Modelling and simulation of biased agonism dynamics at a G protein-coupled receptor.

Theoretical models of G protein-coupled receptor (GPCR) concentration-response relationships often assume an agonist producing a single functional response via a single active state of the receptor. These models have largely been analysed assuming steady-state conditions. There is now much experimental evidence to suggest that many GPCRs can exist in multiple receptor conformations and elicit numerous functional responses, with ligands having the potential to activate different signalling pathways to varying extents-a concept referred to as biased agonism, functional selectivity or pluri-dimensional efficacy. Moreover, recent experimental results indicate a clear possibility for time-dependent bias, whereby an agonist's bias with respect to different pathways may vary dynamically. Efforts towards understanding the implications of temporal bias by characterising and quantifying ligand effects on multiple pathways will clearly be aided by extending current equilibrium binding and biased activation models to include G protein activation dynamics. Here, we present a new model of time-dependent biased agonism, based on ordinary differential equations for multiple cubic ternary complex activation models with G protein cycle dynamics. This model allows simulation and analysis of multi-pathway activation bias dynamics at a single receptor for the first time, at the level of active G protein (αGTP), towards the analysis of dynamic functional responses. The model is generally applicable to systems with NG G proteins and N* active receptor states. Numerical simulations for NG=N*=2 reveal new insights into the effects of system parameters (including cooperativities, and ligand and receptor concentrations) on bias dynamics, highlighting new phenomena including the dynamic inter-conversion of bias direction. Further, we fit this model to 'wet' experimental data for two competing G proteins (Gi and Gs) that become activated upon stimulation of the adenosine A1 receptor with adenosine derivative compounds. Finally, we show that our model can qualitatively describe the temporal dynamics of this competing G protein activation

Building an outward-oriented social family legacy: rhetorical history in family business foundations

Scholars have recently paid growing attention to the transfer of family legacies across generations, but existing work has been mainly focused on an inward-oriented, intra-family, perspective. In this article, we seek to understand how family firms engage in rhetorical history to transfer their social family legacy to external stakeholders, what we call “outward-oriented social legacy.” By carrying out a 12-months field study in three Italian family business foundations, our findings unveil three distinctive narrative practices—founder foreshadowing, emplacing the legacy within the broader community, and weaving family history with macro—history—that contribute to transferring outward-oriented social legacies

Successful transition to elementary school and the implementation of facilitative practices specified in the Reggio-Emilia philosophy

Systematic, mandated facilitation of school transitions is an important but understudied aspect of the Reggio-Emilia approach to early childhood education admired internationally as best practice. We studied the links between Northern Italian transition practices and academic achievement, school liking, cooperativeness, and problem behaviors. We followed 288 students across a transition from preschool to elementary school. Schools varied in their implementation of transition practices. High implementation of Reggio-type transition practices was related to significantly more school liking and significantly fewer problem behaviors after the transition. At follow-up at the end of the post-transition year, high-implementation schools were still characterized by lower levels of problem behavior. These data indicate that the facilitation of school transitions in the Reggio-Emilia tradition is associated with successful post-transition adjustment

Discovery of Novel Adenosine Receptor Agonists That Exhibit Subtype Selectivity.

A series of N(6)-bicyclic and N(6)-(2-hydroxy)cyclopentyl derivatives of adenosine were synthesized as novel A1R agonists and their A1R/A2R selectivity assessed using a simple yeast screening platform. We observed that the most selective, high potency ligands were achieved through N(6)-adamantyl substitution in combination with 5'-N-ethylcarboxamido or 5'-hydroxymethyl groups. In addition, we determined that 5'-(2-fluoro)thiophenyl derivatives all failed to generate a signaling response despite showing an interaction with the A1R. Some selected compounds were also tested on A1R and A3R in mammalian cells revealing that four of them are entirely A1R-selective agonists. By using in silico homology modeling and ligand docking, we provide insight into their mechanisms of recognition and activation of the A1R. We believe that given the broad tissue distribution, but contrasting signaling profiles, of adenosine receptor subtypes, these compounds might have therapeutic potential.This study was supported by the Swiss National Science Foundation (SNSF professorship PP00P2_123536 and PP00P2_146321 to M.L.), the BBSRC (G.L., BB/G01227X/1 and BB/M00015X/1), an MRC Doctoral Training Partnership (I.W. MR/J003964/1), and the EPSRC (A.K., EP/G500045/1).This is the author accepted manuscript. The final version is available from the American Chemical Society via http://dx.doi.org/10.1021/acs.jmedchem.5b0140

Overexpression of Extracellular Superoxide Dismutase Protects against Brain Injury Induced by Chronic Hypoxia

Extracellular superoxide dismutase (EC-SOD) is an isoform of SOD normally found both intra- and extra-cellularly and accounting for most SOD activity in blood vessels. Here we explored the role of EC-SOD in protecting against brain damage induced by chronic hypoxia. EC-SOD Transgenic mice, were exposed to hypoxia (FiO2.1%) for 10 days (H-KI) and compared to transgenic animals housed in room air (RA-KI), wild type animals exposed to hypoxia (H-WT or wild type mice housed in room air (RA-WT). Overall brain metabolism evaluated by positron emission tomography (PET) showed that H-WT mice had significantly higher uptake of (18)FDG in the brain particularly the hippocampus, hypothalamus, and cerebellum. H-KI mice had comparable uptake to the RA-KI and RA-WT groups. To investigate the functional state of the hippocampus, electrophysiological techniques in ex vivo hippocampal slices were performed and showed that H-KI had normal synaptic plasticity, whereas H-WT were severely affected. Markers of oxidative stress, GFAP, IBA1, MIF, and pAMPK showed similar values in the H-KI and RA-WT groups, but were significantly increased in the H-WT group. Caspase-3 assay and histopathological studies showed significant apoptosis/cell damage in the H-WT group, but no significant difference in the H-KI group compared to the RA groups. The data suggest that EC-SOD has potential prophylactic and therapeutic roles in diseases with compromised brain oxygenation

Sclerosing epithelioid fibrosarcoma as a rare cause of ascites in a young man: a case report

<p>Abstract</p> <p>Introduction</p> <p>Sclerosing epithelioid fibrosarcoma is a rare but distinct variant of fibrosarcoma that not only presents as a deep-seated mass on the limbs and neck but can also occur adjacent to the fascia or peritoneum, as well as the trunk and spine. We report the case of an intra-abdominal sclerosing epithelioid fibrosarcoma, which to best of the authors' knowledge has not been described previously. The patient discussed here developed lung metastases but is still alive 1-year post-diagnosis.</p> <p>Case presentation</p> <p>A 29-year-old man presented with a 2-week history of progressive abdominal distension and pain and was found to have marked ascites. A full liver screen was unremarkable with abdominal and chest computed tomography scans only confirming ascites. After a diagnostic laparotomy, biopsies were taken from the greater omentum and peritoneal nodules. Histopathology revealed a malignant tumour composed of sheets and cords of small round cells set in collagenized stroma. After further molecular investigation at the Mayo Clinic, USA, the diagnosis of a high-grade sclerosing epithelioid fibrosarcoma was confirmed.</p> <p>Conclusion</p> <p>Sclerosing epithelioid fibrosarcoma is an extremely rare tumour, which is often difficult to diagnose and which few pathologists have encountered. This case is particularly unusual because of the intra-abdominal origin of the tumour. Owing to the rarity of sclerosing epithelioid fibrosarcoma, there is no clear evidence regarding the prognosis of such a tumour, although sclerosing epithelioid fibrosarcoma is able to metastasize many years post-presentation. It is important that physicians and pathologists are aware of this unusual tumour.</p

A Delayed Recrudescent Case of Sigmoidocutaneous Fistula due to Diverticulitis

Colocutaneous fistula caused by diverticulitis is relatively rare, and a delayed recrudescent case of colocutaneous fistula is very uncommon. We herein report a rare case of a Japanese 56-year-old male with delayed recrudescent sigmoidocutaneous fistula due to diverticulitis. A colocutaneous fistula was formed after a drainage operation against a perforation of the sigmoid colon diverticulum. After 5 years from treatment, he was admitted to our hospital because of lower abdominal pain. We diagnosed the recrudescent sigmoidocutaneous fistula by abdominal computed tomography and gastrografin enema, and managed the patient with total parenteral nutrition and antibiotics. As the fistula formation did not improve, a low anterior resection with fistulectomy was performed. The postoperative course was uneventful and the patient was discharged. It has been reported that, in fistulas of the skin caused by diverticular disease, complete closure of the fistula by conservative therapy may not be possible. This case also implies the possibility of a recurrence of the fistula even if the conservative treatment was effective. In cases of colocutaneous fistulas due to diverticulitis, radical surgery is considered necessary because of possibility of recurrence of the fistula

Sigma-phase in Fe-Cr and Fe-V alloy systems and its physical properties

A review is presented on physical properties of the sigma-phase in Fe-Cr and Fe-V alloy systems as revealed both with experimental -- mostly with the Mossbauer spectroscopy -- and theoretical methods. In particular, the following questions relevant to the issue have been addressed: identification of sigma and determination of its structural properties, kinetics of alpha-to-sigma and sigma-to-alpha phase transformations, Debye temperature and Fe-partial phonon density of states, Curie temperature and magnetization, hyperfine fields, isomer shifts and electric field gradients.Comment: 26 pages, 23 figures and 83 reference

A one-dimensional lattice model for a quantum mechanical free particle

Two types of particles, A and B with their corresponding antiparticles, are defined in a one dimensional cyclic lattice with an odd number of sites. In each step of time evolution, each particle acts as a source for the polarization field of the other type of particle with nonlocal action but with an effect decreasing with the distance: A -->...\bar{B} B \bar{B} B \bar{B} ... ; B --> A \bar{A} A \bar{A} A ... . It is shown that the combined distribution of these particles obeys the time evolution of a free particle as given by quantum mechanics.Comment: 8 pages. Revte

Impact of the Specific Mutation in KRAS Codon 12 Mutated Tumors on Treatment Efficacy in Patients with Metastatic Colorectal Cancer Receiving Cetuximab-Based First-Line Therapy: A Pooled Analysis of Three Trials

Purpose: This study investigated the impact of specific mutations in codon 12 of the Kirsten-ras (KRAS) gene on treatment efficacy in patients with metastatic colorectal cancer (mCRC). Patients: Overall, 119 patients bearing a KRAS mutation in codon 12 were evaluated. All patients received cetuximab-based first-line chemotherapy within the Central European Cooperative Oncology Group (CECOG), AIO KRK-0104 or AIO KRK-0306 trials. Results: Patients with KRAS codon 12 mutant mCRC showed a broad range of outcome when treated with cetuximab-based first-line regimens. Patients with tumors bearing a KRAS p.G12D mutation showed a strong trend to a more favorable outcome compared to other mutations (overall survival 23.3 vs. 14-18 months; hazard ratio 0.66, range 0.43-1.03). An interaction model illustrated that KRAS p.G12C was associated with unfavorable outcome when treated with oxaliplatin plus cetuximab. Conclusion: The present analysis suggests that KRAS codon 12 mutation may not represent a homogeneous entity in mCRC when treated with cetuximab-based first-line therapy. Copyright (C) 2012 S. Karger AG, Base