Background independent action for double field theory

Double field theory describes a massless subsector of closed string theory with both momentum and winding excitations. The gauge algebra is governed by the Courant bracket in certain subsectors of this double field theory. We construct the associated nonlinear background-independent action that is T-duality invariant and realizes the Courant gauge algebra. The action is the sum of a standard action for gravity, antisymmetric tensor, and dilaton fields written with ordinary derivatives, a similar action for dual fields with dual derivatives, and a mixed term that is needed for gauge invariance.Comment: 45 pages, v2: minor corrections, refs. added, to appear in JHE

Yang-Mills instantons and dyons on homogeneous G_2-manifolds

We consider Lie G-valued Yang-Mills fields on the space R x G/H, where G/H is a compact nearly K"ahler six-dimensional homogeneous space, and the manifold R x G/H carries a G_2-structure. After imposing a general G-invariance condition, Yang-Mills theory with torsion on R x G/H is reduced to Newtonian mechanics of a particle moving in R^6, R^4 or R^2 under the influence of an inverted double-well-type potential for the cases G/H = SU(3)/U(1)xU(1), Sp(2)/Sp(1)xU(1) or G_2/SU(3), respectively. We analyze all critical points and present analytical and numerical kink- and bounce-type solutions, which yield G-invariant instanton configurations on those cosets. Periodic solutions on S^1 x G/H and dyons on iR x G/H are also given.Comment: 1+26 pages, 14 figures, 6 miniplot

Dental management considerations for the patient with an acquired coagulopathy. Part 1: Coagulopathies from systemic disease

Current teaching suggests that many patients are at risk for prolonged bleeding during and following invasive dental procedures, due to an acquired coagulopathy from systemic disease and/or from medications. However, treatment standards for these patients often are the result of long-standing dogma with little or no scientific basis. The medical history is critical for the identification of patients potentially at risk for prolonged bleeding from dental treatment. Some time-honoured laboratory tests have little or no use in community dental practice. Loss of functioning hepatic, renal, or bone marrow tissue predisposes to acquired coagulopathies through different mechanisms, but the relationship to oral haemostasis is poorly understood. Given the lack of established, science-based standards, proper dental management requires an understanding of certain principles of pathophysiology for these medical conditions and a few standard laboratory tests. Making changes in anticoagulant drug regimens are often unwarranted and/or expensive, and can put patients at far greater risk for morbidity and mortality than the unlikely outcome of postoperative bleeding. It should be recognised that prolonged bleeding is a rare event following invasive dental procedures, and therefore the vast majority of patients with suspected acquired coagulopathies are best managed in the community practice setting

Sexual Size Dimorphism and Body Condition in the Australasian Gannet

Funding: The research was financially supported by the Holsworth Wildlife Research Endowment. Acknowledgments We thank the Victorian Marine Science Consortium, Sea All Dolphin Swim, Parks Victoria, and the Point Danger Management Committee for logistical support. We are grateful for the assistance of the many field volunteers involved in the study.Peer reviewedPublisher PD

Plasma and rectal mucosal oxylipin levels during aspirin and eicosapentaenoic acid treatment in the seAFOod polyp prevention trial

BACKGROUND: Aspirin and eicosapentaenoic acid (EPA) have colorectal polyp prevention activity, alone and in combination. This study measured levels of plasma and rectal mucosal oxylipins in participants of the seAFOod 2 × 2 factorial, randomised, placebo-controlled trial, who received aspirin 300 mg daily and EPA 2000 mg free fatty acid, alone and in combination, for 12 months. METHODS: Resolvin (Rv) E1, 15-epi-lipoxin (LX) A4 and respective precursors 18-HEPE and 15-HETE (with chiral separation) were measured by ultra-high performance liquid chromatography-tandem mass spectrometry in plasma taken at baseline, 6 months and 12 months, as well as rectal mucosa obtained at trial exit colonoscopy at 12 months, in 401 trial participants. RESULTS: Despite detection of S- and R- enantiomers of 18-HEPE and 15-HETE in ng/ml concentrations, RvE1 or 15‑epi-LXA4 were not detected above a limit of detection of 20 pg/ml in plasma or rectal mucosa, even in individuals randomised to both aspirin and EPA. We have confirmed in a large clinical trial cohort that prolonged (12 months) treatment with EPA is associated with increased plasma 18-HEPE concentrations (median [inter-quartile range] total 18-HEPE 0.51 [0.21-1.95] ng/ml at baseline versus 0.95 [0.46-4.06] ng/ml at 6 months [P<0.0001] in those randomised to EPA alone), which correlate strongly with respective rectal mucosal 18-HEPE levels (r = 0.82; P<0.001), but which do not predict polyp prevention efficacy by EPA or aspirin. CONCLUSION: Analysis of seAFOod trial plasma and rectal mucosal samples has not provided evidence of synthesis of the EPA-derived specialised pro-resolving mediator RvE1 or aspirin-trigged lipoxin 15‑epi-LXA4. We cannot rule out degradation of individual oxylipins during sample collection and storage but readily measurable precursor oxylipins argues against widespread degradation

The Relationship Between Dietary and Supplemental omega-3 Highly Unsaturated Fatty Acid Intake, Blood and Tissue omega-3 Highly Unsaturated Fatty Acid Concentrations, and Colorectal Polyp Recurrence: A Secondary Analysis of the seAFOod Polyp Prevention Trial

\ua9 2024 The Author(s). Background: The seAFOod randomized controlled trial tested colorectal polyp prevention by the omega-3 (ω-3) highly unsaturated fatty acid (HUFA) eicosapentaenoic acid (EPA) and aspirin. Variable dietary intake of omega-3 HUFAs (also including docosahexaenoic acid [DHA]) and differential EPA capsule compliance could confound analysis of trial outcomes. Objective: The objective of this study was to investigate the relationship between total (diet and capsule) daily omega-3 HUFA intake, red blood cell (RBC), and rectal mucosa omega-3 HUFA concentrations, and colorectal polyp outcomes in a secondary analysis of the seAFOod trial. Methods: Individual-participant dietary omega-3 HUFA intake (mg/d) was derived from food frequency questionnaires using the European Prospective Investigation into Cancer and Nutrition-Norfolk fatty acid nutrient database. Capsule EPA intake (mg/d) was adjusted for compliance (capsule counting). Fatty acids were analyzed by liquid chromatography-tandem mass spectrometry (as % of total fatty acids). HUFA oxidation was measured using the HUFA/saturated fatty acid (SAT) ratio. The colorectal polyp detection rate (PDR; % with ≥1 polyps) and polyp number per participant were analyzed according to the change in RBC EPA concentrations during the trial (ΔEPA), irrespective of treatment allocation. Results: There was a small degree of HUFA degradation over time in RBC samples stored at &gt; −80oC at research sites (r = −0.36, P&lt;0.001 for HUFA/SAT ratio over time), which did not affect analysis of omega-3 HUFA concentrations. Low baseline EPA concentration, as well as allocation to EPA and % compliance, were associated with a high ΔEPA. Individuals with a ΔEPA value &gt;+0.5% points (ΔEPAhigh), irrespective of allocation to EPA or placebo, had a lower PDR than ΔEPAlow individuals (odds ratio: 0.63; 95% confidence interval [CI]: 0.40, 1.01) and reduced colorectal polyp number (incidence rate ratio: 0.74; 95% CI: 0.54, 1.02). Conclusions: Analysis of the seAFOod trial according to the change in EPA concentration, instead of treatment allocation, revealed a protective effect of EPA treatment on colorectal polyp recurrence (ISRCTN05926847)

The effect of aspirin and eicosapentaenoic acid on urinary biomarkers of prostaglandin E2 synthesis and platelet activation in participants of the seAFOod polyp prevention trial

Urinary prostaglandin (PG) E metabolite (PGE-M) and 11-dehydro (d)-thromboxane (TX) B2 are biomarkers of cyclooxygenase-dependent prostanoid synthesis. We investigated (1) the effect of aspirin 300 mg daily and eicosapentaenoic acid (EPA) 2000 mg daily, alone and in combination, on urinary biomarker levels and, (2) whether urinary biomarker levels predicted colorectal polyp risk, during participation in the seAFOod polyp prevention trial. Urinary PGE-M and 11-d-TXB2 were measured by liquid chromatography-tandem mass spectrometry. The relationship between urinary biomarker levels and colorectal polyp outcomes was investigated using negative binomial (polyp number) and logistic (% with one or more polyps) regression models. Despite wide temporal variability in PGE-M and 11-d-TXB2 levels within individuals, both aspirin and, to a lesser extent, EPA decreased levels of both biomarkers (74% [P ≤.001] and 8% [P ≤.05] reduction in median 11-d-TXB2 values, respectively). In the placebo group, a high (quartile [Q] 2-4) baseline 11-d-TXB2 level predicted increased polyp number (incidence rate ratio [IRR] [95% CI] 2.26 [1.11,4.58]) and risk (odds ratio [95% CI] 3.56 [1.09,11.63]). A low (Q1) on-treatment 11-d-TXB2 level predicted reduced colorectal polyp number compared to placebo (IRR 0.34 [0.12,0.93] for combination aspirin and EPA treatment) compared to high on-treatment 11-d-TXB2 values (0.61 [0.34,1.11]). Aspirin and EPA both inhibit PGE-M and 11-d-TXB2 synthesis in keeping with shared in vivo cyclooxygenase inhibition. Colorectal polyp risk and treatment response prediction by 11-d-TXB2 is consistent with a role for platelet activation during early colorectal carcinogenesis. The use of urinary 11-d-TXB2 measurement for a precision approach to colorectal cancer risk prediction and chemoprevention requires prospective evaluation

Cyclooxygenase activity mediates colorectal cancer cell resistance to the omega-3 polyunsaturated fatty acid eicosapentaenoic acid

Purpose The naturally-occurring omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA) is safe, well-tolerated and inexpensive, making it an attractive anti-cancer intervention. However, EPA has only modest anti-colorectal cancer (CRC) activity, when used alone. Both cyclooxygenase (COX) isoforms metabolise EPA and are over-expressed in CRC cells. We investigated whether COX inhibition increases the sensitivity of CRC cells to growth inhibition by EPA. Methods A panel of 18 human and mouse CRC cell lines was used to characterize the differential sensitivity of CRC cells to the growth inhibitory effects of EPA. The effect of CRISPR-Cas9 genetic deletion and pharmacological inhibition of COX-1 and COX-2 on the anti-cancer activity of EPA was determined using in vitro and in vivo models. Results Genetic ablation of both COX isoforms increased sensitivity of CT26 mouse CRC cells to growth inhibition by EPA in vitro and in vivo. The non-selective COX inhibitor aspirin and the selective COX-2 inhibitor celecoxib increased sensitivity of several human and mouse CRC cell lines to EPA in vitro. However, in a MC38 mouse CRC cell tumour model, with dosing that mirrored low-dose aspirin use in humans, thereby producing significant platelet COX-1 inhibition, there was ineffective intra-tumoral COX-2 inhibition by aspirin and no effect on EPA sensitivity of MC38 cell tumours. Conclusion Cyclooxygenase inhibition by non-steroidal anti-inflammatory drugs represents a therapeutic opportunity to augment the modest anti-CRC activity of EPA. However, intra-tumoral COX inhibition is likely to be critical for this drug-nutrient interaction and careful tissue pharmacodynamic profiling is required in subsequent pre-clinical and human studies