound, it is an ideal modulator of basic processes, such as osmotic pressure, cation homeostasis, enzyme activity, receptor regulation, cell development and cell signalling. The present review discusses several physiological functions of taurine. First, the observation that taurine depletion leads to the development of a cardiomyopathy indicates a role for taurine in the maintenance of normal contractile function. Evidence is provided that this function of taurine is mediated by changes in the activity of key Ca2+ transporters and the modulation Ca2+ sensitivity of the myofibrils. Second, in some species, taurine is an established osmoregulator, however, in mammalian heart the osmoregulatory function of taurine has recently been questioned. Third, taurine functions as an indirect regulator of oxidative stress. Although this action of taurine has been widely discussed, its mechanism of action is unclear. A potential mechanism for the antioxidant activity of taurine is discussed. Fourth, taurine stabilizes membranes through direct interactions with phospholipids. However, its inhibition of the enzyme, phospholipid N-methyltransferase, alters the phosphatidylcholine and phosphatidylethanolamine content of membranes, which in turn affects the function of key proteins within the membrane. Finally, taurine serves as a modulator of protein kinases and phosphatases within the cardiomyocyte. The mechanism of this action has not been studied. Taurine is a chemically simple compound, but it has profound effects on cells. This has led to the suggestion that taurine is an essential or semi-essential nutrient for many mammals.
Background
Emergency contraception can prevent pregnancy when taken after unprotected intercourse. Obtaining emergency contraception within the recommended time frame is difficult for many women. ...Advance provision could circumvent some obstacles to timely use.
Objectives
To summarize randomized controlled trials evaluating advance provision of emergency contraception to explore effects on pregnancy rates, sexually transmitted infections, and sexual and contraceptive behaviors.
Search methods
In November 2009, we searched CENTRAL, EMBASE, POPLINE, MEDLINE via PubMed, and a specialized emergency contraception article database. We also searched reference lists and contacted experts to identify additional published or unpublished trials.
Selection criteria
We included randomized controlled trials comparing advance provision and standard access (i.e., counseling which may or may not have included information about emergency contraception, or provision of emergency contraception on request at a clinic or pharmacy).
Data collection and analysis
Two reviewers independently ed data and assessed study quality. We entered and analyzed data using RevMan 5.0.23.
Main results
Eleven randomized controlled trials met our criteria for inclusion, representing 7695 patients in the United States, China, India and Sweden. Advance provision did not decrease pregnancy rates (odds ratio (OR) 0.98, 95% confidence interval (CI) 0.76 to 1.25 in studies for which we included twelve‐month follow‐up data; OR 0.48, 95% CI 0.18 to 1.29 in a study with seven‐month follow‐up data; OR 0.92, 95% CI 0.70 to 1.20 in studies for which we included six‐month follow‐up data; OR 0.49, 95% CI 0.09 to 2.74 in a study with three‐month follow‐up data), despite reported increased use (single use: OR 2.47, 95% CI 1.80 to 3.40; multiple use: OR 4.13, 95% CI 1.77 to 9.63) and faster use (weighted mean difference (WMD) ‐12.98 hours, 95% CI ‐16.66 to ‐9.31 hours). Advance provision did not lead to increased rates of sexually transmitted infections (OR 1.01, 95% CI 0.75 to 1.37), increased frequency of unprotected intercourse, or changes in contraceptive methods. Women who received emergency contraception in advance were equally likely to use condoms as other women.
Authors' conclusions
Advance provision of emergency contraception did not reduce pregnancy rates when compared to conventional provision. Results from primary analyses suggest that advance provision does not negatively impact sexual and reproductive health behaviors and outcomes. Women should have easy access to emergency contraception, because it can decrease the chance of pregnancy. However, the interventions tested thus far have not reduced overall pregnancy rates in the populations studied.
We report measurements of the cosmic microwave background (CMB) power spectrum from the complete 2008 South Pole Telescope (SPT) data set. We analyze twice as much data as the first SPT power ...spectrum analysis, using an improved cosmological parameter estimator which fits multi-frequency models to the SPT 150 and 220 GHz bandpowers. We find an excellent fit to the measured bandpowers with a model that includes lensed primary CMB anisotropy, secondary thermal (tSZ) and kinetic (kSZ) Sunyaev-Zel'dovich anisotropies, unclustered synchrotron point sources, and clustered dusty point sources. In addition to measuring the power spectrum of dusty galaxies at high signal-to-noise, the data primarily constrain a linear combination of the kSZ and tSZ anisotropy contributions at 150 GHz and l = 3000: D tSZ 3000 + 0.5 D kSZ 3000 = 4.5 ? 1.0 Delta *mK2. The 95% confidence upper limits on secondary anisotropy power are D tSZ 3000 < 5.3 Delta *mK2 and D kSZ 3000 < 6.5 Delta *mK2. We also consider the potential correlation of dusty and tSZ sources and find it incapable of relaxing the tSZ upper limit. These results increase the significance of the lower than expected tSZ amplitude previously determined from SPT power spectrum measurements. We find that models including non-thermal pressure support in groups and clusters predict tSZ power in better agreement with the SPT data. Combining the tSZ power measurement with primary CMB data halves the statistical uncertainty on Delta *s8. However, the preferred value of Delta *s8 varies significantly between tSZ models. Improved constraints on cosmological parameters from tSZ power spectrum measurements require continued progress in the modeling of the tSZ power.
Vancomycin-resistant enterococci (VRE) are important nosocomial pathogens. Invasive VRE infections are difficult to treat since common therapeutic options including ampicillin and glycopeptides often ...fail. In vitro, most VRE remain susceptible to last-resort antibiotics such as linezolid, tigecycline and daptomycin. However, neither tigecycline nor linezolid act in a bactericidal manner, and daptomycin has proven activity only at high dosages licensed for treating enterococcal endocarditis. Despite these pharmacological and therapeutic limitations, reports on resistance to these last-resort drugs in VRE, and enterococci in general, have increased in recent years. In this review, we briefly recapitulate the current knowledge on the mode of action as well as the known and novel mechanisms of resistance and describe surveillance data on resistance to linezolid, tigecycline and daptomycin in enterococci. In addition, we also suggest a common nomenclature for designating enterococci and VRE with resistances to these important last-resort antibiotics.
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