Constraint solving in non-permutative nominal abstract syntax

Nominal abstract syntax is a popular first-order technique for encoding, and reasoning about, abstract syntax involving binders. Many of its applications involve constraint solving. The most commonly used constraint solving algorithm over nominal abstract syntax is the Urban-Pitts-Gabbay nominal unification algorithm, which is well-behaved, has a well-developed theory and is applicable in many cases. However, certain problems require a constraint solver which respects the equivariance property of nominal logic, such as Cheney's equivariant unification algorithm. This is more powerful but is more complicated and computationally hard. In this paper we present a novel algorithm for solving constraints over a simple variant of nominal abstract syntax which we call non-permutative. This constraint problem has similar complexity to equivariant unification but without many of the additional complications of the equivariant unification term language. We prove our algorithm correct, paying particular attention to issues of termination, and present an explicit translation of name-name equivariant unification problems into non-permutative constraints

Synthesis, resolution, and diastereoselectivity of the chiral auxiliary trans-2-(9H-fluoren-9-yl)cyclohexanol

The synthesis of the chiral auxiliary trans-2-(9 H-fluoren-9-yl)cyclohexanol was performed using fluorene, potassium tert-amylate, n-butyl lithium, and cyclohexene oxide in benzene. After deprotonation at the methylene position of fluorene, the fluorenyl anion attacks cyclohexene oxide to produce enantiomers of the chiral auxiliary in 33% yield. The enzymatic esterification of this chiral auxiliary was carried out using Candida rugosa lipase and several acids. The reactions were conducted in cyclohexane at 40°C and observed by chiral column High Pressure Liquid Chromatography. Using lauric acid, the reaction was enantioselective with an enantiomeric ratio, E, of 11 at an enantiomeric excess, e.e., of 89% at 60% conversion. Using pyruvic acid, the reaction was not enantioselective and also difficult to reproduce. On one occasion was racemic chiral auxiliary esterified into pyruvate ester. Racemic trans-2-(9 H-fluoren-9-yl)cyclohexyl pyruvate ester was synthesized using DMAP and DCC in a 28% yield. The diastereoselectivity of the chiral auxiliary was measured by reducing the pyruvate ester with NaBH4 in anhydrous THF, producing trans-2-(9H-fluoren-9-yl)cyclohexyl lactate ester. The diastereomeric excess, d.e., was found to be 87% by silica column HPLC

Evidence for nuclear internalisation of biocompatible [60]fullerene1)

Many types of nanoparticles (NPs) have been shown to internalise within mammalian cells (1), but only a few have been observed to internalise within the cell nucleus-most likely due to the tightly-regulated nuclear membrane (2). Internalisation of NPs into the nucleus is desirable for several reasons, including their use as 1. transfection agents (3), 2. drug delivery platforms for drugs that act on DNA (4), and 3. hyperthermia-inducing agents for cancer therapy using non-invasive stimulation by radiofrequency irradiation (5), magnetic-field cycling (6), or photonic activation (7). For example, derivatised NPs, including protein-functionalised quantum dots (8) and peptide-functionalised gold NPs (9), have been shown to internalise into the nucleus. For underivatised NPs, single-walled carbon nanotubes (SWNTs), have been observed by direct transmission electron microscopy (TEM) imaging to also localise in the nucleus of human macrophage cells with dose-dependent cytotoxicity (10). Fullerene C60ﾠis another classic carbon-based NP, however it was not been shown to enter the cell nucleus until recently. In particular, a water soluble derivative of C60ﾠfluorescently labelled with a small molecule fluorophore was shown to enter cell nuclei through nuclear pore complexes in liver cancer cells (11). Here, we validate the nuclear internalisation ability of the C60derivative in several other cell types, further supporting the unique intracellular biodistribution property of this specific fullerene compound

18F-FMISO PET/CT visualization of tumor hypoxia in patients with chordoma of the mobile and sacrococcygeal spine

Abstract presented at the American Society for Radiation Oncology 56th Annual Meeting, ASTRO\u27s 56th Annual Meeting, San Francisco, United States, 14–17 September 201

Cytotoxicity and variant cellular internalization behavior of water-soluble sulfonated nanographene sheets in liver cancer cells

Highly exfoliated sulfonated graphene sheets (SGSs), an alternative to graphene oxide and graphene derivatives, were synthesized, characterized, and applied to liver cancer cells in vitro. Cytotoxicity profiles were obtained using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, WST-1[2-(4-iodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, and lactate dehydrogenase release colorimetric assays. These particles were found to be non-toxic across the concentration range of 0.1 to 10 μg/ml. Internalization of SGSs was also studied by means of optical and electron microscopy. Although not conclusive, high-resolution transmission and scanning electron microscopy revealed variant internalization behaviors where some of the SGS became folded and compartmentalized into tight bundles within cellular organelles. The ability for liver cancer cells to internalize, fold, and compartmentalize graphene structures is a phenomenon not previously documented for graphene cell biology and should be further investigated

Fecal microbiota transplantation for the improvement of metabolism in obesity: The FMT-TRIM double-blind placebo-controlled pilot trial.

BACKGROUND:There is intense interest about whether modulating gut microbiota can impact systemic metabolism. We investigated the safety of weekly oral fecal microbiota transplantation (FMT) capsules from healthy lean donors and their ability to alter gut microbiota and improve metabolic outcomes in patients with obesity. METHODS AND FINDINGS:FMT-TRIM was a 12-week double-blind randomized placebo-controlled pilot trial of oral FMT capsules performed at a single US academic medical center. Between August 2016 and April 2018, we randomized 24 adults with obesity and mild-moderate insulin resistance (homeostatic model assessment of insulin resistance [HOMA-IR] between 2.0 and 8.0) to weekly healthy lean donor FMT versus placebo capsules for 6 weeks. The primary outcome, assessed by intention to treat, was change in insulin sensitivity between 0 and 6 weeks as measured by hyperinsulinemic euglycemic clamps. Additional metabolic parameters were evaluated at 0, 6, and 12 weeks, including HbA1c, body weight, body composition by dual-energy X-ray absorptiometry, and resting energy expenditure by indirect calorimetry. Fecal samples were serially collected and evaluated via 16S V4 rRNA sequencing. Our study population was 71% female, with an average baseline BMI of 38.8 ± 6.7 kg/m2 and 41.3 ± 5.1 kg/m2 in the FMT and placebo groups, respectively. There were no statistically significant improvements in insulin sensitivity in the FMT group compared to the placebo group (+5% ± 12% in FMT group versus -3% ± 32% in placebo group, mean difference 9%, 95% CI -5% to 28%, p = 0.16). There were no statistically significant differences between groups for most of the other secondary metabolic outcomes, including HOMA-IR (mean difference 0.2, 95% CI -0.9 to 0.9, p = 0.96) and body composition (lean mass mean difference -0.1 kg, 95% CI -1.9 to 1.6 kg, p = 0.87; fat mass mean difference 1.2 kg, 95% CI -0.6 to 3.0 kg, p = 0.18), over the 12-week study. We observed variable engraftment of donor bacterial groups among FMT recipients, which persisted throughout the 12-week study. There were no significant differences in adverse events (AEs) (10 versus 5, p = 0.09), and no serious AEs related to FMT. Limitations of this pilot study are the small sample size, inclusion of participants with relatively mild insulin resistance, and lack of concurrent dietary intervention. CONCLUSIONS:Weekly administration of FMT capsules in adults with obesity results in gut microbiota engraftment in most recipients for at least 12 weeks. Despite engraftment, we did not observe clinically significant metabolic effects during the study. TRIAL REGISTRATION:ClinicalTrials.gov NCT02530385

[18F]-fluoromisonidazole positron emission tomography/computed tomography visualization of tumor hypoxia in patients with chordoma of the mobile and sacrococcygeal spine

Purpose To investigate [18F]-fluoromisonidazole positron emission tomography/computed tomography (FMISO-PET/CT) detection of targetable hypoxic subvolumes (HSVs) in chordoma of the mobile or sacrococcygeal spine. Methods and Materials A prospective, pilot study of 20 patients with primary or locally recurrent chordoma of the mobile or sacrococcygeal spine treated with proton or combined proton/photon radiation therapy (RT) with or without surgery was completed. The FMISO-PET/CT was performed before RT and after 19.8-34.2 GyRBE (relative biologic effectiveness). Gross tumor volumes were delineated and HSVs defined including voxels with standardized uptake values ≥1.4 times the muscle mean. Clinical characteristics and treatments received were compared between patients with and without HSVs. Results The FMISO-PET/CT detected HSVs in 12 of 20 patients (60%). Baseline and interval HSV spatial concordance varied (0%-94%). Eight HSVs were sufficiently large (≥5 cm3) to potentially allow an intensity modulated proton therapy boost. Patients with HSVs had significantly larger gross tumor volumes (median 410.0 cm3 vs 63.4 cm3; P=.02) and were significantly more likely to have stage T2 tumors (5 of 12 vs 0 of 8; P=.04). After a median follow-up of 1.8 years (range, 0.2-4.4 years), a local recurrence has yet to be observed. Three patients developed metastatic disease, 2 with HSVs. Conclusions Detection of targetable HSVs by FMISO-PET/CT within patients undergoing RT with or without surgery for treatment of chordoma of the mobile and sacrococcygeal spine is feasible. The study\u27s inability to attribute interval HSV changes to treatment, rapidly changing hypoxic physiology, or imaging inconsistencies is a limitation. Further study of double-baseline FMISO-PET/CT and hypoxia-directed RT dose escalation, particularly in patients at high risk for local recurrence, is warranted