The presence of tumor cells in the circulation is associated with a higher risk of metastasis in patients with breast cancer. Circulating breast tumor cells use tubulin-based structures known as ...microtentacles (McTNs) to re-attach to endothelial cells and arrest in distant organs. McTN formation is dependent on the opposing cytoskeletal forces of stable microtubules and the actin network. AMP-activated protein kinase (AMPK) is a cellular metabolic regulator that can alter actin and microtubule organization in epithelial cells. We report that AMPK can regulate the cytoskeleton of breast cancer cells in both attached and suspended conditions. We tested the effects of AMPK on microtubule stability and the actin-severing protein, cofilin. AMPK inhibition with compound c increased both microtubule stability and cofilin activation, which also resulted in higher McTN formation and re-attachment. Conversely, AMPK activation with A-769662 decreased microtubule stability and cofilin activation with concurrent decreases in McTN formation and cell re-attachment. This data shows for the first time that AMPK shifts the balance of cytoskeletal forces in suspended breast cancer cells, which affect their ability to form McTNs and re-attach. These results support a model where AMPK activators may be used therapeutically to reduce the metastatic efficiency of breast tumor cells.
The Nuclear Compton Telescope (NCT) is a balloon-borne Compton telescope designed for the study of astrophysical sources in the soft gamma-ray regime (200 keV-20 MeV). NCT's 10 high-purity germanium ...crossed-strip detectors measure the deposited energies and three-dimensional positions of gamma-ray interactions in the sensitive volume, and this information is used to restrict the initial photon to a circle on the sky using the Compton scatter technique. Thus NCT is able to perform spectroscopy, imaging, and polarization analysis on soft gamma-ray sources. NCT is one of the next generation of Compton telescopes--the so-called compact Compton telescopes (CCTs)--which can achieve effective areas comparable to the Imaging Compton Telescope's with an instrument that is a fraction of the size. The Crab Nebula was the primary target for the second flight of the NCT instrument, which occurred on 2009 May 17 and 18 in Fort Sumner, New Mexico. Analysis of 29.3 ks of data from the flight reveals an image of the Crab at a significance of 4 Delta *s. This is the first reported detection of an astrophysical source by a CCT.
UDP‐3‐O‐(R‐3‐hydroxymyristoyl)‐N‐acetylglucosamine deacetylase (LpxC) is a Zn2+ deacetylase that is essential for the survival of most pathogenic Gram‐negative bacteria. ACHN‐975 ...(N‐((S)‐3‐amino‐1‐(hydroxyamino)‐3‐methyl‐1‐oxobutan‐2‐yl)‐4‐(((1R,2R)‐2‐(hydroxymethyl)cyclopropyl)buta‐1,3‐diyn‐1‐yl)benzamide) was the first LpxC inhibitor to reach human clinical testing and was discovered to have a dose‐limiting cardiovascular toxicity of transient hypotension without compensatory tachycardia. Herein we report the effort beyond ACHN‐975 to discover LpxC inhibitors optimized for enzyme potency, antibacterial activity, pharmacokinetics, and cardiovascular safety. Based on its overall profile, compound 26 (LPXC‐516, (S)‐N‐(2‐(hydroxyamino)‐1‐(3‐methoxy‐1,1‐dioxidothietan‐3‐yl)‐2‐oxoethyl)‐4‐(6‐hydroxyhexa‐1,3‐diyn‐1‐yl)benzamide) was chosen for further development. A phosphate prodrug of 26 was developed that provided a solubility of >30 mg mL−1 for parenteral administration and conversion into the active drug with a t1/2 of approximately two minutes. Unexpectedly, and despite our optimization efforts, the prodrug of 26 still possesses a therapeutic window insufficient to support further clinical development.
It's not the hydroxamate! Antibacterial LpxC inhibitors have been optimized for enzymatic potency, anti‐pseudomonal activity, pharmacokinetics, and cardiovascular safety. We demonstrate that the much‐maligned hydroxamic acid is not responsible for the cardiovascular toxicity observed with LpxC inhibitors. The development of a phosphate prodrug enabled high solubility and rapid conversion into active drug upon intravenous administration.
A multiple ion-counting total evaporation technique has been developed for precise analysis of sub-picogram (pg) quantities of .sup.238Pu by thermal ionization mass spectrometry (TIMS). A resin bead ...loading procedure was tailored to minimize uranium (U) contamination during loading. This loading technique, coupled with a mass spectrometry protocol that minimizes U ionization and removal of bulk U with ion exchange chromatography, allows for single pg-sized aliquots of plutonium (Pu) to be measured without interference from .sup.238U. This technique has the potential to provide complete isotopic characterization of trace amounts of Pu by TIMS, without the need for alpha spectrometry.
The isolation and purification of protactinium from uranium materials is essential for
Pa-
U radiochronometry, but separating Pa from uranium-niobium alloys, a common material in the nuclear fuel ...cycle, is challenging due to the chemical similarity of Pa and Nb. Here we present three resin chromatography separation techniques for isolating Pa from U and Nb which were independently developed by three different laboratories through ad hoc adaptations of standard operating procedures. Our results underscore the need for and value of purification methods suitable for a diversity of uranium-based materials to ensure the operational readiness of nuclear forensics laboratories.
The online version contains supplementary material available at 10.1007/s10967-023-08928-y.
Water quantity and quality data were compared from six headwater watersheds on two distinct soil formations, Carolina Slate Belt (CSB) and Triassic Basins (TB). CSB soils are generally thicker, less ...erodible, and contain less clay content than soils found in TB. TB generated significantly more discharge/precipitation ratio than CSB (0.33 vs. 0.24) in the 2009 dormant season. In the 2009 growing season, TB generated significantly less discharge/precipitation ratio than CSB (0.02 vs. 0.07). Over the entire monitoring period, differences in discharge/precipitation ratios between CSB and TB were not significantly different (0.17 vs. 0.20, respectively). Storm-flow rates were significantly higher in TB than CSB in both dormant and growing season. Benthic macroinvertebrate biotic index scores were excellent for all streams. Nutrient concentrations and exports in CSB and TB were within background levels for forests. Low-stream nitrate and ammonium concentrations and exports suggested that both CSB and TB were nitrogen limited. Soils appear to have had a significant influence on seasonal and storm-flow generation, but not on long-term total water yield and water quality under forested conditions. This study indicated that watersheds on TB soils might be more prone to storm-flow generation than on CSB soils when converted from forest to urban. Future urban growth in the area should consider differences in baseline hydrology and effects of landuse change on water quantity and quality. PUBLICATION ABSTRACT
Ab initio calculations on the ground and valence-excited states of the sulfur monofluoride radical have been performed using entirely uncontracted all-electron augmented correlation consistent ...polarized valence quintuple zeta basis sets and the internally contracted multireference configuration interaction with single and double excitations method and Davidson correction (+Q). Potential-energy curves of all valence electronic states and the spectroscopic constants of several bound states are fitted. It is the first time that the entire 27-omega states generated from the 12 valence lambda-S states which come from the S(3P(g)) and F(2P(u)) atomic states of SF radical have been studied theoretically. The effects of spin-orbit coupling and the avoided crossing rule between omega states of the same symmetry are analyzed. The calculated results reproduce well the available experimental values and predict the properties of several bound excited states that have never been observed in experiment. The transition properties of the dipole-allowed transitions from bound excited states to the ground state are predicted for the first time, including the transition dipole moments, the Franck-Condon factors, and the radiative lifetimes.
Knowledge of the dietary components of fish species is important for understanding their growth, survival, and recruitment. Deficiency in thiamine (vitamin B1) leading to reproductive failure and ...physiological illness among freshwater fishes has been attributed to thiaminase activity in fish in the Great Lakes and the New York Finger Lakes, but the causes of variation in thiaminase activity among freshwater fishes is unclear. We characterized thiaminase activity in 29 species of freshwater fishes across 7 ray-finned and 1 jawless family. All fish were further categorized by phylogeny, trophic category (trophic level and feeding mode), and native or non-native status to evaluate how ecological processes correspond with thiaminase activity. Thiaminase activity varied significantly across species, families, trophic factors, phylogenetic groups, and sites. Teleosts that were more recently derived had higher thiaminase activity than more basal species. Thiaminase activity was also higher among herbivores than omnivores or carnivores. This trend was clearest in the Cyprinidae family, which had the greatest range in thiaminase activity and a wide range in trophic-level position and trophic categories (herbivores, omnivores, and carnivores). Variation in average thiaminase activity of Spotfin Shiners (Cyprinella spiloptera) among sites within a watershed was correlated with anthropogenic and natural components of land cover. Our study contributes much-needed quantitative ecological information related to thiaminase activity in a suite of fish species that vary in evolutionary history, trophic level, and foraging modes. However, more studies are needed to identify interacting causes of thiaminase variation and examine the implications of these findings on the overall health of aquatic populations and freshwater ecosystems.
Previous studies have suggested that metabolic syndrome may be associated with an increased risk of breast cancer, particularly in postmenopausal women, but U.S. black women have not been assessed. ...We examined the associations of abdominal obesity, type 2 diabetes, hypertension, and high cholesterol individually and in combination with breast cancer incidence in the Black Women’s Health Study. By means of Cox regression models, we estimated incidence rate ratios (IRR) and 95 % confidence intervals (CI) for the associations of baseline and time-dependent values of self-reported abdominal obesity, type 2 diabetes, hypertension, and high cholesterol with breast cancer incidence. During 516,452 person years of follow-up (mean years = 10.5; standard deviation = 2.9) from 1995 to 2007, 1,228 breast cancer cases were identified. After adjustment for age, education, body mass index at age 18, physical activity, and individual cardiometabolic factors, neither individual nor combinations of cardiometabolic factors were associated with breast cancer incidence overall; the multivariable IRR was 1.04 (95 % CI 0.86–1.25) for the combination of ≥3 factors relative to the absence of all factors, and 1.17 (0.85–1.60) for having all four factors. Among postmenopausal women, however, the comparable IRRs were 1.23 (0.93–1.62) and 1.63 (1.12–2.37), respectively. Our findings provide some support for an association between cardiometabolic factors and breast cancer incidence among postmenopausal U.S. black women.
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