Printed Colorimetric Arrays for the Identification and Quantification of Acids and Bases.

Solid supported colorimetric sensing arrays have the advantage of portability and ease of use when deployed in the field, such as crime scenes, disaster zones, or in war zones, but many sensor arrays require complex fabrication methods. Here, we report a practical method for the fabrication of 4 × 4 colorimetric sensor arrays, which are printed on nylon membranes, using a commercially available inkjet printer. In order to test the efficacy of the printed arrays, they were exposed to 43 analytes at concentrations ranging from 0.001 to 3.0 M for a total of 559 samples of inorganic and organic acids or bases including hydrochloric, acetic, phthalic, malonic, picric, and trifluoroacetic acid, ammonium hydroxide, sodium hydroxide, lysine, and water as the control. Colorimetric data from the imaged arrays was analyzed with linear discriminant analysis and k-nearest neighbors to determine the analyte and concentration with ∼88-90% accuracy. Overall, the arrays have impressive analytical power to identify a variety of analytes at different concentrations while being simple to fabricate.

Comparative Chemometric Analysis for Classification of Acids and Bases via a Colorimetric Sensor Array.

With the increasing availability of digital imaging devices, colorimetric sensor arrays are rapidly becoming a simple, yet effective tool for the identification and quantification of various analytes. Colorimetric arrays utilize colorimetric data from many colorimetric sensors, with the multidimensional nature of the resulting data necessitating the use of chemometric analysis. Herein, an 8 sensor colorimetric array was used to analyze select acid and basic samples (0.5 - 10 M) to determine which chemometric methods are best suited for classification quantification of analytes within clusters. PCA, HCA, and LDA were used to visualize the data set. All three methods showed well-separated clusters for each of the acid or base analytes and moderate separation between analyte concentrations, indicating that the sensor array can be used to identify and quantify samples. Furthermore, PCA could be used to determine which sensors showed the most effective analyte identification. LDA, KNN, and HQI were used for identification of analyte and concentration. HQI and KNN could be used to correctly identify the analytes in all cases, while LDA correctly identified 95 of 96 analytes correctly. Additional studies demonstrated that controlling for solvent and image effects was unnecessary for all chemometric methods utilized in this study.

The Identification of Seven Chemical Warfare Mimics Using a Colorimetric Array.

Chemical warfare agents pose significant threats in the 21st century, especially for armed forces. A colorimetric detection array was developed to identify warfare mimics, including mustard gas and nerve agents. In total, 188 sensors were screened to determine the best sensor performance, in order to identify warfare mimics 2-chloro ethyl ethylsulfide, 2-2'-thiodiethanol, trifluoroacetic acid, methylphosphonic acid, dimethylphosphite, diethylcyanophosphonate, and diethyl (methylthiomethyl)phosphonate. The highest loadings in the principle component analysis (PCA) plots were used to identify the sensors that were most effective in analyzing the RGB data to classify the warfare mimics. The dataset was reduced to only twelve sensors, and PCA results gave comparable results as the large data did, demonstrating that only twelve sensors are needed to classify the warfare mimics.

Open-label, single-dose, parallel-group study in healthy volunteers to determine the drug-drug interaction potential between KAE609 (cipargamin) and piperaquine.

KAE609 represents a new class of potent, fast-acting, schizonticidal antimalarials. This study investigated the safety and pharmacokinetics of KAE609 in combination with the long-acting antimalarial piperaquine (PPQ) in healthy volunteers. A two-way pharmacokinetic interaction was hypothesized for KAE609 and PPQ, as both drugs are CYP3A4 substrates and inhibitors. The potential for both agents to affect the QT interval was also assessed. This was an open-label, parallel-group, single-dose study with healthy volunteers. Subjects were randomized to four parallel dosing arms with five cohorts (2:2:2:2:1), receiving 75 mg KAE609 plus 320 mg PPQ, 25 mg KAE609 plus 1,280 mg PPQ, 25 mg KAE609 alone, 320 mg PPQ alone, or 1,280 mg PPQ alone. Triplicate electrocardiograms were performed over the first 24 h after dosing, with single electrocardiograms at other time points. Routine safety (up to 89 days) and pharmacokinetic (up to 61 days) assessments were performed. Of the 110 subjects recruited, 99 completed the study. Coadministration of PPQ had no overall effect on exposure to KAE609, although 1,280 mg PPQ decreased the KAE609 maximum concentration (Cmax) by 17%. The group that received 25 mg KAE609 plus 1,280 mg PPQ showed a 32% increase in the PPQ area under the concentration-time curve from 0 to infinity (AUCinf), while the group that received 75 mg KAE609 plus 320 mg PPQ showed a 14% reduction. Mean changes from baseline in the QT interval corrected by Fridericia's method (QTcF) and the QT interval corrected by Bazett's method (QTcB) with PPQ were consistent with its known effects. PPQ but not KAE609 exposure correlated with corrected QT interval (QTc) increases, and KAE609 did not affect the PPQ exposure-QTc relationship. The QTcF effect for PPQ (least-squares estimate of the difference in mean maximal changes from baseline of 7.47 ms [90% confidence interval, 3.55 to 11.4 ms]) was consistent with the criteria for a positive thorough QT study. No subject had QTcF or QTcB values of >500 ms. Both drugs given alone or in combination were well tolerated, with no deaths, serious adverse events (AEs), or severe AEs reported. Most AEs were mild; upper respiratory tract infections, headache, diarrhea, and oropharyngeal pain were most common. PPQ and KAE609 coadministration had no relevant effect on exposure to either agent, and KAE609 did not affect or potentiate the known effects of PPQ on cardiac conduction.

Investigation of Fe incorporation in LnCr2Al20 (Ln = La, Gd, Yb) with 57Fe Mössbauer and single crystal X-ray diffraction.

Crystal growth, structure determination, and magnetic properties of LnCr2Al(20-x)Fe(x) (Ln = La, Gd, Yb) adopting the CeCr2Al20 structure type with space group Fd3m, a ∼ 14.5 Å, are reported. Single crystal X-ray diffraction and Mössbauer spectroscopy are employed to fully characterize the crystal structure of LnCr2Al(20-x)Fe(x) (Ln = La, Gd, Yb). LnCr2Al(20-x)Fe(x) (Ln = La, Gd, Yb) are the first pseudoternaries adopting the CeCr2Al20 structure type with a transition metal occupying the main group site. The Yb analogues are Pauli paramagnets with the Yb ion adopting an electronic configuration close to Yb(2+), while the Gd analogues show paramagnetic behavior with no magnetic order down to 3 K.

Crystal growth, structure, and physical properties of LnCu2(Al,Si)5 (Ln = La and Ce).

LnCu(2)(Al,Si)(5) (Ln = La and Ce) were synthesized and characterized. These compounds adopt the SrAu(2)Ga(5) structure type and crystallize in the tetragonal space group P4/mmm with unit cell dimensions of a ≈ 4.2 Å and c ≈ 7.9 Å. Herein, we report the structure as obtained from single crystal X-ray diffraction. Additionally, we report the magnetic susceptibility, magnetization, resistivity, and specific heat capacity data obtained for polycrystalline samples of LnCu(2)(Al,Si)(5) (Ln = La and Ce).

Synthesis, structure, and physical properties of Ln(Cu,Al,Ga)(13-x) (Ln = La-Pr, and Eu) and Eu(Cu,Al)(13-x).

Ln(Cu,Al,Ga)(13-x) (Ln = La-Pr, and Eu; x ~ 0.2) were synthesized by a combined Al/Ga flux. Single crystal X-ray and neutron diffraction experiments revealed that these compounds crystallize in the NaZn(13) structure-type (space group Fm3[overline]c) with lattice parameters of a ~ 12 Å, V ~ 1600 Å, and Z ~ 8. Our final neutron models led us to conclude that Cu is occupationally disordered on the 8b Wyckoff site while Cu, Al, and Ga are substitutionally disordered on the 96i Wyckoff site of this well-known structure-type. The magnetic susceptibility data show that Ce(Cu,Al,Ga)(13-x) and Pr(Cu,Al,Ga)(13-x) exhibit paramagnetic behavior down to the lowest temperatures measured while Eu(Cu,Al,Ga)(13-x) displays ferromagnetic behavior below 6 K. Eu(Cu,Al)(13-x) was prepared via arc-melting and orders ferromagnetically below 8 K. The magnetocaloric properties of Eu(Cu,Al,Ga)(13-x) and Eu(Cu,Al)(13-x) were measured and compared. Additionally, an enhanced value of the Sommerfeld coefficient (γ = 356 mJ/mol-K(2)) was determined for Pr(Cu,Al,Ga)(13-x). Herein, we present the synthesis, structural refinement details, and physical properties of Ln(Cu,Al,Ga)(13-x) (Ln = La-Pr, and Eu) and Eu(Cu,Al)(13-x).

tert-Butyl (2S)-2-{3-[(R)-bis-(tert-but-oxy-carbon-yl)amino]-2-oxopiperidin-1-yl}-3-methyl-butano-ate.

The title compound, C(24)H(42)N(2)O(7), is a chiral lactam-constrained amino acid with a six-membered ring backbone and isopropyl and tert-butyl ester side chains. The conformation of the six-membered ring can be described as a half chair, with two CH(2) C atoms lying 0.443 (1) and -0.310 (1) Šout of the best plane of the other four atoms (mean deviation = 0.042 Å). Both N atoms are sp(2) hybridized, lying 0.0413 (9) and 0.067 (1) Šout of the planes defined by the three C atoms bonded to them. The absolute configuration was determined, based on resonant scattering of light atoms in Cu Kα radiation.

Crystal growth, transport, and the structural and magnetic properties of Ln(4)FeGa(12) with Ln = Y, Tb, Dy, Ho, and Er.

Ln(4)FeGa(12), where Ln is Y, Tb, Dy, Ho, and Er, prepared by flux growth, crystallize with the cubic Y(4)PdGa(12) structure with the Im3m space group and with a = 8.5650(4), 8.5610(4), 8.5350(3), 8.5080(3), and 8.4760(3) A, respectively. The crystal structure consists of an iron-gallium octahedra and face-sharing rare-earth cuboctahedra of the Au(3)Cu type. Er(4)Fe(0.67)Ga(12) is iron-deficient, leading to a distortion of the octahedral and cuboctahedral environments due to the splitting of the Ga2 site into Ga2 and Ga3 sites. Further, interstitial octahedral sites that are unoccupied in Ln(4)FeGa(12) (Ln = Y, Tb, Dy, and Ho) are partially occupied by Fe2. Y(4)FeGa(12) exhibits weak itinerant ferromagnetism below 36 K. In contrast, Tb(4)FeGa(12), Dy(4)FeGa(12), Ho(4)FeGa(12), and Er(4)Fe(0.67)Ga(12) order antiferromagnetically with maxima in the molar magnetic susceptibilities at 26, 18.5, 9, and 6 K. All of the compounds exhibit metallic electric resistivity, and their iron-57 Mossbauer spectra, obtained between 4.2 and 295 K, exhibit a single-line absorption with a 4.2 K isomer shift of ca. 0.50 mm/s, a shift that is characteristic of iron in an iron-gallium intermetallic compound. A small but significant broadening in the spectral absorption line width is observed for Y(4)FeGa(12) below 40 K and results from the small hyperfine field arising from its spin-polarized itinerant electrons.

Using Fluorescence Intensity of Enhanced Green Fluorescent Protein to Quantify Pseudomonas aeruginosa.

A variety of direct and indirect methods have been used to quantify planktonic and biofilm bacterial cells. Direct counting methods to determine the total number of cells include plate counts, microscopic cell counts, Coulter cell counting, flow cytometry, and fluorescence microscopy. However, indirect methods are often used to supplement direct cell counting, as they are often more convenient, less time-consuming, and require less material, while providing a number that can be related to the direct cell count. Herein, an indirect method is presented that uses fluorescence emission intensity as a proxy marker for studying bacterial accumulation. A clinical strain of Pseudomonas aeruginosa was genetically modified to express a green fluorescent protein (PA14/EGFP). The fluorescence intensity of EGFP in live cells was used as an indirect measure of live cell density, and was compared with the traditional cell counting methods of optical density (OD600) and plate counting (colony-forming units (CFUs)). While both OD600 and CFUs are well-established methods, the use of fluorescence spectroscopy to quantify bacteria is less common. This study demonstrates that EGFP intensity is a convenient reporter for bacterial quantification. In addition, we demonstrate the potential for fluorescence spectroscopy to be used to measure the quantity of PA14/EGFP biofilms, which have important human health implications due to their antimicrobial resistance. Therefore, fluorescence spectroscopy could serve as an alternative or complementary quick assay to quantify bacteria in planktonic cultures and biofilms.

An Improved Comparison of Chemometric Analyses for the Identification of Acids and Bases With Colorimetric Sensor Arrays.

Colorimetric sensor arrays incorporating red, green, and blue (RGB) image analysis use value changes from multiple sensors for the identification and quantification of various analytes. RGB data can be easily obtained using image analysis software such as ImageJ. Subsequent chemometric analysis is becoming a key component of colorimetric array RGB data analysis, though literature contains mainly principal component analysis (PCA) and hierarchical cluster analysis (HCA). Seeking to expand the chemometric methods toolkit for array analysis, we explored the performance of nine chemometric methods were compared for the task of classifying 631 solutions (0.1 to 3 M) of acetic acid, malonic acid, lysine, and ammonia using an eight sensor colorimetric array. PCA and LDA (linear discriminant analysis) were effective for visualizing the dataset. For classification, linear discriminant analysis (LDA), (k nearest neighbors) KNN, (soft independent modelling by class analogy) SIMCA, recursive partitioning and regression trees (RPART), and hit quality index (HQI) were very effective with each method classifying compounds with over 90% correct assignments. Support vector machines (SVM) and partial least squares - discriminant analysis (PLS-DA) struggled with ~85 and 39% correct assignments, respectively. Additional mathematical treatments of the data set, such as incrementally increasing the exponents, did not improve the performance of LDA and KNN. The literature precedence indicates that the most common methods for analyzing colorimetric arrays are PCA, LDA, HCA, and KNN. To our knowledge, this is the first report of comparing and contrasting several more diverse chemometric methods to analyze the same colorimetric array data.

A phase I biological and pharmacologic study of the heparanase inhibitor PI-88 in patients with advanced solid tumors.

PURPOSE: PI-88 is a mixture of highly sulfated oligosaccharides that inhibits heparanase, an extracellular matrix endoglycosidase, and the binding of angiogenic growth factors to heparan sulfate. This agent showed potent inhibition of placental blood vessel angiogenesis as well as growth inhibition in multiple xenograft models, thus forming the basis for this study. EXPERIMENTAL DESIGN: This study evaluated the toxicity and pharmacokinetics of PI-88 (80-315 mg) when administered s.c. daily for 4 consecutive days bimonthly (part 1) or weekly (part 2). RESULTS: Forty-two patients [median age, 53 years (range, 19-78 years); median performance status, 1] with a range of advanced solid tumors received a total of 232 courses. The maximum tolerated dose was 250 mg/d. Dose-limiting toxicity consisted of thrombocytopenia and pulmonary embolism. Other toxicity was generally mild and included prolongation of the activated partial thromboplastin time and injection site echymosis. The pharmacokinetics were linear with dose. Intrapatient variability was low and interpatient variability was moderate. Both AUC and C(max) correlated with the percent increase in activated partial thromboplastin time, showing that this pharmacodynamic end point can be used as a surrogate for drug exposure. No association between PI-88 administration and vascular endothelial growth factor or basic fibroblast growth factor levels was observed. One patient with melanoma had a partial response, which was maintained for >50 months, and 9 patients had stable disease for >or=6 months. CONCLUSION: The recommended dose of PI-88 administered for 4 consecutive days bimonthly or weekly is 250 mg/d. PI-88 was generally well tolerated. Evidence of efficacy in melanoma supports further evaluation of PI-88 in phase II trials.

Colorimetric Sensor Arrays for the Detection and Identification of Chemical Weapons and Explosives.

There is a significant demand for devices that can rapidly detect chemical-biological-explosive (CBE) threats on-site and allow for immediate responders to mitigate spread, risk, and loss. The key to an effective reconnaissance mission is a unified detection technology that analyzes potential threats in real time. In addition to reviewing the current state of the art in the field, this review illustrates the practicality of colorimetric arrays composed of sensors that change colors in the presence of analytes. This review also describes an outlook toward future technologies, and describes how they could possibly be used in areas such as war zones to detect and identify hazardous substances.

Clinical efficacy of omalizumab in chronic spontaneous urticaria is associated with a reduction of FcεRI-positive cells in the skin.

Background. Treatment with omalizumab, a humanized recombinant monoclonal anti-IgE antibody, results in clinical efficacy in patients with Chronic Spontaneous Urticaria (CSU). The mechanism of action of omalizumab in CSU has not been elucidated in detail. Objectives. To determine the effects of omalizumab on levels of high affinity IgE receptor-positive (FcεRI+) and IgE-positive (IgE+) dermal cells and blood basophils. Treatment efficacy and safety were also assessed. Study design. In a double-blind study, CSU patients aged 18­75 years were randomized to receive 300 mg omalizumab (n=20) or placebo (n=10) subcutaneously every 4 weeks for 12 weeks. Changes in disease activity were assessed by use of the weekly Urticaria Activity Score (UAS7). Circulating IgE levels, basophil numbers and levels of expression of FcεRI+ and IgE+ cells in the skin and in blood basophils were determined. Results. Patients receiving omalizumab showed a significantly greater decrease in UAS7 compared with patients receiving placebo. At Week 12 the mean difference in UAS7 between treatment groups was -14.82 (p=0.0027), consistent with previous studies. Total IgE levels in serum were increased after omalizumab treatment and remained elevated up to Week 12. Free IgE levels decreased after omalizumab treatment. Mean levels of FcεRI+ skin cells in patients treated with omalizumab 300 mg were decreased at Week 12 compared with baseline in the dermis of both non-lesional and lesional skin, reaching levels comparable with those seen in healthy volunteers (HVs). There were no statistically significant changes in mean FcɛRI+ cell levels in the placebo group. Similar results were seen for changes in IgE+ cells, although the changes were not statistically significant. The level of peripheral blood basophils increased immediately after treatment start and returned to Baseline values after the follow-up period. The levels of FcεRI and IgE expression on peripheral blood basophils were rapidly reduced by omalizumab treatment up to Week 12. Conclusions. Treatment with omalizumab resulted in rapid clinical benefits in patients with CSU. Treatment with omalizumab was associated with reduction in FcɛRI+ and IgE+ basophils and intradermal cells.

A Low-Cost Imaging Method for the Temporal and Spatial Colorimetric Detection of Free Amines on Maize Root Surfaces.

Plant root exudates are important mediators in the interactions that occur between plants and microorganisms in the soil, yet much remains to be learned about spatial and temporal variation in their production. This work outlines a method utilizing a novel colorimetric paper to detect spatial and temporal changes in the production of nitrogen-containing compounds on the root surface. While existing methods have made it possible to conduct detailed analysis of root exudate composition, relatively less is known about where in the root system exudates are produced and how this localization changes as the root grows. Furthermore, there is much to learn about how exudate localization and composition varies in response to stress. Root exudates are chemically diverse secretions composed of organic acids, amino acids, proteins, sugars, and other metabolites. The sensor utilized for the method, ninhydrin, is a colorless substance in solution that reacts with free amino groups to form a purple dye. A detection paper was developed by formulating ninhydrin into a print solution that was uniformly deposited onto paper with a commercial ink jet printer. This "ninhydrin paper" was used to analyze the chemical makeup of root surfaces from maize seedlings grown vertically on germination paper. Through contact between the ninhydrin paper and seedling root surfaces, combined with images of both the seedlings and dried ninhydrin papers captured using a standard flatbed scanner, nitrogen-containing substances on the root surface can be localized and concentration of signal estimated for over 2 weeks of development. The method was found to be non-inhibiting to plant growth over the analysis period although damage to root hairs was observed. The method is sensitive in the detection of free amines at concentrations as little as 140 µM. Furthermore, ninhydrin paper is stable, showing consistent color changes up to 2 weeks after printing. This relatively simple, low-cost method could contribute to a better understanding of root exudates and mechanisms used by plants to interact with the complex soil environment during growth and development.

Crystal growth, structure, and physical properties of Ln(Ag, Al, Si)2 (Ln = Ce and Gd).

Single crystals of CeM2 and GdM2 (M = Ag, Al, and Si) were grown by the flux growth technique and characterized by means of single crystal x-ray diffraction, magnetic susceptibility, resistivity, and heat capacity measurements. CeM2 and GdM2 crystallize in the tetragonal I4(1)/amd space group with the α-ThSi2 structure type with lattice parameters a ~4.2 Å and c ~14.4 Å. Curie-Weiss behavior is observed for both analogues with CeM2 ordering first ferromagnetically at 11 K with a second antiferromagnetic transition at 8.8 K while GdM2 orders antiferromagnetically at 24 K. Heat capacity measurements on CeM2 show two magnetic transitions at 10.8 and 8.8 K with an electronic specific heat coefficient, γ(0), of ~53 mJ K(-2) mol(-1). The entropy at the magnetic transition is less than the expected Rln2 for CeM2, reinforcing the assertions of an enhanced mass state and Kondo behavior being observed in the resistivity.