Effects of novel muscarinic M3 receptor ligand C1213 in pulmonary arterial hypertension models.

Pulmonary hypertension (PH) is a complex disease comprising a pathologic remodeling and thickening of the pulmonary vessels causing an after load on the right heart ventricle that can result in ventricular failure. Triggered by oxidative stress, episodes of hypoxia, and other undetermined causes, PH is associated with poor outcomes and a high rate of morbidity. In the neonate, this disease has a similar etiology but is further complicated by the transition to breathing after birth, which requires a reduction in vascular resistance. Persistent pulmonary hypertension of the newborn (PPHN) is one form of PH that is frequently unresponsive to current therapies including inhaled nitric oxide (due to lack of proper absorption and diffusion), and other therapeutics targeting signaling mediators in vascular endothelium and smooth muscle. The need for novel agents, which target distinct pathways in pulmonary hypertension, remains. Herein, we investigated the therapeutic effects of novel muscarinic receptor ligand C1213 in models of PH We demonstrated that via M3 muscarinic receptors, C1213 induced activating- eNOS phosphorylation (serine-1177), which is known to lead to nitric oxide (NO) production in endothelial cells. Using signaling pathway inhibitors, we discovered that AKT and calcium signaling contributed to eNOS phosphorylation induced by C1213. As expected for an eNOS-stimulating agent, in ex vivo and in vivo models, C1213 triggered pulmonary vasodilation and induced both pulmonary artery and systemic blood pressure reductions demonstrating its potential value in PH and PPHN In brief, this proof-of-concept study provides evidence that an M3 muscarinic receptor functionally selective ligand stimulates downstream pathways leading to antihypertensive effects using in vitro, ex vivo, and in vivo models of PH

Possible alternative mechanism to SUSY: conservative extensions of the Poincar\'e group

A group theoretical mechanism is outlined, which can indecomposably extend the Poincar\'e group by the compact internal (gauge) symmetries at the price of allowing some nilpotent (or, more precisely: solvable) internal symmetries in addition. Due to the presence of this nilpotent part, the prohibitive argument of the well known Coleman-Mandula and McGlinn no-go theorems do not go through. In contrast to SUSY or extended SUSY, in our construction the symmetries extending the Poincar\'e group will be all internal, i.e. they do not act on the spacetime, merely on some internal degrees of freedom -- hence the name: conservative extensions of the Poincar\'e group. Using the Levi decomposition and O'Raifeartaigh theorem, the general structure of all possible conservative extensions of the Poincar\'e group is outlined, and a concrete example group is presented with U(1) being the compact gauge group component. It is argued that such nilpotent internal symmetries may be inapparent symmetries of some more fundamental field variables, and therefore do not carry an ab initio contradiction with the present experimental understanding in particle physics. The construction is compared to (extended) SUSY, since SUSY is somewhat analogous to the proposed mechanism. It is pointed out, however, that the proposed mechanism is less irregular in comparison to SUSY, in certain aspects. The only exoticity needed in comparison to a traditional gauge theory setting is that the full group of internal symmetries is not purely compact, but is a semi-direct product of a nilpotent and of a compact part.Comment: 10 pages, contribution to Proceedings of X. International Symposium on Quantum Theory and Symmetries, Springer (2018

Reproductive hormone analyses and effects of adjuvant zoledronic acid in early breast cancer – an AZURE (BIG 01/04) sub-study

Purpose: Adjuvant bisphosphonates have been shown to improve disease outcomes in early breast cancer in women who are postmenopausal at the start of treatment. We explored the influence of pretreatment serum levels of reproductive hormones in the hypothalamic-pituitary-gonadal (HPG) axis from a subset of patients included in the AZURE trial to investigate their impact on disease recurrence and whether reproductive hormone measurements are of value in selecting patients for treatment with adjuvant zoledronic acid. Patients and methods: The AZURE trial is an academic, multi-centre, international phase III trial that randomised patients to standard adjuvant therapy (chemotherapy and/or endocrine therapy) +/- intravenous zoledronic acid, 4 mg for 5 years. Serum from 865 patients taken at randomisation was stored at -80°C prior to central batch analysis for inhibin A, oestradiol and follicle stimulating hormone (FSH). We assessed the clinical value of pretreatment hormone levels for predicting invasive disease free survival (IDFS), skeletal recurrence and distant recurrence and response to treatment with zoledronic acid. Results: Oestradiol in the postmenopausal range (26IU/l) was associated with a longer time to bone as first recurrence (HR 0.66 95%CI: 0.41–1.04 p=0.072) compared to an FSH ≤26IU/l. When all 3 hormone levels were within the assay specified postmenopausal range, a trend to improved IDFS was seen with addition of zoledronic acid in biochemically postmenopausal women only (postmenopausal HR=0.81; 95%CI: 0.54–1.22, non-postmenopausal HR=0.99; 95%CI: 0.69–1.39) with risk reductions that mirrored the results of the main AZURE study, although the interaction between menopausal status and treatment effect was not statistically significant (p=0.47). Conclusion: Oestradiol and FSH may influence the pattern of disease recurrence with postmenopausal levels possibly creating a less conducive environment for the formation of bone metastases, therefore disseminated tumour cells could seek alternative niches outside of bone. Biochemical evaluation of a panel of reproductive hormones may be helpful to assist selection of patients for adjuvant zoledronic acid when menopausal status is unknown

Up and away: ontogenic transference as a pathway for aerial dispersal of microplastics

Microplastics (MPs) are ubiquitous pollutants found in marine, freshwater and terrestrial ecosystems. With so many MPs in aquatic systems it is inevitable that they will be ingested by aquatic organisms, and be transferred up through the food chain. However, to date, no study has considered whether MPs can be transmitted by means of ontogenic transference i.e. between life stages that utilise different habitats. Here, we determine whether fluorescent polystyrene beads could transfer between Culex mosquito life stages and, particularly, could move into the flying adult stage. We show for the first time that MPs can be transferred ontogenically from a feeding (larva) into a non-feeding (pupa) life stage and subsequently into the adult terrestrial life stage. However, transference is dependent on particle size, with smaller 2 µm MPs transferring readily into pupae and adult stages, whilst 15 µm MPs transferred at a significantly reduced rate. Microplastics appear to accumulate in the Malpighian tubule renal excretion system. The transfer of MPs to the adults represents a potential aerial pathway to contamination of new environments. Thus, any organism that feeds on terrestrial life phases of freshwater insects could be impacted by MPs found in aquatic ecosystems

In situ accretion of gaseous envelopes on to planetary cores embedded in evolving protoplanetary discs

The core accretion hypothesis posits that planets with significant gaseous envelopes accreted them from their protoplanetary discs after the formation of rocky/icy cores. Observations indicate that such exoplanets exist at a broad range of orbital radii, but it is not known whether they accreted their envelopes in situ, or originated elsewhere and migrated to their current locations. We consider the evolution of solid cores embedded in evolving viscous discs that undergo gaseous envelope accretion in situ with orbital radii in the range 0.1–10 au. Additionally, we determine the long-term evolution of the planets that had no runaway gas accretion phase after disc dispersal. We find the following. (i) Planets with 5 M⊕ cores never undergo runaway accretion. The most massive envelope contained 2.8 M⊕ with the planet orbiting at 10 au. (ii) Accretion is more efficient on to 10 M⊕ and 15 M⊕ cores. For orbital radii ap ≥ 0.5 au, 15 M⊕ cores always experienced runaway gas accretion. For ap ≥ 5 au, all but one of the 10 M⊕ cores experienced runaway gas accretion. No planets experienced runaway growth at ap = 0.1 au. (iii) We find that, after disc dispersal, planets with significant gaseous envelopes cool and contract on Gyr time-scales, the contraction time being sensitive to the opacity assumed. Our results indicate that Hot Jupiters with core masses ≲15 M⊕ at ≲0.1 au likely accreted their gaseous envelopes at larger distances and migrated inwards. Consistently with the known exoplanet population, super-Earths and mini-Neptunes at small radii during the disc lifetime, accrete only modest gaseous envelopes.The simulations presented in this paper utilized Queen Mary's MidPlus computational facilities, supported by QMUL Research-IT and funded by EPSRC grant EP/K000128/1. This research was supported in part by the National Science Foundation under Grant No. NSF PHY-1125915. We acknowledge the referee, Kaitlin Kratter, whose comments helped to improve this paper

An Upper Bound on the Higgs Boson Mass from a Positivity Condition on the Mass Matrix

We impose the condition that the eigenvalues of the mass matrix in the shifted Lagrangian density be positive at \phi=\phi_{0}, the vacuum expectation value of the scalar field. Using the one-loop effective potential of the standard model, this condition leads to an upper bound on the Higgs boson mass m_{H}: m_{H}<230GeV, for a top quark mass of 175GeV.Comment: LaTex, 5 page

Cost-effectiveness of Paediatric Surgery: An Economic Evaluation of World Paediatric Project Surgical Interventions in St. Vincent and the Grenadines (2002–2019)

Objectives The purpose of this study is to examine the cost-effectiveness of six types of surgical interventions as part of a sustained paediatric surgical programme in St.Vincent and the Grenadines from 2002 to 2019. Design In this economic model, six paediatric surgical interventions (ophthalmic, orthopaedic, plastic, general, urology, neurosurgery) were compared with no surgery in a deterministic cost-effectiveness model. We assessed health benefits as averted disability-adjusted life-years (DALYs). Costs were included from the programme perspective and measured using standard micro-costing methods. Incremental cost-effectiveness ratios (ICERs) were calculated for each type of surgical intervention. Interventions with ICERs of \u3c50% of gross domestic product (GDP) per capita were considered cost-effective. Costs are reported in 2019 US$. Univariate sensitivity analyses were conducted to assess the effect of uncertainty. Results The average cost per procedure was US$16 685 (range: US$9791.78–US$72 845.76). The cumulative discounted 18-year health impact was 5815 DALYs averted with a cost per DALY averted of US$2622. Most paediatric surgical interventions were cost-effective, yielding cost per DALY estimates less than 50% of GDP per capita of St. Vincent and the Grenadines. When undiscounted, only orthopaedic surgeries had cost per DALY more than 50% GDP per capita. When considering discounting, orthopaedic and urology surgeries exceeded the adopted threshold for cost-effectiveness. Conclusions We found that short-term, recurrent surgical interventions could yield substantial economic benefits in this limited resource setting. This research indicates that investment in paediatric surgical interventions is cost-effective for the majority of specialties. These findings are of clinical significance given the large burden of disease attributable to surgically treatable diseases. This work demonstrates that scaling up dedicated surgical programmes for children is a cost-effective and essential component to improve paediatric health