The formation of carboxylic acids and dimer esters from α-pinene oxidation was investigated in a smog chamber and in ambient aerosol samples collected during the Biosphere Effects on Aerosols and ...Photochemistry Experiment (BEARPEX). Chamber experiments of α-pinene ozonolysis in dry air and at low NOx concentrations demonstrated formation of two dimer esters, pinyl-diaterpenyl (MW 358) and pinonyl-pinyl dimer ester (MW 368), under both low- and high-temperature conditions. Concentration levels of the pinyl-diaterpenyl dimer ester were lower than the assumed first-generation oxidation products cis-pinic and terpenylic acids, but similar to the second-generation oxidation products 3-methyl-1,2,3-butane tricarboxylic acid (MBTCA) and diaterpenylic acid acetate (DTAA). Dimer esters were observed within the first 30 min, indicating rapid production simultaneous to their structural precursors. However, the sampling time resolution precluded conclusive evidence regarding formation from gas- or particle-phase processes. CCN activities of the particles formed in the smog chamber displayed a modest variation during the course of experiments, with κ values in the range 0.06–0.09 (derived at a supersaturation of 0.19%). The pinyl-diaterpenyl dimer ester was also observed in ambient aerosol samples collected above a ponderosa pine forest in the Sierra Nevada Mountains of California during two seasonally distinct field campaigns in September 2007 and July 2009. The pinonyl-pinyl ester was observed for the first time in ambient air during the 2009 campaign, and although present at much lower concentrations, it was correlated with the abundance of the pinyl-diaterpenyl ester, suggesting similarities in their formation. The maximum concentration of the pinyl-diaterpenyl ester was almost 10 times higher during the warmer 2009 campaign relative to 2007, while the concentration of cis-pinic acid was approximately the same during both periods, and lack of correlation with levels of cis-pinic and terpenylic acids for both campaigns indicate that the formation of the pinyl-diaterpenyl ester was not controlled by their ambient abundance. In 2009 the concentration of the pinyl-diaterpenyl ester was well correlated with the concentration of DTAA, a supposed precursor of diaterpenylic acid, suggesting that the formation of pinyl-diaterpenyl dimer was closely related to DTAA. Generally, the pinyl-diaterpenyl ester was found at higher concentrations under higher temperature conditions, both in the smog-chamber study and in ambient air aerosol samples, and exhibited much higher concentrations at night relative to daytime in line with previous results. We conclude that analysis of pinyl dimer esters provides valuable information on pinene oxidation processes and should be included in studies of formation and photochemical aging of biogenic secondary organic aerosols, especially at high temperatures.
Abstract This study explores the dynamics of charge transport within a cryogenic P-type Ge particle detector, fabricated from a crystal cultivated at the University of South Dakota. By subjecting the ...detector to cryogenic temperatures and an Am-241 source, we observe evolving charge dynamics and the emergence of cluster dipole states, leading to the impact ionization process at 40 mK. Our analysis focuses on crucial parameters: the zero-field cross-section of cluster dipole states and the binding energy of these states. For the Ge detector in our investigation, the zero-field cross-section of cluster dipole states is determined to be 8.45 × 10 −11 ± 4.22 × 10 −12 cm 2 . Examination of the binding energy associated with cluster dipole states, formed by charge trapping onto dipole states during the freeze-out process, reveals a value of 0.034 ± 0.0017 meV. These findings shed light on the intricate charge states influenced by the interplay of temperature and electric field, with potential implications for the sensitivity in detecting low-mass dark matter.
A tunable resistive pulse sensor, utilising a polyurethane nanopore, has been used to characterise nanoparticles as they traverse the pore opening. Herein we demonstrate that the translocation speed, ...conductive and resistive pulse magnitude, can be used to infer the surface charge of a nanoparticle, and act as a specific transduction signal for the binding of metal ions to ligands on the particle surface. Surfaces of silica nanoparticles were modified with a ligand to demonstrate the concept, and used to extract copper(ii) ions (Cu
) from solution. By tuning the pH and ionic strength of the solution, a biphasic pulse, a conductive followed by a resistive pulse is recorded. Biphasic pulses are becoming a powerful means to characterise materials, and provide insight into the translocation mechanism, and herein we present their first use to detect the presence of metal ions in solution. We demonstrate how combinations of translocation speed and/or biphasic pulse behaviour are used to detect Cu
with quantitative responses across a range of pH and ionic strengths. Using a generic ligand this assay allows a clear signal for Cu
as low as 1 ppm with a short 5-minute incubation time, and is capable of measuring 10 ppm Cu
in the presence of 5 other ions. The method has potential for monitoring heavy metals in biological and environmental samples.
The discovery and characterisation of nanomaterials represents a multidisciplinary problem. Their properties and applications within biological, physical and medicinal sciences depend on their size, ...shape, concentration and surface charge. No single technology can currently measure all characteristics. Here we combine resistive pulse sensing with predictive logistic regression models, termed RPS-LRM, to rapidly characterise a nanomaterial's size, aspect ratio, shape and concentration when mixtures of nanorods and nanospheres are present in the same solution. We demonstrate that RPS-LRM can be applied to the characterisation of nanoparticles over a wide size range, and varying aspect ratios, and can distinguish between nanorods over nanospheres when they possess an aspect ratio grater then two. The RPS-LRM can rapidly measure the ratios of nanospheres to nanorods in solution within mixtures, regardless of their relative sizes and ratios
i.e.
many large nanospherical particles do not interfere with the characterisation of smaller nanorods. This was done with a 91% correct classification of nanospherical particles and 72% correct classification of nanorods even when the fraction of nanorods in solution is as low as 20%. The methodology here will enable the classification of nanomedicines, new nanomaterials and biological analytes in solution.
The discovery and characterisation of nanomaterials represents a multidisciplinary problem, here we apply predictive logistic regression models with resistive pulse sensing to create an rapid analysis technology.
Cooking processes produce gaseous and particle emissions that are potentially deleterious to human health. Using a highly controlled experimental setup involving a proton-transfer-reaction ...time-of-flight mass spectrometer (PTR-ToF-MS), we investigate the emission factors and the detailed chemical composition of gas phase emissions from a broad variety of cooking styles and techniques. A total of 95 experiments were conducted to characterize nonmethane organic gas (NMOG) emissions from boiling, charbroiling, shallow frying, and deep frying of various vegetables and meats, as well as emissions from vegetable oils heated to different temperatures. Emissions from boiling vegetables are dominated by methanol. Significant amounts of dimethyl sulfide are emitted from cruciferous vegetables. Emissions from shallow frying, deep frying and charbroiling are dominated by aldehydes of differing relative composition depending on the oil used. We show that the emission factors of some aldehydes are particularly large which may result in considerable negative impacts on human health in indoor environments. The suitability of some of the aldehydes as tracers for the identification of cooking emissions in ambient air is discussed.
Niemann‐Pick type C (NPC) disease is a fatal neurodegenerative disorder caused by mutations in NPC1 or NPC2 with decreased functions leading to lysosomal accumulation of cholesterol and ...sphingolipids. FTY720/ fingolimod, used for treatment of multiple sclerosis, is phosphorylated by nuclear sphingosine kinase 2, and its active phosphorylated form (FTY720‐P) is an inhibitor of class I histone deacetylases. In this study, administration of clinically relevant doses of FTY720 to mice increased expression of NPC1 and −2 in brain and liver and decreased cholesterol in an SphK2‐dependent manner. FTY720 greatly increased expression of NPC1 and −2 in human NPC1 mutant fibroblasts that correlated with formation of FTY720‐P and significantly reduced the accumulation of cholesterol and glycosphingolipids. In agreement with this finding, FTY720 pretreatment of human NPC1 mutant fibroblasts restored transport of the cholera toxin B subunit, which binds ganglioside GM1, to the Golgi apparatus. Together, these findings suggest that FTY720 administration can ameliorate cholesterol and sphingolipid storage and trafficking defects in NPC1 mutant fibroblasts. Because neurodegeneration is the main clinical feature of NPC disease, and FTY720 accumulates in the CNS and has several advantages over available histone deacetylase inhibitors now in clinical trials, our work provides a potential opportunity for treatment of this incurable disease. —Newton, J., Hait, N. C., Maceyka, M., Colaco, A., Maczis, M., Wassif, C. A., Cougnoux, A., Porter, F. D., Milstien, S., Platt, N., Platt, F. M., Spiegel, S. FTY720/fingolimod increases NPC1 and NPC2 expression and reduces cholesterol and sphingolipid accumulation in Niemann‐Pick type C mutant fibroblasts. FASEB J. 31, 1719–1730 (2017) www.fasebj.org
Purpose: The phosphatidylinositol 3-kinase (PI3K) pathway can be activated by alterations affecting several pathway components. For
rational application of targeted therapies, detailed understanding ...of tumor biology and approaches to predict efficacy in
individual tumors are required. Our aim was to assess the frequency and distribution of pathway alterations in bladder cancer.
Experimental Design: We examined the pathway components ( PIK3CA, PTEN, TSC1, RHEB , and LKB1 ) and putative upstream regulators ( FGFR3 and RAS genes) for mutation, allelic loss, copy number alteration, and expression in bladder tumors and cell lines.
Results: No mutations were found in RHEB and only a single mutation in LKB1. PIK3CA mutations were detected in 25% of tumors and 26% of cell lines with a significant excess of helical domain mutations (E542K
and E545K). There was over-representation but not amplification of the gene. Loss of heterozygosity of the PTEN region and homozygous deletion were found in 12% and 1.4% of tumors, and reduced expression in 49%. Forty-six percent of
cell lines showed alterations that implicated PTEN. Sixteen percent of tumors and 11% of cell lines showed TSC1 mutation, and 9q loss of heterozygosity was common (57%). Pathway alterations were independently distributed, suggesting
that the mutation of two pathway members may have additive or synergistic effects through noncanonical functions.
Conclusions: PI3K pathway alterations are common in bladder cancer. The lack of redundancy of alterations suggests that single-agent PI3K-targeted
therapy may not be successful in these cancers. This study provides a well-characterized series of cell lines for use in preclinical
studies of targeted agents. (Clin Cancer Res 2009;15(19):6008â17)
GM1 gangliosidosis is a progressive, neurosomatic, lysosomal storage disorder caused by mutations in the
gene encoding the enzyme β-galactosidase. Absent or reduced β-galactosidase activity leads to ...the accumulation of β-linked galactose-containing glycoconjugates including the glycosphingolipid (GSL) GM1-ganglioside in neuronal tissue. GM1-gangliosidosis is classified into three forms Type I (infantile), Type II (late-infantile and juvenile), and Type III (adult), based on the age of onset of clinical symptoms, although the disorder is really a continuum that correlates only partially with the levels of residual enzyme activity. Severe neurocognitive decline is a feature of Type I and II disease and is associated with premature mortality. Most of the disease-causing β-galactosidase mutations reported in the literature are clustered in exons 2, 6, 15, and 16 of the
gene. So far 261 pathogenic variants have been described, missense/nonsense mutations being the most prevalent. There are five mouse models of GM1-gangliosidosis reported in the literature generated using different targeting strategies of the
murine locus. Individual models differ in terms of age of onset of the clinical, biochemical, and pathological signs and symptoms, and overall lifespan. However, they do share the major abnormalities and neurological symptoms that are characteristic of the most severe forms of GM1-gangliosidosis. These mouse models have been used to study pathogenic mechanisms, to identify biomarkers, and to evaluate therapeutic strategies. Three
gene therapy trials are currently recruiting Type I and Type II patients (NCT04273269, NCT03952637, and NCT04713475) and Type II and Type III patients are being recruited for a trial utilizing the glucosylceramide synthase inhibitor, venglustat (NCT04221451).
The majority of lysosomal enzymes are targeted to the lysosome by post‐translational tagging with N‐glycans terminating in mannose‐6‐phosphate (M6P) residues. Some current enzyme replacement ...therapies (ERTs) for lysosomal storage disorders are limited in their efficacy by the extent to which the recombinant enzymes bear the M6P‐terminated glycans required for effective trafficking. Chemical synthesis was combined with endo‐β‐N‐acetylglucosaminidase (ENGase) catalysis to allow the convergent synthesis of glycosyl amino acids bearing M6P residues. This approach can be extended to the remodeling of proteins, as exemplified by RNase. The powerful synergy of chemical synthesis and ENGase‐mediated biocatalysis enabled the first synthesis of a glycoprotein bearing M6P‐terminated N‐glycans in which the glycans are attached to the peptide backbone by entirely natural linkages.
ENGase‐ineering glycoproteins: The combination of chemical synthesis and ENGase‐mediated biocatalysis enabled the production of a glycoprotein bearing mannose‐6‐phosphate‐terminated N‐glycans that are linked to the peptide backbone by natural linkages.